@article{an_pires_conant_2024, title={Gene expression bias between the subgenomes of allopolyploid hybrids is an emergent property of the kinetics of expression}, volume={20}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1011803}, abstractNote={Hybridization coupled to polyploidy, or allopolyploidy, has dramatically shaped the evolution of flowering plants, teleost fishes, and other lineages. Studies of recently formed allopolyploid plants have shown that the two subgenomes that merged to form that new allopolyploid do not generally express their genes equally. Instead, one of the two subgenomes expresses its paralogs more highly on average. Meanwhile, older allopolyploidy events tend to show biases in duplicate losses, with one of the two subgenomes retaining more genes than the other. Since reduced expression is a pathway to duplicate loss, understanding the origins of expression biases may help explain the origins of biased losses. Because we expect gene expression levels to experience stabilizing selection, our conceptual frameworks for how allopolyploid organisms form tend to assume that the new allopolyploid will show balanced expression between its subgenomes. It is then necessary to invoke phenomena such as differences in the suppression of repetitive elements to explain the observed expression imbalances. Here we show that, even for phenotypically identical diploid progenitors, the inherent kinetics of gene expression give rise to biases between the expression levels of the progenitor genes in the hybrid. Some of these biases are expected to be gene-specific and not give rise to global differences in progenitor gene expression. However, particularly in the case of allopolyploids formed from progenitors with different genome sizes, global expression biases favoring one subgenome are expected immediately on formation. Hence, expression biases are arguably the expectation upon allopolyploid formation rather than a phenomenon needing explanation. In the future, a deeper understanding of the kinetics of allopolyploidy may allow us to better understand both biases in duplicate losses and hybrid vigor.}, number={1}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={An, Hong and Pires, J. Chris and Conant, Gavin C.}, year={2024}, month={Jan} }
 @article{naranjo_sither_conant_2024, title={Shared single copy genes are generally reliable for inferring phylogenetic relationships among polyploid taxa}, volume={196}, ISSN={["1095-9513"]}, DOI={10.1016/j.ympev.2024.108087}, abstractNote={Polyploidy, or whole-genome duplication, is expected to confound the inference of species trees with phylogenetic methods for two reasons. First, the presence of retained duplicated genes requires the reconciliation of the inferred gene trees to a proposed species tree. Second, even if the analyses are restricted to shared single copy genes, the occurrence of reciprocal gene loss, where the surviving genes in different species are paralogs from the polyploidy rather than orthologs, will mean that such genes will not have evolved under the corresponding species tree and may not produce gene trees that allow inference of that species tree. Here we analyze three different ancient polyploidy events, using synteny-based inferences of orthology and paralogy to infer gene trees from nearly 17,000 sets of homologous genes. We find that the simple use of single copy genes from polyploid organisms provides reasonably robust phylogenetic signals, despite the presence of reciprocal gene losses. Such gene trees are also most often in accord with the inferred species relationships inferred from maximum likelihood models of gene loss after polyploidy: a completely distinct phylogenetic signal present in these genomes. As seen in other studies, however, we find that methods for inferring phylogenetic confidence yield high support values even in cases where the underlying data suggest meaningful conflict in the phylogenetic signals.}, journal={MOLECULAR PHYLOGENETICS AND EVOLUTION}, author={Naranjo, Jaells G. and Sither, Charles B. and Conant, Gavin C.}, year={2024}, month={Jul} }
 @article{mabry_abrahams_al-shehbaz_baker_barak_barker_barrett_beric_bhattacharya_carey_et al._2023, title={Complementing model species with model clades}, volume={10}, ISSN={["1532-298X"]}, DOI={10.1093/plcell/koad260}, abstractNote={Abstract}, journal={PLANT CELL}, author={Mabry, Makenzie E. and Abrahams, R. Shawn and Al-Shehbaz, Ihsan A. and Baker, William J. and Barak, Simon and Barker, Michael S. and Barrett, Russell L. and Beric, Aleksandra and Bhattacharya, Samik and Carey, Sarah B. and et al.}, year={2023}, month={Oct} }
 @article{yang_xu_conant_kishino_thorne_ji_2023, title={Interlocus Gene Conversion, Natural Selection, and Paralog Homogenization}, volume={40}, ISSN={["1537-1719"]}, DOI={10.1093/molbev/msad198}, abstractNote={Abstract}, number={9}, journal={MOLECULAR BIOLOGY AND EVOLUTION}, author={Yang, Yixuan and Xu, Tanchumin and Conant, Gavin and Kishino, Hirohisa and Thorne, Jeffrey L. and Ji, Xiang}, year={2023}, month={Sep} }
 @article{conant_2023, title={POInT: Modeling Polyploidy in the Era of Ubiquitous Genomics}, ISBN={["978-1-0716-2563-7", "978-1-0716-2560-6"]}, ISSN={["1940-6029"]}, DOI={10.1007/978-1-0716-2561-3_4}, abstractNote={Thirteen years ago, we described an evolutionary modeling tool that could resolve the orthology relationships among the homologous genomic regions created by a whole-genome duplication. This tool, which we subsequently named POInT (the Polyploid Orthology Inference Tool), was originally only useful for studying a genome duplication known from bakers' yeast and its relatives. Now, with hundreds of genome sequences that contain the relicts of ancient polyploidy available, POInT can be used to study dozens of different polyploidies, asking both questions about the history of individual events and about the commonalities and differences seen between those events. In this chapter, I give a brief history of the development of POInT as an illustration of the interconnected nature of computational biology research. I then further describe how POInT operates and some of the strengths and drawbacks of its structure. I close with a few examples of discoveries we have made using it.}, journal={POLYPLOIDY}, author={Conant, Gavin C.}, year={2023}, pages={77–90} }
 @article{siddiqui_conant_2023, title={POInTbrowse: orthology prediction and synteny exploration for paleopolyploid genomes}, volume={24}, ISSN={["1471-2105"]}, DOI={10.1186/s12859-023-05298-w}, abstractNote={Abstract}, number={1}, journal={BMC BIOINFORMATICS}, author={Siddiqui, Mustafa and Conant, Gavin C. C.}, year={2023}, month={Apr} }
 @article{hao_fleming_petterson_lyons_edger_pires_thorne_conant_2022, title={Convergent evolution of polyploid genomes from across the eukaryotic tree of life}, volume={5}, ISSN={["2160-1836"]}, DOI={10.1093/g3journal/jkac094}, abstractNote={Abstract}, journal={G3-GENES GENOMES GENETICS}, author={Hao, Yue and Fleming, Jonathon and Petterson, Joanna and Lyons, Eric and Edger, Patrick P. and Pires, J. Chris and Thorne, Jeffrey L. and Conant, Gavin C.}, year={2022}, month={May} }
 @article{mcrae_beric_conant_2022, title={Hybridization order is not the driving factor behind biases in duplicate gene losses among the hexaploid Solanaceae}, volume={289}, ISSN={["1471-2954"]}, DOI={10.1098/rspb.2022.1810}, abstractNote={We model the post-hexaploidy evolution of four genomes from the Solanaceae, a group of flowering plants comprising tomatoes, potatoes and their relatives. The hexaploidy that these genomes descend from occurred through two sequential allopolyploidy events and was marked by the unequal losses of duplicated genes from the different progenitor subgenomes. In contrast with the hexaploid Brassiceae (broccoli and its relatives), where the subgenome with the most surviving genes arrived last in the hexaploidy, among the Solanaceae the most preserved subgenome descends from one of the original two tetraploid progenitors. In fact, the last-arriving subgenome in these plants actually has the fewest surviving genes in the modern genomes. We explore whether the distribution of repetitive elements (REs) in these genomes can explain the biases in gene losses, but while the signals we find are broadly consistent with a role for high RE density in driving gene losses, the REs turn over so quickly that little signal of the RE condition at the time of paleopolyploidy is extant in the modern genomes.}, number={1985}, journal={PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES}, author={McRae, Logan and Beric, Aleksandra and Conant, Gavin C.}, year={2022}, month={Oct} }
 @article{patil_ellison_austin_lamberson_cammack_conant_2021, title={A metagenomic analysis of the effect of antibiotic feed additives on the ovine rumen metabolism}, volume={205}, ISSN={["1879-0941"]}, DOI={10.1016/j.smallrumres.2021.106539}, abstractNote={Antibiotics are used as feed additives for domesticated ruminants as they can improve feed efficiency and simultaneously reduce disease. However, the effects of such antibiotic usage on the symbiotic relationship between those animals and their ruminal microorganisms is not well understood. We used shotgun metagenomics to compare the microbial communities from 16 sheep fed an antibiotic-supplemented diet to those of 16 sheep fed an unsupplemented diet. Metagenomic reads from each sheep were mapped to a microbial metabolic network which was linked to the host metabolic network by sets of metabolites that are assumed to be absorbed by that host. Several differences in the global structure of this network were evident between the two groups of animals. There were 546 microbial enzymes that were significantly different in their relative abundance between the two groups. On a broader scale, the animals fed antibiotics showed a set of microbial enzymes that were closer in network space to the host metabolism than were the enzymes of the microbes of animals not fed antibiotics. There were also differences in the microbial taxa present in the two groups of animals, with members of the genus Prevotella representing approximately 68 % of microbial individuals in sheep not fed antibiotics, but only 46 % in antibiotic-fed sheep. We found greater microbial taxonomic diversity in sheep fed antibiotics. The addition of antibiotics to ruminant feed alters both the taxonomic and functional structure of their ruminal microbial communities, even if the overall effects of these changes are not fully understood.}, journal={SMALL RUMINANT RESEARCH}, author={Patil, Rocky D. and Ellison, Melinda J. and Austin, Kathy J. and Lamberson, William R. and Cammack, Kristi M. and Conant, Gavin C.}, year={2021}, month={Dec} }
 @article{beric_mabry_harkess_brose_schranz_conant_edger_meyers_pires_2021, title={Comparative phylogenetics of repetitive elements in a diverse order of flowering plants (Brassicales)}, volume={11}, ISSN={["2160-1836"]}, DOI={10.1093/g3journal/jkab140}, abstractNote={Abstract}, number={7}, journal={G3-GENES GENOMES GENETICS}, author={Beric, Aleksandra and Mabry, Makenzie E. and Harkess, Alex E. and Brose, Julia and Schranz, M. Eric and Conant, Gavin C. and Edger, Patrick P. and Meyers, Blake C. and Pires, J. Chris}, year={2021}, month={Jul} }
 @article{washburn_strable_dickinson_kothapalli_brose_covshoff_conant_hibberd_pires_2021, title={Distinct C-4 sub-types and C-3 bundle sheath isolation in the Paniceae grasses}, volume={5}, ISSN={["2475-4455"]}, DOI={10.1002/pld3.373}, abstractNote={Abstract}, number={12}, journal={PLANT DIRECT}, author={Washburn, Jacob D. and Strable, Josh and Dickinson, Patrick and Kothapalli, Satya S. and Brose, Julia M. and Covshoff, Sarah and Conant, Gavin C. and Hibberd, Julian M. and Pires, Joseph Chris}, year={2021}, month={Dec} }
 @article{qi_an_hall_di_blischak_mckibben_hao_conant_pires_barker_2021, title={Genes derived from ancient polyploidy have higher genetic diversity and are associated with domestication in Brassica rapa}, volume={230}, ISSN={["1469-8137"]}, DOI={10.1111/nph.17194}, abstractNote={Summary}, number={1}, journal={NEW PHYTOLOGIST}, author={Qi, Xinshuai and An, Hong and Hall, Tara E. and Di, Chenlu and Blischak, Paul D. and McKibben, Michael T. W. and Hao, Yue and Conant, Gavin C. and Pires, J. Chris and Barker, Michael S.}, year={2021}, month={Apr}, pages={372–386} }
 @article{hao_mabry_edger_freeling_zheng_jin_vanburen_colle_an_abrahams_et al._2021, title={The contributions from the progenitor genomes of the mesopolyploid Brassiceae are evolutionarily distinct but functionally compatible}, volume={31}, ISSN={["1549-5469"]}, DOI={10.1101/gr.270033.120}, abstractNote={The members of the tribe Brassiceae share a whole-genome triplication (WGT), and one proposed model for its formation is a two-step pair of hybridizations producing hexaploid descendants. However, evidence for this model is incomplete, and the evolutionary and functional constraints that drove evolution after the hexaploidy are even less understood. Here, we report a new genome sequence of Crambe hispanica, a species sister to most sequenced Brassiceae. Using this new genome and three others that share the hexaploidy, we traced the history of gene loss after the WGT using the Polyploidy Orthology Inference Tool (POInT). We confirm the two-step formation model and infer that there was a significant temporal gap between those two allopolyploidizations, with about a third of the gene losses from the first two subgenomes occurring before the arrival of the third. We also, for the 90,000 individual genes in our study, make parental subgenome assignments, inferring, with measured uncertainty, from which of the progenitor genomes of the allohexaploidy each gene derives. We further show that each subgenome has a statistically distinguishable rate of homoeolog losses. There is little indication of functional distinction between the three subgenomes: the individual subgenomes show no patterns of functional enrichment, no excess of shared protein–protein or metabolic interactions between their members, and no biases in their likelihood of having experienced a recent selective sweep. We propose a “mix and match” model of allopolyploidy, in which subgenome origin drives homoeolog loss propensities but where genes from different subgenomes function together without difficulty.}, number={5}, journal={GENOME RESEARCH}, author={Hao, Yue and Mabry, Makenzie E. and Edger, Patrick P. and Freeling, Michael and Zheng, Chunfang and Jin, Lingling and VanBuren, Robert and Colle, Marivi and An, Hong and Abrahams, R. Shawn and et al.}, year={2021}, month={May}, pages={799–810} }
 @article{schoonmaker_hao_bird_conant_2020, title={A Single, Shared Triploidy in Three Species of Parasitic Nematodes}, volume={10}, ISSN={["2160-1836"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85077664460&partnerID=MN8TOARS}, DOI={10.1534/g3.119.400650}, abstractNote={Abstract}, number={1}, journal={G3-GENES GENOMES GENETICS}, author={Schoonmaker, Ashley and Hao, Yue and Bird, David McK. and Conant, Gavin C.}, year={2020}, month={Jan}, pages={225–233} }
 @article{hao_lee_baraboo_burch_maurer_somarelli_conant_2020, title={Baby Genomics: Tracing the Evolutionary Changes That Gave Rise to Placentation}, volume={12}, ISSN={["1759-6653"]}, DOI={10.1093/gbe/evaa026}, abstractNote={Abstract}, number={3}, journal={GENOME BIOLOGY AND EVOLUTION}, author={Hao, Yue and Lee, Hyuk Jin and Baraboo, Michael and Burch, Katherine and Maurer, Taylor and Somarelli, Jason A. and Conant, Gavin C.}, year={2020}, month={Mar}, pages={35–47} }
 @article{mabry_brose_blischak_sutherland_dismukes_bottoms_edger_washburn_an_hall_et al._2020, title={Phylogeny and multiple independent whole-genome duplication events in the Brassicales}, volume={107}, ISSN={["1537-2197"]}, DOI={10.1002/ajb2.1514}, abstractNote={PremiseWhole‐genome duplications (WGDs) are prevalent throughout the evolutionary history of plants. For example, dozens of WGDs have been phylogenetically localized across the order Brassicales, specifically, within the family Brassicaceae. A WGD event has also been identified in the Cleomaceae, the sister family to Brassicaceae, yet its placement, as well as that of WGDs in other families in the order, remains unclear.}, number={8}, journal={AMERICAN JOURNAL OF BOTANY}, author={Mabry, Makenzie E. and Brose, Julia M. and Blischak, Paul D. and Sutherland, Brittany and Dismukes, Wade T. and Bottoms, Christopher A. and Edger, Patrick P. and Washburn, Jacob D. and An, Hong and Hall, Jocelyn C. and et al.}, year={2020}, month={Aug}, pages={1148–1164} }
 @article{conant_2020, title={The lasting after-effects of an ancient polyploidy on the genomes of teleosts}, volume={15}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0231356}, abstractNote={The ancestor of most teleost fishes underwent a whole-genome duplication event three hundred million years ago. Despite its antiquity, the effects of this event are evident both in the structure of teleost genomes and in how the surviving duplicated genes still operate to drive form and function. I inferred a set of shared syntenic regions that survive from the teleost genome duplication (TGD) using eight teleost genomes and the outgroup gar genome (which lacks the TGD). I then phylogenetically modeled the TGD’s resolution via shared and independent gene losses and applied a new simulation-based statistical test for the presence of bias toward the preservation of genes from one parental subgenome. On the basis of that test, I argue that the TGD was likely an allopolyploidy. I find that duplicate genes surviving from this duplication in zebrafish are less likely to function in early embryo development than are genes that have returned to single copy at some point in this species’ history. The tissues these ohnologs are expressed in, as well as their biological functions, lend support to recent suggestions that the TGD was the source of a morphological innovation in the structure of the teleost retina. Surviving duplicates also appear less likely to be essential than singletons, despite the fact that their single-copy orthologs in mouse are no less essential than other genes.}, number={4}, journal={PLOS ONE}, author={Conant, Gavin C.}, year={2020}, month={Apr} }
 @article{osman_bolding_villalon_kaifer_lorson_tisdale_hao_conant_pires_pellizzoni_et al._2019, title={Functional characterization of SMN evolution in mouse models of SMA}, volume={9}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-019-45822-8}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Osman, Erkan Y. and Bolding, Madeline R. and Villalon, Eric and Kaifer, Kevin A. and Lorson, Zachary C. and Tisdale, Sarah and Hao, Yue and Conant, Gavin C. and Pires, J. Chris and Pellizzoni, Livio and et al.}, year={2019}, month={Jul} }
 @article{ellison_conant_lamberson_austin_kirk_cunningham_rule_cammack_2019, title={Predicting residual feed intake status using rumen microbial profiles in ewe lambs}, volume={97}, ISSN={["1525-3163"]}, DOI={10.1093/jas/skz170}, abstractNote={Abstract}, number={7}, journal={JOURNAL OF ANIMAL SCIENCE}, author={Ellison, Melinda J. and Conant, Gavin C. and Lamberson, William R. and Austin, Kathleen J. and Kirk, Edward and Cunningham, Hannah C. and Rule, Daniel C. and Cammack, Kristi M.}, year={2019}, month={Jul}, pages={2878–2888} }
 @article{an_qi_gaynor_hao_gebken_mabry_mcalvay_teakle_conant_barker_et al._2019, title={Transcriptome and organellar sequencing highlights the complex origin and diversification of allotetraploid Brassica napus}, volume={10}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-019-10757-1}, abstractNote={Abstract}, journal={NATURE COMMUNICATIONS}, author={An, Hong and Qi, Xinshuai and Gaynor, Michelle L. and Hao, Yue and Gebken, Sarah C. and Mabry, Makenzie E. and McAlvay, Alex C. and Teakle, Graham R. and Conant, Gavin C. and Barker, Michael S. and et al.}, year={2019}, month={Jun} }
 @article{washburn_schnable_conant_brutnell_shao_zhang_ludwig_davidse_pires_2018, title={Author Correction: Genome-Guided Phylo-Transcriptomic Methods and the Nuclear Phylogenetic Tree of the Paniceae Grasses}, volume={8}, ISSN={2045-2322}, url={http://dx.doi.org/10.1038/S41598-018-25620-4}, DOI={10.1038/S41598-018-25620-4}, abstractNote={A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.}, number={1}, journal={Scientific Reports}, publisher={Springer Science and Business Media LLC}, author={Washburn, Jacob D. and Schnable, James C. and Conant, Gavin C. and Brutnell, Thomas P. and Shao, Ying and Zhang, Yang and Ludwig, Martha and Davidse, Gerrit and Pires, J. Chris}, year={2018}, month={May} }
 @article{washburn_schnable_conant_brutnell_shao_zhang_ludwig_davidse_pires_2018, title={Genome-guided phylo-transcriptomic methods and the nuclear phylogenetic tree of the paniceae grasses (vol 7, 13528, 2017)}, volume={8}, journal={Scientific Reports}, author={Washburn, J. D. and Schnable, J. C. and Conant, G. C. and Brutnell, T. P. and Shao, Y. and Zhang, Y. and Ludwig, M. and Davidse, G. and Pires, J. C.}, year={2018} }
 @article{blischak_mabry_conant_pires_2018, title={Integrating Networks, Phylogenomics, and Population Genomics for the Study of Polyploidy}, volume={49}, ISSN={["1545-2069"]}, DOI={10.1146/annurev-ecolsys-121415-032302}, abstractNote={ Duplication events are regarded as sources of evolutionary novelty, but our understanding of general trends for the long-term trajectory of additional genomic material is still lacking. Organisms with a history of whole genome duplication (WGD) offer a unique opportunity to study potential trends in the context of gene retention and/or loss, gene and network dosage, and changes in gene expression. In this review, we discuss the prevalence of polyploidy across the tree of life, followed by an overview of studies investigating genome evolution and gene expression. We then provide an overview of methods in network biology, phylogenomics, and population genomics that are critical for advancing our understanding of evolution post-WGD, highlighting the need for models that can accommodate polyploids. Finally, we close with a brief note on the importance of random processes in the evolution of polyploids with respect to neutral versus selective forces, ancestral polymorphisms, and the formation of autopolyploids versus allopolyploids. }, journal={ANNUAL REVIEW OF ECOLOGY, EVOLUTION, AND SYSTEMATICS, VOL 49}, author={Blischak, Paul D. and Mabry, Makenzie E. and Conant, Gavin C. and Pires, J. Chris}, year={2018}, pages={253–278} }
 @article{hao_washburn_rosenthal_nielsen_lyons_edger_pires_conant_2018, title={Patterns of Population Variation in Two Paleopolyploid Eudicot Lineages Suggest That Dosage-Based Selection on Homeologs Is Long-Lived}, volume={10}, ISSN={["1759-6653"]}, DOI={10.1093/gbe/evy061}, abstractNote={Abstract Genes that are inherently subject to strong selective constraints tend to be overretained in duplicate after polyploidy. They also continue to experience similar, but somewhat relaxed, constraints after that polyploidy event. We sought to assess for how long the influence of polyploidy is felt on these genes’ selective pressures. We analyzed two nested polyploidy events in Brassicaceae: the At-α genome duplication that is the most recent polyploidy in the model plant Arabidopsis thaliana and a more recent hexaploidy shared by the genus Brassica and its relatives. By comparing the strength and direction of the natural selection acting at the population and at the species level, we find evidence for continued intensified purifying selection acting on retained duplicates from both polyploidies even down to the present. The constraint observed in preferentially retained genes is not a result of the polyploidy event: the orthologs of such genes experience even stronger constraint in nonpolyploid outgroup genomes. In both the Arabidopsis and Brassica lineages, we further find evidence for segregating mildly deleterious variants, confirming that the population-level data uncover patterns not visible with between-species comparisons. Using the A. thaliana metabolic network, we also explored whether network position was correlated with the measured selective constraint. At both the population and species level, nodes/genes tended to show similar constraints to their neighbors. Our results paint a picture of the long-lived effects of polyploidy on plant genomes, suggesting that even yesterday’s polyploids still have distinct evolutionary trajectories.}, number={3}, journal={GENOME BIOLOGY AND EVOLUTION}, author={Hao, Yue and Washburn, Jacob D. and Rosenthal, Jacob and Nielsen, Brandon and Lyons, Eric and Edger, Patrick P. and Pires, J. Chris and Conant, Gavin C.}, year={2018}, month={Mar}, pages={999–1011} }
 @article{patil_ellison_wolff_shearer_wright_cockrum_austin_lamberson_cammack_conant_et al._2018, title={Poor feed efficiency in sheep is associated with several structural abnormalities in the community metabolic network of their ruminal microbes}, volume={96}, ISSN={["1525-3163"]}, DOI={10.1093/jas/sky096}, abstractNote={Ruminant animals have a symbiotic relationship with the microorganisms in their rumens. In this relationship, rumen microbes efficiently degrade complex plant-derived compounds into smaller digestible compounds, a process that is very likely associated with host animal feed efficiency. The resulting simpler metabolites can then be absorbed by the host and converted into other compounds by host enzymes. We used a microbial community metabolic network inferred from shotgun metagenomics data to assess how this metabolic system differs between animals that are able to turn ingested feedstuffs into body mass with high efficiency and those that are not. We conducted shotgun sequencing of microbial DNA from the rumen contents of 16 sheep that differed in their residual feed intake (RFI), a measure of feed efficiency. Metagenomic reads from each sheep were mapped onto a database-derived microbial metabolic network, which was linked to the sheep metabolic network by interface metabolites (metabolites transferred from microbes to host). No single enzyme was identified as being significantly different in abundance between the low and high RFI animals (P > 0.05, Wilcoxon test). However, when we analyzed the metabolic network as a whole, we found several differences between efficient and inefficient animals. Microbes from low RFI (efficient) animals use a suite of enzymes closer in network space to the host's reactions than those of the high RFI (inefficient) animals. Similarly, low RFI animals have microbial metabolic networks that, on average, contain reactions using shorter carbon chains than do those of high RFI animals, potentially allowing the host animals to extract metabolites more efficiently. Finally, the efficient animals possess community networks with greater Shannon diversity among their enzymes than do inefficient ones. Thus, our system approach to the ruminal microbiome identified differences attributable to feed efficiency in the structure of the microbes' community metabolic network that were undetected at the level of individual microbial taxa or reactions.}, number={6}, journal={JOURNAL OF ANIMAL SCIENCE}, author={Patil, R. D. and Ellison, M. J. and Wolff, S. M. and Shearer, C. and Wright, A. M. and Cockrum, R. R. and Austin, K. J. and Lamberson, W. R. and Cammack, K. M. and Conant, Gavin and et al.}, year={2018}, month={Jun}, pages={2113–2124} }
 @article{emery_willis_hao_barry_oakgrove_peng_schmutz_lyons_pires_edger_et al._2018, title={Preferential retention of genes from one parental genome after polyploidy illustrates the nature and scope of the genomic conflicts induced by hybridization}, volume={14}, ISSN={["1553-7404"]}, DOI={10.1371/journal.pgen.1007267}, abstractNote={Polyploidy is increasingly seen as a driver of both evolutionary innovation and ecological success. One source of polyploid organisms’ successes may be their origins in the merging and mixing of genomes from two different species (e.g., allopolyploidy). Using POInT (the Polyploid Orthology Inference Tool), we model the resolution of three allopolyploidy events, one from the bakers’ yeast (Saccharomyces cerevisiae), one from the thale cress (Arabidopsis thaliana) and one from grasses including Sorghum bicolor. Analyzing a total of 21 genomes, we assign to every gene a probability for having come from each parental subgenome (i.e., derived from the diploid progenitor species), yielding orthologous segments across all genomes. Our model detects statistically robust evidence for the existence of biased fractionation in all three lineages, whereby genes from one of the two subgenomes were more likely to be lost than those from the other subgenome. We further find that a driver of this pattern of biased losses is the co-retention of genes from the same parental genome that share functional interactions. The pattern of biased fractionation after the Arabidopsis and grass allopolyploid events was surprisingly constant in time, with the same parental genome favored throughout the lineages’ history. In strong contrast, the yeast allopolyploid event shows evidence of biased fractionation only immediately after the event, with balanced gene losses more recently. The rapid loss of functionally associated genes from a single subgenome is difficult to reconcile with the action of genetic drift and suggests that selection may favor the removal of specific duplicates. Coupled to the evidence for continuing, functionally-associated biased fractionation after the A. thaliana At-α event, we suggest that, after allopolyploidy, there are functional conflicts between interacting genes encoded in different subgenomes that are ultimately resolved through preferential duplicate loss.}, number={3}, journal={PLOS GENETICS}, author={Emery, Marianne and Willis, M. Madeline S. and Hao, Yue and Barry, Kerrie and Oakgrove, Khouanchy and Peng, Yi and Schmutz, Jeremy and Lyons, Eric and Pires, J. Chris and Edger, Patrick P. and et al.}, year={2018}, month={Mar} }
 @article{cammack_austin_lamberson_conant_cunningham_2018, title={RUMINANT NUTRITION SYMPOSIUM: Tiny but mighty: the role of the rumen microbes in livestock production (vol 96, pg 752, 2018)}, volume={96}, ISSN={["1525-3163"]}, DOI={10.1093/jas/sky331}, number={10}, journal={JOURNAL OF ANIMAL SCIENCE}, author={Cammack, Kristi M. and Austin, Kathleen J. and Lamberson, William R. and Conant, Gavin C. and Cunningham, Hannah C.}, year={2018}, month={Oct}, pages={4481–4481} }
 @article{cammack_austin_lamberson_conant_cunningham_2018, title={Tiny but mighty: The role of the rumen microbes in livestock production}, volume={1}, ISSN={0021-8812 1525-3163}, url={http://dx.doi.org/10.1093/jas/skx053}, DOI={10.1093/jas/skx053}, abstractNote={The microbes inhabiting the rumen convert low-quality, fibrous, plant material into useable energy for the host ruminant. Consisting of bacteria, protozoa, fungi, archaea, and viruses, the rumen microbiome composes a sophisticated network of symbiosis essential to maintenance, immune function, and overall production efficiency of the host ruminant. Robert Hungate laid the foundation for rumen microbiome research. This area of research has expanded immensely with advances in methodology and technology that have not only improved the ability to describe microbes in taxonomic and density terms but also characterize populations of microbes, their functions, and their interactions with each other and the host. The interplay between the rumen microbiome and the host contributes to variation in many phenotypic traits expressed by the host animal. A better understanding of how the rumen microbiome influences host health and performance may lead to novel strategies and treatments for trait improvement. Furthermore, elucidation of maternal, genetic, and environmental factors that influence rumen microbiome establishment and development may provide novel insights into possible mechanisms for manipulating the rumen microbial composition to enhance long-term host health and performance. The potential for these tiny but mighty rumen microbes to play a role in improving livestock production is appreciated despite being relatively obscure.}, journal={Journal of Animal Science}, publisher={Oxford University Press (OUP)}, author={Cammack, K M and Austin, K J and Lamberson, W R and Conant, G C and Cunningham, H C}, year={2018}, month={Jan} }
 @article{ellison_conant_lamberson_cockrum_austin_rule_cammack_2017, title={Diet and feed efficiency status affect rumen microbial profiles of sheep}, volume={156}, ISSN={["1879-0941"]}, DOI={10.1016/j.smallrumres.2017.08.009}, abstractNote={The rumen microbiota plays a large role in the digestion of consumed feeds in ruminant livestock and likely influences feed efficiency. The objective of this study was to determine associations of diet and feed efficiency status with rumen microbial profiles in growing lambs. Growing wethers were fed either a concentrate- (C; n = 39) or forage-based (F; n = 38) diet. Individual feed intake was measured over a 49 d intake trial and initial, mid and final BW were recorded for estimation of feed efficiency. Rumen fluid samples were collected at the end of the trial, and DNA for sequencing was extracted from the rumen fluid of the 10% lowest ranking and highest ranking wethers for feed efficiency on each diet. Paired-end reads were filtered, quality trimmed and compared with a database of known 16S rDNA genes. Operational taxonomic units (OTUs) were defined as sequence clusters with ≥ 97% identity in a 16S rDNA database; 349 prokaryotic OTUs were present in at least one animal. Of these OTUs, 27 were affected (P ≤ 0.05) by the interaction of diet with feed efficiency status, 44 were affected (P ≤ 0.05) by the main effect of diet, and 11 were affected (P ≤ 0.05) by the main effect of feed efficiency status. These results confirm that diet is a major influence on composition of the rumen microbiome. Also, key microbial species may play important roles in the regulation of feed efficiency, and those species may differ according to diet composition.}, journal={SMALL RUMINANT RESEARCH}, author={Ellison, M. J. and Conant, G. C. and Lamberson, W. R. and Cockrum, R. R. and Austin, K. J. and Rule, D. C. and Cammack, K. M.}, year={2017}, month={Nov}, pages={12–19} }
 @article{wolff_ellison_hao_cockrum_austin_baraboo_burch_lee_maurer_patil_et al._2017, title={Diet shifts provoke complex and variable changes in the metabolic networks of the ruminal microbiome}, volume={5}, ISSN={["2049-2618"]}, DOI={10.1186/s40168-017-0274-6}, abstractNote={Grazing mammals rely on their ruminal microbial symbionts to convert plant structural biomass into metabolites they can assimilate. To explore how this complex metabolic system adapts to the host animal's diet, we inferred a microbiome-level metabolic network from shotgun metagenomic data. Using comparative genomics, we then linked this microbial network to that of the host animal using a set of interface metabolites likely to be transferred to the host. When the host sheep were fed a grain-based diet, the induced microbial metabolic network showed several critical differences from those seen on the evolved forage-based diet. Grain-based (e.g., concentrate) diets tend to be dominated by a smaller set of reactions that employ metabolites that are nearer in network space to the host's metabolism. In addition, these reactions are more central in the network and employ substrates with shorter carbon backbones. Despite this apparent lower complexity, the concentrate-associated metabolic networks are actually more dissimilar from each other than are those of forage-fed animals. Because both groups of animals were initially fed on a forage diet, we propose that the diet switch drove the appearance of a number of different microbial networks, including a degenerate network characterized by an inefficient use of dietary nutrients. We used network simulations to show that such disparate networks are not an unexpected result of a diet shift. We argue that network approaches, particularly those that link the microbial network with that of the host, illuminate aspects of the structure of the microbiome not seen from a strictly taxonomic perspective. In particular, different diets induce predictable and significant differences in the enzymes used by the microbiome. Nonetheless, there are clearly a number of microbiomes of differing structure that show similar functional properties. Changes such as a diet shift uncover more of this type of diversity.}, journal={MICROBIOME}, author={Wolff, Sara M. and Ellison, Melinda J. and Hao, Yue and Cockrum, Rebecca R. and Austin, Kathy J. and Baraboo, Michael and Burch, Katherine and Lee, Hyuk Jin and Maurer, Taylor and Patil, Rocky and et al.}, year={2017}, month={Jun} }
 @inproceedings{khan_conant_xu_2017, title={Effects of evolutionary pressure on histone modifications}, DOI={10.1109/bibm.2017.8218019}, abstractNote={With the advent of next-generation sequencing technologies, a considerable effort has been put into sequencing the epigenomes of different species. The efforts such as “Encode” and “Roadmap” epigenomics projects provide an opportunity to compare epigenomes across species (especially between human and mouse). This study is an effort to understand how different histone modifications vary/co-appear between orthologous regions of the two species. In this work, we have used various measures of orthologous similarity between each pair of orthologous genes and explore how histone modifications are conserved with respect to changes in these similarity measures. These measures of similarity “codon usage frequency similarity” (CUFS), Ka/Ks ratio and gene expression similarity. Our simulation indicates that evolutionary selection pressure of an orthologous pair (Ka/Ks ratio) is more strongly correlated with its histone modification than any other similarity measure. We also found that genes with low Ka/Ks have more similar histone profiles across species than the ones with high Ka/Ks, suggesting more differential regulation for genes with higher selection pressure.}, booktitle={2017 ieee international conference on bioinformatics and biomedicine (bibm)}, author={Khan, S. M. and Conant, Gavin and Xu, D.}, year={2017}, pages={2267–2267} }
 @article{washburn_schnable_conant_brutnell_shao_zhang_ludwig_davidse_pires_2017, title={Genome-Guided Phylo-Transcriptomic Methods and the Nuclear Phylogentic Tree of the Paniceae Grasses}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-13236-z}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Washburn, Jacob D. and Schnable, James C. and Conant, Gavin C. and Brutnell, Thomas P. and Shao, Ying and Zhang, Yang and Ludwig, Martha and Davidse, Gerrit and Pires, J. Chris}, year={2017}, month={Oct} }
 @article{washburn_bird_conant_pires_2016, title={Convergent Evolution and the Origin of Complex Phenotypes in the Age of Systems Biology}, volume={177}, ISSN={1058-5893 1537-5315}, url={http://dx.doi.org/10.1086/686009}, DOI={10.1086/686009}, abstractNote={Convergent evolution has fascinated and occasionally mystified biologists since the principle of universal common ancestry was accepted. Similar phenotypes can arise by common ancestry (including preadaptations) or through constraints in the space of possible phenotypes and can increase in a population via either drift or selection. Assessing which of these mechanisms to invoke for any given example remains challenging for both simple and complex phenotypes. However, barriers in this area are slowly breaking down with recent advances in genomics and systems biology. A renaissance in the study of convergent evolution may be on its way, as surprising explanations for similar phenotypes, such as the metabolic similarities between yeast and cancer cells, are uncovered with network and metabolic models. We argue that although examples of convergence are known from many domains of life, green plants in particular have remarkable promise for the study of convergence because they are experimentally tractable, have considerable “-omics” and systems biology resources available, and show convergence in a number of important and complex traits. Four such examples include the domestication syndrome, duplicate loss and retention patterns following whole-genome duplication, the multiple appearances of C4 and crassulacean acid metabolism photosynthesis, and hybrid vigor.}, number={4}, journal={International Journal of Plant Sciences}, publisher={University of Chicago Press}, author={Washburn, Jacob D. and Bird, Kevin A. and Conant, Gavin C. and Pires, J. Chris}, year={2016}, month={May}, pages={305–318} }
 @book{pires_conant_2016, title={Robust Yet Fragile: Expression Noise, Protein Misfolding, and Gene Dosage in the Evolution of Genomes}, volume={50}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85000470522&partnerID=MN8TOARS}, DOI={10.1146/annurev-genet-120215-035400}, abstractNote={ The complex manner in which organisms respond to changes in their gene dosage has long fascinated geneticists. Oddly, although the existence of dominance implies that dosage reductions often have mild phenotypes, extra copies of whole chromosomes (aneuploidy) are generally strongly deleterious. Even more paradoxically, an extra copy of the genome is better tolerated than is aneuploidy. We review the resolution of this paradox, highlighting the roles of biochemistry, protein aggregation, and disruption of cellular microstructure in that explanation. Returning to life's curious combination of robustness and sensitivity to dosage changes, we argue that understanding how biological robustness evolved makes these observations less inexplicable. We propose that noise in gene expression and evolutionary strategies for its suppression play a role in generating dosage phenotypes. Finally, we outline an unappreciated mechanism for the preservation of duplicate genes, namely preservation to limit expression noise, arguing that it is particularly relevant in polyploid organisms. }, journal={Annual Review of Genetics}, author={Pires, J.C. and Conant, G.C.}, year={2016}, pages={113–131} }
 @article{mordhorst_wilson_conant_2016, title={Some assembly required: evolutionary and systems perspectives on the mammalian reproductive system}, volume={363}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84952980366&partnerID=MN8TOARS}, DOI={10.1007/s00441-015-2257-x}, abstractNote={In this review, we discuss the way that insights from evolutionary theory and systems biology shed light on form and function in mammalian reproductive systems. In the first part of the review, we contrast the rapid evolution seen in some reproductive genes with the generally conservative nature of development. We discuss directional selection and coevolution as potential drivers of rapid evolution in sperm and egg proteins. Such rapid change is very different from the highly conservative nature of later embryo development. However, it is not unique, as some regions of the sex chromosomes also show elevated rates of evolutionary change. To explain these contradictory trends, we argue that it is not reproductive functions per se that induce rapid evolution. Rather, it is the fact that biotic interactions, such as speciation events and sexual conflict, have no evolutionary endpoint and hence can drive continuous evolutionary changes. Returning to the question of sex chromosome evolution, we discuss the way that recent advances in evolutionary genomics and systems biology and, in particular, the development of a theory of gene balance provide a better understanding of the evolutionary patterns seen on these chromosomes. We end the review with a discussion of a surprising and incompletely understood phenomenon observed in early embryos: namely the Warburg effect, whereby glucose is fermented to lactate and alanine rather than respired to carbon dioxide. We argue that evolutionary insights, from both yeasts and tumor cells, help to explain the Warburg effect, and that new metabolic modeling approaches are useful in assessing the potential sources of the effect.}, number={1}, journal={Cell and Tissue Research}, author={Mordhorst, B.R. and Wilson, M.L. and Conant, G.C.}, year={2016}, pages={267–278} }
 @article{scienski_fay_conant_2015, title={Patterns of gene conversion in duplicated yeast histones suggest strong selection on a coadapted macromolecular complex}, volume={7}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84982084121&partnerID=MN8TOARS}, DOI={10.1093/gbe/evv216}, abstractNote={We find evidence for interlocus gene conversion in five duplicated histone genes from six yeast species. The sequences of these duplicated genes, surviving from the ancient genome duplication, show phylogenetic patterns inconsistent with the well-resolved orthology relationships inferred from a likelihood model of gene loss after the genome duplication. Instead, these paralogous genes are more closely related to each other than any is to its nearest ortholog. In addition to simulations supporting gene conversion, we also present evidence for elevated rates of radical amino acid substitutions along the branches implicated in the conversion events. As these patterns are similar to those seen in ribosomal proteins that have undergone gene conversion, we speculate that in cases where duplicated genes code for proteins that are a part of tightly interacting complexes, selection may favor the fixation of gene conversion events in order to maintain high protein identities between duplicated copies.}, number={12}, journal={Genome Biology and Evolution}, author={Scienski, K. and Fay, J.C. and Conant, G.C.}, year={2015}, pages={3249–3258} }
 @book{conant_2015, title={Structure, interaction, and evolution: Reflections on the natural history of proteins}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84955748996&partnerID=MN8TOARS}, DOI={10.1007/978-3-319-19932-0_10}, journal={Evolutionary Biology: Biodiversification from Genotype to Phenotype}, author={Conant, G.C.}, year={2015}, pages={187–201} }
 @article{edger_heidel-fischer_bekaert_rota_glöckner_platts_heckel_der_wafula_tang_et al._2015, title={The butterfly plant arms-race escalated by gene and genome duplications}, volume={112}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84936817684&partnerID=MN8TOARS}, DOI={10.1073/pnas.1503926112}, abstractNote={Significance}, number={27}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Edger, P.P. and Heidel-Fischer, H.M. and Bekaert, M. and Rota, J. and Glöckner, G. and Platts, A.E. and Heckel, D.G. and Der, J.P. and Wafula, E.K. and Tang, M. and et al.}, year={2015}, pages={8362–8366} }
 @article{taxis_wolff_gregg_minton_zhang_dai_schnabel_taylor_kerley_pires_et al._2015, title={The players may change but the game remains: Network analyses of ruminal microbiomes suggest taxonomic differences mask functional similarity}, volume={43}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84951815312&partnerID=MN8TOARS}, DOI={10.1093/nar/gkv973}, abstractNote={By mapping translated metagenomic reads to a microbial metabolic network, we show that ruminal ecosystems that are rather dissimilar in their taxonomy can be considerably more similar at the metabolic network level. Using a new network bi-partition approach for linking the microbial network to a bovine metabolic network, we observe that these ruminal metabolic networks exhibit properties consistent with distinct metabolic communities producing similar outputs from common inputs. For instance, the closer in network space that a microbial reaction is to a reaction found in the host, the lower will be the variability of its enzyme copy number across hosts. Similarly, these microbial enzymes that are nearby to host nodes are also higher in copy number than are more distant enzymes. Collectively, these results demonstrate a widely expected pattern that, to our knowledge, has not been explicitly demonstrated in microbial communities: namely that there can exist different community metabolic networks that have the same metabolic inputs and outputs but differ in their internal structure.}, number={20}, journal={Nucleic Acids Research}, author={Taxis, T.M. and Wolff, S. and Gregg, S.J. and Minton, N.O. and Zhang, C. and Dai, J. and Schnabel, R.D. and Taylor, J.F. and Kerley, M.S. and Pires, J.C. and et al.}, year={2015}, pages={9600–9612} }
 @article{conant_2014, title={Comparative genomics as a time machine: How relative gene dosage and metabolic requirements shaped the time-dependent resolution of yeast polyploidy}, volume={31}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84925003517&partnerID=MN8TOARS}, DOI={10.1093/molbev/msu250}, abstractNote={Using a phylogenetic model of evolution after genome duplication (i.e., polyploidy) and 12 yeast genomes with a shared genome duplication, I show that the loss of duplicate genes after that duplication occurred in three phases. First, losses that occurred immediately after the event were biased toward genes functioning in DNA repair and organellar functions. Then, the main group of duplicate losses appear to have been shaped by a requirement to maintain balance in protein levels: There is a strong statistical association between the number of protein interactions a gene's product is involved in and its propensity to have remained in duplicate. Moreover, when duplicated genes with interactions were lost, it was more common than expected for both members of an interaction pair to have been lost on the same branch of the phylogeny. Finally, in the third phase of the resolution process, overretention of duplicated enzymes carrying high flux and of duplicated genes involved in transcriptional regulation became dominant. I speculate that initial retention of such genes by a requirement to maintain gene dosage set the stage for the later functional changes that then maintained these duplicates for long periods.}, number={12}, journal={Molecular Biology and Evolution}, author={Conant, G.C.}, year={2014}, pages={3184–3193} }
 @article{conant_birchler_pires_2014, title={Dosage, duplication, and diploidization: clarifying the interplay of multiple models for duplicate gene evolution over time}, volume={19}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84901818848&partnerID=MN8TOARS}, DOI={10.1016/j.pbi.2014.05.008}, abstractNote={Requirements to maintain dosage balance shape many genome-scale patterns in organisms, including the resolution of whole genome duplications (WGD), as well as the varied effects of aneuploidy, segmental duplications, tandem duplications, gene copy number variations (CNV), and epigenetic marks. Like neofunctionalization and subfunctionalization, the impact of absolute and relative dosage varies over time. These variations are of particular importance in understanding the role of dosage in the evolution of polyploid organisms. Numerous investigations have found the consequences of polyploidy remain distinct from small-scale duplications (SSD). This observation is significant as all flowering plants have experienced at least two ancient polyploid events, and many angiosperm lineages have undergone additional rounds of polyploidy. Intriguingly, recent studies indicate a link between how epigenetic marks in recent allopolyploids may induce immediate changes in gene expression and the longer-term patterns of biased fractionation and chromosomal evolution. We argue that dosage effects represent one aspect of an emerging pluralistic framework, a framework that will use biophysics, genomic technologies, and systems-level models of cells to broaden our view of how genomes evolve.}, journal={Current Opinion in Plant Biology}, author={Conant, G.C. and Birchler, J.A. and Pires, J.C.}, year={2014}, month={Jun}, pages={91–98} }
 @article{bekaert_conant_2014, title={Gene duplication and phenotypic changes in the evolution of mammalian metabolic networks}, volume={9}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84900303150&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0087115}, abstractNote={Metabolic networks attempt to describe the complete suite of biochemical reactions available to an organism. One notable feature of these networks in mammals is the large number of distinct proteins that catalyze the same reaction. While the existence of these isoenzymes has long been known, their evolutionary significance is still unclear. Using a phylogenetically-aware comparative genomics approach, we infer enzyme orthology networks for sixteen mammals as well as for their common ancestors. We find that the pattern of isoenzymes copy-number alterations (CNAs) in these networks is suggestive of natural selection acting on the retention of certain gene duplications. When further analyzing these data with a machine-learning approach, we found that that the pattern of CNAs is also predictive of several important phenotypic traits, including milk composition and geographic range. Integrating tools from network analyses, phylogenetics and comparative genomics both allows the prediction of phenotypes from genetic data and represents a means of unifying distinct biological disciplines.}, number={1}, journal={PLoS ONE}, author={Bekaert, M. and Conant, G.C.}, year={2014} }
 @article{zimmerman_yi_sutovsky_van leeuwen_conant_sutovsky_2014, title={Identification and characterization of RING-finger ubiquitin ligase UBR7 in mammalian spermatozoa}, volume={356}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84898860365&partnerID=MN8TOARS}, DOI={10.1007/s00441-014-1808-x}, abstractNote={The ubiquitin-proteasome system (UPS) controls intracellular protein turnover in a substrate-specific manner via E3-type ubiquitin ligases. Mammalian fertilization and particularly sperm penetration through the oocyte vitelline coat, the zona pellucida (ZP), is regulated by UPS. We use an extrinsic substrate of the proteasome-dependent ubiquitin-fusion degradation pathway, the mutant ubiquitin UBB(+1), to provide evidence that an E3-type ligase activity exists in sperm-acrosomal fractions. Protein electrophoresis gels from such de novo ubiquitination experiments contained a unique protein band identified by tandem mass spectrometry as being similar to ubiquitin ligase UBR7 (alternative name: C14ORF130). Corresponding mRNA was amplified from boar testis and several variants of the UBR7 protein were detected in boar, mouse and human sperm extracts by Western blotting. Genomic analysis indicated a high degree of evolutionary conservation, remarkably constant purifying selection and conserved testis expression of the UBR7 gene. By immunofluorescence, UBR7 was localized to the spermatid acrosomal cap and sperm acrosome, in addition to hotspots of proteasomal activity in spermatids, such as the cytoplasmic lobe, caudal manchette, nucleus and centrosome. During fertilization, UBR7 remained with the ZP-bound acrosomal shroud following acrosomal exocytosis. Thus, UBR7 is present in the acrosomal cap of round spermatids and within the acrosomal matrix of mature boar spermatozoa. These data provide the first evidence of ubiquitin ligase activity in mammalian spermatozoa and indicate UBR7 involvement in spermiogenesis.}, number={1}, journal={Cell and Tissue Research}, author={Zimmerman, S.W. and Yi, Y.-J. and Sutovsky, M. and Van Leeuwen, F.W. and Conant, G. and Sutovsky, P.}, year={2014}, pages={261–278} }
 @article{truong_li_sajjapongse_conant_becchi_2014, title={Large-Scale Pairwise Alignments on GPU Clusters: Exploring the Implementation Space}, volume={77}, ISSN={1939-8018 1939-8115}, url={http://dx.doi.org/10.1007/s11265-014-0883-2}, DOI={10.1007/s11265-014-0883-2}, number={1-2}, journal={Journal of Signal Processing Systems}, publisher={Springer Science and Business Media LLC}, author={Truong, Huan and Li, Da and Sajjapongse, Kittisak and Conant, Gavin and Becchi, Michela}, year={2014}, month={Apr}, pages={131–149} }
 @article{edger_tang_bird_mayfield_conant_mummenhoff_koch_pires_2014, title={Secondary structure analyses of the nuclear rRNA internal transcribed spacers and assessment of its phylogenetic utility across the brassicaceae (mustards)}, volume={9}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84903709077&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0101341}, abstractNote={The internal transcribed spacers of the nuclear ribosomal RNA gene cluster, termed ITS1 and ITS2, are the most frequently used nuclear markers for phylogenetic analyses across many eukaryotic groups including most plant families. The reasons for the popularity of these markers include: 1.) Ease of amplification due to high copy number of the gene clusters, 2.) Available cost-effective methods and highly conserved primers, 3.) Rapidly evolving markers (i.e. variable between closely related species), and 4.) The assumption (and/or treatment) that these sequences are non-functional, neutrally evolving phylogenetic markers. Here, our analyses of ITS1 and ITS2 for 50 species suggest that both sequences are instead under selective constraints to preserve proper secondary structure, likely to maintain complete self-splicing functions, and thus are not neutrally-evolving phylogenetic markers. Our results indicate the majority of sequence sites are co-evolving with other positions to form proper secondary structure, which has implications for phylogenetic inference. We also found that the lowest energy state and total number of possible alternate secondary structures are highly significantly different between ITS regions and random sequences with an identical overall length and Guanine-Cytosine (GC) content. Lastly, we review recent evidence highlighting some additional problematic issues with using these regions as the sole markers for phylogenetic studies, and thus strongly recommend additional markers and cost-effective approaches for future studies to estimate phylogenetic relationships.}, number={7}, journal={PLoS ONE}, author={Edger, P.P. and Tang, M. and Bird, K.A. and Mayfield, D.R. and Conant, G. and Mummenhoff, K. and Koch, M.A. and Pires, J.C.}, year={2014} }
 @article{dhroso_korkin_conant_2014, title={The yeast protein interaction network has a capacity for self-organization}, volume={281}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84905190510&partnerID=MN8TOARS}, DOI={10.1111/febs.12870}, abstractNote={The organization of the cellular interior gives rise to properties including metabolic channeling and micro‐compartmentalization of signaling. Here, we use a lattice model of molecular crowding, together with literature‐derived protein interactions and abundances, to describe the molecular organization and stoichiometry of local cellular regions, showing that physical protein–protein interactions induce emergent structures not seen when random interaction networks are modeled. Specifically, we find that the lattices give rise to micro‐groups of enzymes on the surfaces of protein clusters. These arrangements of proteins are also robust to protein overexpression, while still showing evidence for expression tuning. Our results indicate that some of the complex organization of the cell may derive from simple rules of molecular aggregation and interaction.}, number={15}, journal={FEBS Journal}, author={Dhroso, A. and Korkin, D. and Conant, G.C.}, year={2014}, pages={3420–3432} }
 @article{a conserved mammalian protein interaction network_2013, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84871740262&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0052581}, abstractNote={Physical interactions between proteins mediate a variety of biological functions, including signal transduction, physical structuring of the cell and regulation. While extensive catalogs of such interactions are known from model organisms, their evolutionary histories are difficult to study given the lack of interaction data from phylogenetic outgroups. Using phylogenomic approaches, we infer a upper bound on the time of origin for a large set of human protein-protein interactions, showing that most such interactions appear relatively ancient, dating no later than the radiation of placental mammals. By analyzing paired alignments of orthologous and putatively interacting protein-coding genes from eight mammals, we find evidence for weak but significant co-evolution, as measured by relative selective constraint, between pairs of genes with interacting proteins. However, we find no strong evidence for shared instances of directional selection within an interacting pair. Finally, we use a network approach to show that the distribution of selective constraint across the protein interaction network is non-random, with a clear tendency for interacting proteins to share similar selective constraints. Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.}, number={1}, journal={PLoS ONE}, year={2013} }
 @inproceedings{li_sajjapongse_truong_conant_becchi_2013, title={A distributed CPU-GPU framework for pairwise alignments on large-scale sequence datasets}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84883348361&partnerID=MN8TOARS}, DOI={10.1109/ASAP.2013.6567598}, abstractNote={Several problems in computational biology require the all-against-all pairwise comparisons of tens of thousands of individual biological sequences. Each such comparison can be performed with the well-known Needleman-Wunsch alignment algorithm. However, with the rapid growth of biological databases, performing all possible comparisons with this algorithm in serial becomes extremely time-consuming. The massive computational power of graphics processing units (GPUs) makes them an appealing choice for accelerating these computations. As such, CPU-GPU clusters can enable all-against-all comparisons on large datasets.}, booktitle={Proceedings of the International Conference on Application-Specific Systems, Architectures and Processors}, author={Li, D. and Sajjapongse, K. and Truong, H. and Conant, G. and Becchi, M.}, year={2013}, pages={329–338} }
 @article{ellison_conant_cockrum_austin_truong_becchi_lamberson_cammack_2013, title={Diet Alters Both the Structure and Taxonomy of the Ovine Gut Microbial Ecosystem}, volume={21}, ISSN={1340-2838 1756-1663}, url={http://dx.doi.org/10.1093/dnares/dst044}, DOI={10.1093/dnares/dst044}, abstractNote={We surveyed the ruminal metagenomes of 16 sheep under two different diets using Illumina pair-end DNA sequencing of raw microbial DNA extracted from rumen samples. The resulting sequence data were bioinformatically mapped to known prokaryotic 16S rDNA sequences to identify the taxa present in the samples and then analysed for the presence of potentially new taxa. Strikingly, the majority of the microbial individuals found did not map to known taxa from 16S sequence databases. We used a novel statistical modelling approach to compare the taxonomic distributions between animals fed a forage-based diet and those fed concentrated grains. With this model, we found significant differences between the two groups both in the dominant taxa present in the rumen and in the overall shape of the taxa abundance curves. In general, forage-fed animals have a more diverse microbial ecosystem, whereas the concentrate-fed animals have ruminal systems more heavily dominated by a few taxa. As expected, organisms from methanogenic groups are more prevalent in forage-fed animals. Finally, all of these differences appear to be grounded in an underlying common input of new microbial individuals into the rumen environment, with common organisms from one feed group being present in the other, but at much lower abundance.}, number={2}, journal={DNA Research}, publisher={Oxford University Press (OUP)}, author={Ellison, M. J. and Conant, G. C. and Cockrum, R. R. and Austin, K. J. and Truong, H. and Becchi, M. and Lamberson, W. R. and Cammack, K. M.}, year={2013}, month={Oct}, pages={115–125} }
 @article{warren_wan_conant_korkin_2013, title={Extreme evolutionary conservation of functionally important regions in H1N1 influenza proteome}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84894288236&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0081027}, abstractNote={The H1N1 subtype of influenza A virus has caused two of the four documented pandemics and is responsible for seasonal epidemic outbreaks, presenting a continuous threat to public health. Co-circulating antigenically divergent influenza strains significantly complicates vaccine development and use. Here, by combining evolutionary, structural, functional, and population information about the H1N1 proteome, we seek to answer two questions: (1) do residues on the protein surfaces evolve faster than the protein core residues consistently across all proteins that constitute the influenza proteome? and (2) in spite of the rapid evolution of surface residues in influenza proteins, are there any protein regions on the protein surface that do not evolve? To answer these questions, we first built phylogenetically-aware models of the patterns of surface and interior substitutions. Employing these models, we found a single coherent pattern of faster evolution on the protein surfaces that characterizes all influenza proteins. The pattern is consistent with the events of inter-species reassortment, the worldwide introduction of the flu vaccine in the early 80’s, as well as the differences caused by the geographic origins of the virus. Next, we developed an automated computational pipeline to comprehensively detect regions of the protein surface residues that were 100% conserved over multiple years and in multiple host species. We identified conserved regions on the surface of 10 influenza proteins spread across all avian, swine, and human strains; with the exception of a small group of isolated strains that affected the conservation of three proteins. Surprisingly, these regions were also unaffected by genetic variation in the pandemic 2009 H1N1 viral population data obtained from deep sequencing experiments. Finally, the conserved regions were intrinsically related to the intra-viral macromolecular interaction interfaces. Our study may provide further insights towards the identification of novel protein targets for influenza antivirals.}, number={11}, journal={PLoS ONE}, author={Warren, S. and Wan, X.-F. and Conant, G. and Korkin, D.}, year={2013} }
 @article{mayfield-jones_washburn_arias_edger_pires_conant_2013, title={Watching the grin fade: Tracing the effects of polyploidy on different evolutionary time scales}, volume={24}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84876726255&partnerID=MN8TOARS}, DOI={10.1016/j.semcdb.2013.02.002}, abstractNote={Polyploidy, or whole-genome duplication (WGD), is a recurrent mutation both in cell lineages and over evolutionary time. By globally changing the relationship between gene copy number and other cellular entities, it can induce dramatic changes at the cellular and phenotypic level. Perhaps surprisingly, then, the insights that these events can bring to understanding other cellular features are not as well appreciated as they could be. In this review, we draw on examples of polyploidy from animals, plants and yeast to explore how investigations of polyploid cells have improved our understanding of the cell cycle, biological network complexity, metabolic phenotypes and tumor biology. We argue that the study of polyploidy across organisms, cell types, and time scales serves not only as a window into basic cell biology, but also as a basis for a predictive biology with applications ranging from crop improvement to treating cancer.}, number={4}, journal={Seminars in Cell and Developmental Biology}, author={Mayfield-Jones, D. and Washburn, J.D. and Arias, T. and Edger, P.P. and Pires, J.C. and Conant, G.C.}, year={2013}, pages={320–331} }
 @article{tang_woodhouse_cheng_schnable_pedersen_conant_wang_freeling_pires_2012, title={Altered patterns of fractionation and exon deletions in Brassica rapa support a two-step model of paleohexaploidy}, volume={190}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84859564587&partnerID=MN8TOARS}, DOI={10.1534/genetics.111.137349}, abstractNote={Abstract}, number={4}, journal={Genetics}, author={Tang, H. and Woodhouse, M.R. and Cheng, F. and Schnable, J.C. and Pedersen, B.S. and Conant, G. and Wang, X. and Freeling, M. and Pires, J.C.}, year={2012}, pages={1563–1574} }
 @article{wang_conant_ou_beerntsen_2012, title={Cloning and characterization of the peptidoglycan recognition protein genes in the mosquito, Armigeres subalbatus (Diptera: Culicidae)}, volume={49}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84861128976&partnerID=MN8TOARS}, DOI={10.1603/ME11165}, abstractNote={ABSTRACT 
 Peptidoglycan recognition proteins (PGRPs) are a group of proteins that are responsible for the recognition and, in some cases, binding of peptidoglycan (PGN), a unique cell wall component of bacteria, and initiation of immune responses to various types of pathogens. In the current study, full-length cDNA sequences of multiple PGRPs, identified via a database search, were cloned in the mosquito Armigeres subalbatus (Coquillett). During cloning, a novel transcript variant (isoform) of AsPGRP-LC (As: Ar. subalbatus) was also identified that shares a large 5′ end fragment with AsPGRP-LC All four AsPGRP genes (six transcripts) contain a conserved PGRP domain, an ortholog of the amidase-2 domain. Based on predicted functional domain, the six Ar. subalbatus PGRPs resemble both short (AsPGRP-S1) and long (AsPGRP-LBa, AsPGRP-LBb, AsPGRP-LCa, AsPGRPLCb, and AsPGRP-LE) forms of PGRPs as in other insects. Sequence alignments showed that PGRPs are conserved across Dipterans. Phylogenetic analysis indicated that PGRPs represent an ancient gene family that has primarily diverged through speciation events among these Dipterans, with only a limited number of lineage specific gene duplications. Developmental profiling of the six AsPGRP transcripts using real-time polymerase chain reaction revealed that AsPGRP-LCa and AsPGRP-LCb are constitutively expressed at high levels in all developmental stages, while AsPGRP-S1, AsPGRP-LBa, AsPGRP-LBb, and AsPGRP-LE transcripts have low expression in most of the life stages and are increased only at certain times. Tissue profiling of the six AsPGRP transcripts showed that they are expressed in various patterns, even between the different isoforms of the same PGRP gene, indicating that these AsPGRPs may play different functions.}, number={3}, journal={Journal of Medical Entomology}, author={Wang, S. and Conant, G.C. and Ou, R. and Beerntsen, B.T.}, year={2012}, pages={656–671} }
 @article{reneker_lyons_conant_pires_freeling_shyu_korkin_2012, title={Long identical multispecies elements in plant and animal genomes}, volume={109}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84860788430&partnerID=MN8TOARS}, DOI={10.1073/pnas.1121356109}, abstractNote={Ultraconserved elements (UCEs) are DNA sequences that are 100% identical (no base substitutions, insertions, or deletions) and located in syntenic positions in at least two genomes. Although hundreds of UCEs have been found in animal genomes, little is known about the incidence of ultraconservation in plant genomes. Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes. Among six animal genomes, we found the previously known syntenic UCEs as well as previously undescribed nonsyntenic elements. In contrast, among six plant genomes, we only found nonsyntenic LIMEs. LIMEs can also be classified as either simple (repetitive) or complex (nonrepetitive), they may occur in multiple copies in a genome, and they are often spread across multiple chromosomes. Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number. Further analyses of plant LIMEs revealed their functional diversity, encompassing elements found near rRNA and enzyme-coding genes, as well as those found in transposons and noncoding DNA. We conclude that despite the common presence of LIMEs in both animal and plant lineages, the evolutionary processes involved in the creation and maintenance of these elements differ in the two groups and are likely attributable to several mechanisms, including transfer of genetic material from organellar to nuclear genomes, de novo sequence manufacturing, and purifying selection.}, number={19}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Reneker, J. and Lyons, E. and Conant, G.C. and Pires, J.C. and Freeling, M. and Shyu, C.-R. and Korkin, D.}, year={2012} }
 @article{bekaert_edger_hudson_pires_conant_2012, title={Metabolic and evolutionary costs of herbivory defense: Systems biology of glucosinolate synthesis}, volume={196}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84866378393&partnerID=MN8TOARS}, DOI={10.1111/j.1469-8137.2012.04302.x}, abstractNote={Summary}, number={2}, journal={New Phytologist}, author={Bekaert, M. and Edger, P.P. and Hudson, C.M. and Pires, J. and Conant, G.C.}, year={2012}, pages={596–605} }
 @article{huminiecki_conant_2012, title={Polyploidy and the Evolution of Complex Traits}, volume={2012}, ISSN={2090-8032 2090-052X}, url={http://dx.doi.org/10.1155/2012/292068}, DOI={10.1155/2012/292068}, abstractNote={We explore how whole-genome duplications (WGDs) may have given rise to complex innovations in cellular networks, innovations that could not have evolved through sequential single-gene duplications. We focus on two classical WGD events, one in bakers’ yeast and the other at the base of vertebrates (i.e., two rounds of whole-genome duplication: 2R-WGD). Two complex adaptations are discussed in detail: aerobic ethanol fermentation in yeast and the rewiring of the vertebrate developmental regulatory network through the 2R-WGD. These two examples, derived from diverged branches on the eukaryotic tree, boldly underline the evolutionary potential of WGD in facilitating major evolutionary transitions. We close by arguing that the evolutionary importance of WGD may require updating certain aspects of modern evolutionary theory, perhaps helping to synthesize a new evolutionary systems biology.}, journal={International Journal of Evolutionary Biology}, publisher={Hindawi Limited}, author={Huminiecki, Lukasz and Conant, Gavin C.}, year={2012}, pages={1–12} }
 @article{casola_conant_hahn_2012, title={Very low rate of gene conversion in the yeast genome}, volume={29}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84869074763&partnerID=MN8TOARS}, DOI={10.1093/molbev/mss192}, abstractNote={Gene duplication is a major driver of organismal adaptation and evolution and plays an important role in multiple human diseases. Whole-genome analyses have shown similar and high rates of gene duplication across a variety of eukaryotic species. Most of these studies, however, did not address the possible impact of interlocus gene conversion (IGC) on the evolution of gene duplicates. Because IGC homogenizes pairs of duplicates, widespread conversion would cause gene duplication events that happened long ago to appear more recent, resulting in artificially high estimates of duplication rates. Although the majority of genome-wide studies (including in the budding yeast Saccharomyces cerevisiae [Scer]) point to levels of IGC between paralogs ranging from 2% to 18%, Gao and Innan (Gao LZ, Innan H. 2004. Very low gene duplication rate in the yeast genome. Science 306:1367-1370.) found that gene conversion in yeast affected >80% of paralog pairs. If conversion rates really are this high, it would imply that the rate of gene duplication in eukaryotes is much lower than previously reported. In this work, we apply four different methodologies-including one approach that closely mirrors Gao and Innan's method-to estimate the level of IGC in Scer. Our analyses point to a maximum conversion level of 13% between paralogs in this species, in close agreement with most estimates of IGC in eukaryotes. We also show that the exceedingly high levels of conversion found previously derive from application of an accurate method to an inappropriate data set. In conclusion, our work provides the most striking evidence to date supporting the reduced incidence of IGC among Scer paralogs and sets up a framework for future analyses in other eukaryotes.}, number={12}, journal={Molecular Biology and Evolution}, author={Casola, C. and Conant, G.C. and Hahn, M.W.}, year={2012}, pages={3817–3826} }
 @book{hudson_conant_2012, title={Yeast as a window into changes in genome complexity due to polyploidization}, volume={9783642314421}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84949175705&partnerID=MN8TOARS}, DOI={10.1007/978-3-642-31442-1_15}, journal={Polyploidy and Genome Evolution}, author={Hudson, C.M. and Conant, G.C.}, year={2012}, pages={293–308} }
 @article{bekaert_conant_2011, title={Copy number alterations among mammalian enzymes cluster in the metabolic network}, volume={28}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-78751469014&partnerID=MN8TOARS}, DOI={10.1093/molbev/msq296}, abstractNote={Using two high-quality human metabolic networks, we employed comparative genomics techniques to infer metabolic network structures for seven other mammals. We then studied copy number alterations (CNAs) in these networks. Using a graph-theoretic approach, we show that the pattern of CNAs is distinctly different from the random distributions expected under genetic drift. Instead, we find that changes in copy number are most common among transporter genes and that the CNAs differ depending on the mammalian lineage in question. Thus, we find an excess of transporter genes in cattle involved in the milk production, secretion, and regulation. These results suggest a potential role for dosage selection in the evolution of mammalian metabolic networks.}, number={2}, journal={Molecular Biology and Evolution}, author={Bekaert, M. and Conant, G.C.}, year={2011}, pages={1111–1121} }
 @article{hudson_conant_2011, title={Expression level, cellular compartment and metabolic network position all influence the average selective constraint on mammalian enzymes}, volume={11}, ISSN={1471-2148}, url={http://dx.doi.org/10.1186/1471-2148-11-89}, DOI={10.1186/1471-2148-11-89}, abstractNote={A gene's position in regulatory, protein interaction or metabolic networks can be predictive of the strength of purifying selection acting on it, but these relationships are neither universal nor invariably strong. Following work in bacteria, fungi and invertebrate animals, we explore the relationship between selective constraint and metabolic function in mammals. We measure the association between selective constraint, estimated by the ratio of nonsynonymous (Ka) to synonymous (Ks) substitutions, and several, primarily metabolic, measures of gene function. We find significant differences between the selective constraints acting on enzyme-coding genes from different cellular compartments, with the nucleus showing higher constraint than genes from either the cytoplasm or the mitochondria. Among metabolic genes, the centrality of an enzyme in the metabolic network is significantly correlated with Ka/Ks. In contrast to yeasts, gene expression magnitude does not appear to be the primary predictor of selective constraint in these organisms. Our results imply that the relationship between selective constraint and enzyme centrality is complex: the strength of selective constraint acting on mammalian genes is quite variable and does not appear to exclusively follow patterns seen in other organisms.}, number={1}, journal={BMC Evolutionary Biology}, publisher={Springer Nature}, author={Hudson, Corey M and Conant, Gavin C}, year={2011}, month={Apr} }
 @article{pérez-bercoff_mclysaght_conant_2011, title={Patterns of indirect protein interactions suggest a spatial organization to metabolism}, volume={7}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-80054012758&partnerID=MN8TOARS}, DOI={10.1039/c1mb05168g}, abstractNote={It has long been believed that cells organize their cytoplasm so as to efficiently channel metabolites between sequential enzymes. This metabolic channeling has the potential to yield higher metabolic fluxes as well as better regulatory control over metabolism. One mechanism for achieving such channeling is to ensure that sequential enzymes in a pathway are physically close to each other in the cell. We present evidence that indirect protein interactions between related enzymes represent a global mechanism for achieving metabolic channeling; the intuition being that protein interactions between enzymes and non-enzymatic mediator proteins are a powerful means of physically associating enzymes in a modular fashion. By analyzing the metabolic and protein-protein interactions networks of Escherichia coli, yeast and humans, we are able to show that all three species have many more indirect protein interactions linking enzymes that share metabolites than would be expected by chance. Moreover, these interactions are distributed non-randomly in the metabolic network. Our analyses in yeast and E. coli show that reactions possessing such interactions also show higher flux than do those lacking them. On the basis of these observations, we suggest that an important role of protein interactions with mediator proteins is to contribute to the spatial organization of the cell. This hypothesis is supported by the fact that these mediator proteins are also enriched with annotations related to signal transduction, a system where scaffolding proteins are known to limit cross-talk by controlling spatial localization.}, number={11}, journal={Molecular BioSystems}, author={Pérez-Bercoff, A. and McLysaght, A. and Conant, G.C.}, year={2011}, pages={3056–3064} }
 @article{hudson_puckett_bekaert_pires_conant_2011, title={Selection for higher gene copy number after different types of plant gene duplications}, volume={3}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84858779019&partnerID=MN8TOARS}, DOI={10.1093/gbe/evr115}, abstractNote={The evolutionary origins of the multitude of duplicate genes in the plant genomes are still incompletely understood. To gain an appreciation of the potential selective forces acting on these duplicates, we phylogenetically inferred the set of metabolic gene families from 10 flowering plant (angiosperm) genomes. We then compared the metabolic fluxes for these families, predicted using the Arabidopsis thaliana and Sorghum bicolor metabolic networks, with the families' duplication propensities. For duplications produced by both small scale (small-scale duplications) and genome duplication (whole-genome duplications), there is a significant association between the flux and the tendency to duplicate. Following this global analysis, we made a more fine-scale study of the selective constraints observed on plant sodium and phosphate transporters. We find that the different duplication mechanisms give rise to differing selective constraints. However, the exact nature of this pattern varies between the gene families, and we argue that the duplication mechanism alone does not define a duplicated gene's subsequent evolutionary trajectory. Collectively, our results argue for the interplay of history, function, and selection in shaping the duplicate gene evolution in plants.}, number={1}, journal={Genome Biology and Evolution}, author={Hudson, C.M. and Puckett, E.E. and Bekaert, M. and Pires, J.C. and Conant, G.C.}, year={2011}, pages={1369–1380} }
 @article{wang_wang_wang_sun_wu_liu_bai_mun_bancroft_cheng_et al._2011, title={The genome of the mesopolyploid crop species Brassica rapa}, volume={43}, ISSN={1061-4036 1546-1718}, url={http://dx.doi.org/10.1038/ng.919}, DOI={10.1038/ng.919}, abstractNote={We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops.}, number={10}, journal={Nature Genetics}, publisher={Springer Nature}, author={Wang, Xiaowu and Wang, Hanzhong and Wang, Jun and Sun, Rifei and Wu, Jian and Liu, Shengyi and Bai, Yinqi and Mun, Jeong-Hwan and Bancroft, Ian and Cheng, Feng and et al.}, year={2011}, month={Aug}, pages={1035–1039} }
 @article{bekaert_conant_2011, title={Transcriptional robustness and protein interactions are associated in yeast}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79955553036&partnerID=MN8TOARS}, DOI={10.1186/1752-0509-5-62}, abstractNote={Robustness to insults, both external and internal, is a characteristic feature of life. One level of biological organization for which noise and robustness have been extensively studied is gene expression. Cells have a variety of mechanisms for buffering noise in gene expression, but it is not completely clear what rules govern whether or not a given gene uses such tools to maintain appropriate expression.Here, we show a general association between the degree to which yeast cells have evolved mechanisms to buffer changes in gene expression and whether they possess protein-protein interactions. We argue that this effect bears an affinity to epistasis, because yeast appears to have evolved regulatory mechanisms such that distant changes in gene copy number for a protein-protein interaction partner gene can alter a gene's expression. This association is not unexpected given recent work linking epistasis and the deleterious effects of changes in gene dosage (i.e., the dosage balance hypothesis). Using gene expression data from artificial aneuploid strains of bakers' yeast, we found that genes coding for proteins that physically interact with other proteins show less expression variation in response to aneuploidy than do other genes. This effect is even more pronounced for genes whose products interact with proteins encoded on aneuploid chromosomes. We further found that genes targeted by transcription factors encoded on aneuploid chromosomes were more likely to change in expression after aneuploidy.We suggest that these observations can be best understood as resulting from the higher fitness cost of misexpression in epistatic genes and a commensurate greater regulatory control of them.}, journal={BMC Systems Biology}, author={Bekaert, M. and Conant, G.C.}, year={2011} }
 @article{bekaert_edger_chris pires_conant_2011, title={Two-phase resolution of polyploidy in the Arabidopsis metabolic network gives rise to relative and absolute dosage constraints}, volume={23}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79959858471&partnerID=MN8TOARS}, DOI={10.1105/tpc.110.081281}, abstractNote={Abstract}, number={5}, journal={Plant Cell}, author={Bekaert, M. and Edger, P.P. and Chris Pires, J. and Conant, G.C.}, year={2011}, pages={1719–1728} }
 @article{evangelisti_conant_2010, title={Nonrandom survival of gene conversions among yeast ribosomal proteins duplicated through genome doubling.}, volume={2}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-79952199263&partnerID=MN8TOARS}, journal={Genome biology and evolution}, author={Evangelisti, A.M. and Conant, G.C.}, year={2010}, pages={826–834} }
 @article{conant_2010, title={Rapid reorganization of the transcriptional regulatory network after genome duplication in yeast}, volume={277}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-77950290826&partnerID=MN8TOARS}, DOI={10.1098/rspb.2009.1592}, abstractNote={I study the reorganization of the yeast transcriptional regulatory network after whole-genome duplication (WGD). Individual transcription factors (TFs) were computationally removed from the regulatory network, and the resulting networks were analysed. TF gene pairs that survive in duplicate from WGD show detectable redundancy as a result of that duplication. However, in most other respects, these duplicated TFs are indistinguishable from other TFs in the genome, suggesting that the duplicate TFs produced by WGD were rapidly diverted to distinct functional roles in the regulatory network. Separately, I find that genes targeted by many TFs appear to be preferentially retained in duplicate after WGD, an effect I attribute to selection to maintain dosage balance in the regulatory network after WGD.}, number={1683}, journal={Proceedings of the Royal Society B: Biological Sciences}, author={Conant, G.C.}, year={2010}, pages={869–876} }
 @article{foy_jester_conant_devine_2010, title={The T box regulatory element controlling expression of the class i lysyl-tRNA synthetase of Bacillus cereus strain 14579 is functional and can be partially induced by reduced charging of asparaginyl-tRNA<sup>Asn</sup>}, volume={10}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-77954765210&partnerID=MN8TOARS}, DOI={10.1186/1471-2180-10-196}, abstractNote={Abstract}, journal={BMC Microbiology}, author={Foy, N. and Jester, B. and Conant, G.C. and Devine, K.M.}, year={2010} }
 @article{conant_2009, title={Neutral evolution on mammalian protein surfaces}, volume={25}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-69449100706&partnerID=MN8TOARS}, DOI={10.1016/j.tig.2009.07.004}, abstractNote={Because of their low effective population sizes, natural selection is expected to have reduced effectiveness in organisms such as mammals. By comparing the amino acid substitution rates between mammalian protein surfaces and interiors, it was found that almost a third of the proteins surveyed failed to reject the null hypothesis of neutral substitutions among surface residues. Proteins with such partly neutral evolution nonetheless have no fewer protein interactions than do other proteins. I suggest that natural selection can function to preserve protein interactions without requiring strict conservation of the individual residue contacts that impart those interactions. Because of their low effective population sizes, natural selection is expected to have reduced effectiveness in organisms such as mammals. By comparing the amino acid substitution rates between mammalian protein surfaces and interiors, it was found that almost a third of the proteins surveyed failed to reject the null hypothesis of neutral substitutions among surface residues. Proteins with such partly neutral evolution nonetheless have no fewer protein interactions than do other proteins. I suggest that natural selection can function to preserve protein interactions without requiring strict conservation of the individual residue contacts that impart those interactions.}, number={9}, journal={Trends in Genetics}, author={Conant, G.C.}, year={2009}, pages={377–381} }
 @article{decker_pires_conant_mckay_heaton_chen_cooper_vilkki_seabury_caetano_et al._2009, title={Resolving the evolution of extant and extinct ruminants with high-throughput phylogenomics}, volume={106}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-73249118931&partnerID=MN8TOARS}, DOI={10.1073/pnas.0904691106}, abstractNote={The Pecorans (higher ruminants) are believed to have rapidly speciated in the Mid-Eocene, resulting in five distinct extant families: Antilocapridae, Giraffidae, Moschidae, Cervidae, and Bovidae. Due to the rapid radiation, the Pecoran phylogeny has proven difficult to resolve, and 11 of the 15 possible rooted phylogenies describing ancestral relationships among the Antilocapridae, Giraffidae, Cervidae, and Bovidae have each been argued as representations of the true phylogeny. Here we demonstrate that a genome-wide single nucleotide polymorphism (SNP) genotyping platform designed for one species can be used to genotype ancient DNA from an extinct species and DNA from species diverged up to 29 million years ago and that the produced genotypes can be used to resolve the phylogeny for this rapidly radiated infraorder. We used a high-throughput assay with 54,693 SNP loci developed forBos taurus taurusto rapidly genotype 678 individuals representing 61 Pecoran species. We produced a highly resolved phylogeny for this diverse group based upon 40,843 genome-wide SNP, which is five times as many informative characters as have previously been analyzed. We also establish a method to amplify and screen genomic information from extinct species, and placeBison priscuswithin the Bovidae. The quality of genotype calls and the placement of samples within a well-supported phylogeny may provide an important test for validating the fidelity and integrity of ancient samples. Finally, we constructed a phylogenomic network to accurately describe the relationships between 48 cattle breeds and facilitate inferences concerning the history of domestication and breed formation.}, number={44}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Decker, J.E. and Pires, J.C. and Conant, G.C. and McKay, S.D. and Heaton, M.P. and Chen, K. and Cooper, A. and Vilkki, J. and Seabury, C.M. and Caetano, A.R. and et al.}, year={2009}, pages={18644–18649} }
 @article{conant_stadler_2009, title={Solvent exposure imparts similar selective pressures across a range of yeast proteins}, volume={26}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-65349140199&partnerID=MN8TOARS}, DOI={10.1093/molbev/msp031}, abstractNote={We study how an amino acid residue's solvent exposure influences its propensity for substitution by analyzing multiple alignments of 61 yeast genes for which the crystal structure is known. We find that the selective constraint on the interior residues is on average 10 times that of residues on the surface. Surprisingly, there is no correlation between the overall selective constraint observed for a protein alignment and the ratio of constraints on interior and surface residues. By modeling the selective constraint on several amino acid properties, we show that although residue volume and hydropathy are strongly conserved across most alignments, there is little variation in interior versus surface conservation for these two properties. By contrast, residue charge (isoelectric point) is less generally conserved when considering the protein as a whole but shows a strong constraint against the introduction of charged residues into the protein interior.}, number={5}, journal={Molecular Biology and Evolution}, author={Conant, G.C. and Stadler, P.F.}, year={2009}, pages={1155–1161} }
 @article{powell_conant_brown_carbone_dean_2008, title={Altered patterns of gene duplication and differential gene gain and loss in fungal pathogens}, volume={9}, ISSN={["1471-2164"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-42549135491&partnerID=MN8TOARS}, DOI={10.1186/1471-2164-9-147}, abstractNote={Abstract}, journal={BMC GENOMICS}, author={Powell, Amy J. and Conant, Gavin C. and Brown, Douglas E. and Carbone, Ignazio and Dean, Ralph A.}, year={2008}, month={Mar} }
 @article{conant_wolfe_2008, title={GenomeVx: Simple web-based creation of editable circular chromosome maps}, volume={24}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-40749117710&partnerID=MN8TOARS}, DOI={10.1093/bioinformatics/btm598}, abstractNote={Abstract}, number={6}, journal={Bioinformatics}, author={Conant, G.C. and Wolfe, K.H.}, year={2008}, pages={861–862} }
 @article{conant_wolfe_2008, title={Increased glycolytic flux as an outcome of whole-genome duplication in yeast (Molecular Systems Biology (2007) 3 (129) DOI: 10.1038/msb4100170)}, volume={4}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-46349108652&partnerID=MN8TOARS}, DOI={10.1038/msb.2008.46}, abstractNote={Corrigendum1 July 2008Open Access Increased glycolytic flux as an outcome of whole-genome duplication in yeast Gavin C Conant Gavin C Conant Search for more papers by this author Kenneth H Wolfe Kenneth H Wolfe Search for more papers by this author Gavin C Conant Gavin C Conant Search for more papers by this author Kenneth H Wolfe Kenneth H Wolfe Search for more papers by this author Author Information Gavin C Conant and Kenneth H Wolfe Molecular Systems Biology (2008)4:204https://doi.org/10.1038/msb.2008.46 This article corrects the following: Increased glycolytic flux as an outcome of whole-genome duplication in yeast31 July 2007 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Correction to: Molecular Systems Biology 3:129. doi:10.1038/msb4100170; published online 31 July 2007 The authors of the above paper have detected an error in their published paper. In Figure 2C, we incorrectly used a value of Vmax for the PDH reaction that was expressed in terms of flux per minute rather than per second. This updated version of the figure uses the correct value of Vmax from Rizzi et al (1997) cited in the supplemental information of our original manuscript. The change reinforces our conclusion that increasing flux through glycolysis tends to decrease the relative flux through respiration as compared to fermentation. The authors would like to thank Lukas Endler for discovering their error. Figure 1.(A) Changes in the concentration of key metabolites in response to overall decreases in the Vmax values for the reactions of glycolysis (blue, left axis scale), as well as the change in PYK flux over the same range (red, right axis scale). (B) Ratio of the flux through pyruvate decarboxylase (PDC, fermentative pathways) to the flux through pyruvate dehydrogenase (PDH, respiratory pathway) as a function of pyruvate concentration and the ratio of NAD+ to NADH concentration (because NAD+ and NADH are two oxidation states of the same molecule, their concentrations vary inversely and hence are constrained to sum to 8.01 in B; Theobald et al, 1997). (C) Effect of compartmentalization on the relative fluxes of the first reaction in respiration (PDH) and in fermentation (PDC). On the x-axis is the relative enzyme concentration modeling a change from a rough pre-duplication state of 0.65 to a post-duplicate value of 1.0 (see A). On the y-axis is given the ratio of the fluxes between the two reactions relative to the flux when [E] on the x-axis is equal to 1.0. Download figure Download PowerPoint Please see the corrected figure below. The authors apologize for any inconvenience caused. Previous ArticleNext Article Volume 4Issue 11 January 2008In this issue FiguresRelatedDetailsLoading ...}, journal={Molecular Systems Biology}, author={Conant, G.C. and Wolfe, K.H.}, year={2008} }
 @article{conant_wolfe_2008, title={Probabilistic cross-species inference of orthologous genomic regions created by whole-genome duplication in yeast}, volume={179}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-52049091231&partnerID=MN8TOARS}, DOI={10.1534/genetics.107.074450}, abstractNote={Abstract}, number={3}, journal={Genetics}, author={Conant, G.C. and Wolfe, K.H.}, year={2008}, pages={1681–1692} }
 @article{conant_wolfe_2008, title={Turning a hobby into a job: How duplicated genes find new functions}, volume={9}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-56549119570&partnerID=MN8TOARS}, DOI={10.1038/nrg2482}, abstractNote={Gene duplication provides raw material for functional innovation. Recent advances have shed light on two fundamental questions regarding gene duplication: which genes tend to undergo duplication? And how does natural selection subsequently act on them? Genomic data suggest that different gene classes tend to be retained after single-gene and whole-genome duplications. We also know that functional differences between duplicate genes can originate in several different ways, including mutations that directly impart new functions, subdivision of ancestral functions and selection for changes in gene dosage. Interestingly, in many cases the 'new' function of one copy is a secondary property that was always present, but that has been co-opted to a primary role after the duplication.}, number={12}, journal={Nature Reviews Genetics}, author={Conant, G.C. and Wolfe, K.H.}, year={2008}, pages={938–950} }
 @article{conant_wolfe_2007, title={Increased glycolytic flux as an outcome of whole‐genome duplication in yeast}, volume={3}, ISSN={1744-4292 1744-4292}, url={http://dx.doi.org/10.1038/msb4100170}, DOI={10.1038/msb4100170}, abstractNote={Article31 July 2007Open Access Increased glycolytic flux as an outcome of whole-genome duplication in yeast Gavin C Conant Corresponding Author Gavin C Conant Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin, Ireland Search for more papers by this author Kenneth H Wolfe Kenneth H Wolfe Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin, Ireland Search for more papers by this author Gavin C Conant Corresponding Author Gavin C Conant Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin, Ireland Search for more papers by this author Kenneth H Wolfe Kenneth H Wolfe Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin, Ireland Search for more papers by this author Author Information Gavin C Conant 1 and Kenneth H Wolfe1 1Smurfit Institute of Genetics, Trinity College, University of Dublin, Dublin, Ireland *Corresponding author. Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin 2, Ireland. Tel.: +353 1 896 1288; Fax: +353 1 679 8558; E-mail: conantg@tcd.ie Molecular Systems Biology (2007)3:129https://doi.org/10.1038/msb4100170 Correction(s) for this article Increased glycolytic flux as an outcome of whole-genome duplication in yeast01 July 2008 Synopsis Introduction Results Discussion AcknowledgementsSupporting InformationReferencesPDFDownload PDF of article text and main figures. Metrics108MetricsTotal downloads1,826Last 6 Months110Total citations108Last 6 Months3View all metrics ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info After whole-genome duplication (WGD), deletions return most loci to single copy. However, duplicate loci may survive through selection for increased dosage. Here, we show how the WGD increased copy number of some glycolytic genes could have conferred an almost immediate selective advantage to an ancestor of Saccharomyces cerevisiae, providing a rationale for the success of the WGD. We propose that the loss of other redundant genes throughout the genome resulted in incremental dosage increases for the surviving duplicated glycolytic genes. This increase gave post-WGD yeasts a growth advantage through rapid glucose fermentation; one of this lineage's many adaptations to glucose-rich environments. Our hypothesis is supported by data from enzyme kinetics and comparative genomics. Because changes in gene dosage follow directly from post-WGD deletions, dosage selection can confer an almost instantaneous benefit after WGD, unlike neofunctionalization or subfunctionalization, which require specific mutations. We also show theoretically that increased fermentative capacity is of greatest advantage when glucose resources are both large and dense, an observation potentially related to the appearance of angiosperms around the time of WGD. Synopsis Gene duplication has long been recognized as an important route to evolutionary novelty and increased organismal complexity. It has also been recognized that the different scales of possible duplications have the potential to generate differing kinds of novel adaptations. New proteins may evolve from single-gene duplications, while larger duplications, including WGDs, can, in addition, allow more global restructuring of regulatory or metabolic networks in the organism. We describe a potential example of such a global change after a WGD in the bakers’ yeast, S. cerevisiae. The pathway in question is one of the most central in eukaryotes: glycolysis. Our analysis was initially prompted by an apparently different pattern of duplicate gene loss in the glycolytic pathway after WGD, as compared to the remainder of the genome. After WGD, many duplicate genes were lost rapidly, such that, today, only 10% of the duplicates created by WGD survive in S. cerevisiae. However, we show that genes coding for enzymes in the glycolytic pathway are significantly more like to be retained in duplicate than genes in the genome at large (with approximately 45% of the genes in the pathway preserved). Moreover, those genes involved in glycolysis that were preserved in duplicate tend to have greater impact on flux than their non-duplicated counterparts, according to a mathematical model of glycolysis that we adapt. One potential explanation for this pattern of preservation in selection for gene dosage, whereby certain genes are maintained in duplicate because of a requirement for more copies of the proteins they code for. This possibility is of particular interest because it may relate to one of the more intriguing features of the physiology of bakers’ yeast. This yeast is unusual in that it prefers to ferment glucose to ethanol in the presence of oxygen rather than using the apparently more efficient respiratory pathways. Interestingly, several previous studies of fermentation in S. cerevisiae and related species have seemed to indicate a trend toward increased importance of fermentation around the time of the WGD. We argue that the WGD and consequent changes in glycolytic enzyme concentrations may first have increased the overall flux through glycolysis. Because a cell's rate of respiration depends on many complex factors, including the size and location of the mitochondria, the concentration of oxygen and the kinetics of the enzymes involved, we argue that WGD would have had a much less pronounced effect on the rate of respiration than on that of fermentation. Indeed, several mutant strains of yeast seem to support this hypothesis: reducing the concentration of glycolytic enzymes increases the relative importance of respiration, increasing these concentrations decreases its importance. Thus, we believe that the bakers’ yeast's preference for fermentation was enhanced by WGD. This possibility may seem counter-intuitive, given the greater efficiency (in terms of moles of ATP produced per mole of glucose) of respiration. However, we illustrate an example of the well-known phenomenon where a less efficient, but faster growing population has a competitive advantage over a more efficient one (the ‘tragedy of the commons’). This selective advantage may have even been the reason the WGD survived and became fixed, as its survival is otherwise difficult to explain. Thus, in addition to suggesting how an important physiological change in an organism can be wrought by a duplication, our example provides a plausible mechanism by which evolution can generate a complex new adaptation. Introduction Analyses of several yeast genomes have confirmed the presence of a whole-genome duplication (WGD) in the clade including the bakers' yeast Saccharomyces cerevisiae (Wolfe and Shields, 1997; Kellis et al, 2004). One of the most puzzling aspects of any WGD event is the question of what immediate selective advantage it conferred upon its possessor. Such an advantage would have been necessary to counteract the disadvantages of reproductive isolation (Grieg et al, 2002a, 2002b) and increased metabolic costs (Wagner, 2005; Gerstein et al, 2006) experienced by a post-WGD organism compared to its peers. Here, we try to place the genome duplication into the larger picture of the evolutionary history and ecology (Wagner, 2000; Hittinger et al, 2004) of this species. Several authors have speculated that WGD enhanced S. cerevisiae's ability to metabolize glucose (Wolfe and Shields, 1997; Wolfe, 2004; Liti and Louis, 2005) and/or to grow anaerobically (Kwast et al, 2002; Piškur and Langkjær, 2004; Piškur et al, 2006). We provide evidence that the preservation of some duplicate gene pairs created by the WGD was related to their contribution toward high glycolytic flux. We further consider the possibility that this selection was active soon after the WGD and may be the reason for its survival. In the presence of oxygen, most eukaryotes fully oxidize glucose to carbon dioxide and water using the TCA cycle, driving mitochondrial ATP synthesis with the accumulated reduced coenzymes. When oxygen is limited, a fermentative pathway is used instead, so that, in yeasts, glucose is converted to ethanol (Pronk et al, 1996). S. cerevisiae is unusual in that it prefers to ferment glucose into ethanol even in the presence of oxygen (the Crabtree effect; Geladé et al, 2003; Johnston and Kim, 2005), despite this pathway's energetic inefficiency. This phenotype is part of a suite of adaptations that allow S. cerevisiae to maintain very high growth rates when glucose is in excess (Piškur et al, 2006). On the basis of comparative genetics and genomics, some of these Crabtree-related adaptations can be dated to prior to the WGD and some to after it. For instance, the HAP4 gene in S. cerevisiae seems to have acquired a role in the regulation of respiration since the split with the non-WGD species Kluyveromyces lactis (Blom et al, 2000; Buschlen et al, 2003). The alcohol dehydrogenase genes ADH1 and ADH2 in S. cerevisiae are the product of a gene duplication also post-dating the WGD (Thomson et al, 2005). The two resulting gene products allow S. cerevisiae to efficiently use glucose through fermentation (Figure 1). The product of ADH1 is primarily responsible for producing ethanol from acetaldehyde, while ADH2's gene product is optimized to catalyze the reverse reaction (Thomson et al, 2005). Figure 1.Overview of three catabolic pathways in S. cerevisiae: glycolysis, alcohol fermentation and the TCA cycle. Enzymes catalyzing each reaction are illustrated by circled gene names. Single lines joining pairs of enzymes indicate paralogous genes. Enzymes joined by three lines indicate paralogous enzymes derived from whole-genome duplication. The WGD pairs shown in red are preserved in double copy in four extant yeast species: S. cerevisiae, S. bayanus, C. glabrata and S. castellii. Protein localization for the CIT, ADH and ALD genes is taken from Huh et al (2003). The multi-enzyme complex which constitutes PDH is illustrated by the darker blue enclosure. Download figure Download PowerPoint On the other hand, a regulatory circuit that represses pathways that metabolize other sugars when glucose is abundant is conserved in K. lactis. This circuit includes the MIG1 repressor (Dong and Dickson, 1997; Geladé et al, 2003) and the glucose-sensing proteins (RAG4 in K. lactis and SNF3 and RGT2 in S. cerevisiae) that initiate signal cascades that in turn alter gene expression in response to glucose (Özcan et al, 1996, 1998; Betina et al, 2001). SNF3 and RGT2 are WGD paralogs of each other and orthologous to RAG4 in K. lactis. Notably, the two S. cerevisiae paralogs appear to have undergone functional divergence since duplication, with the former signaling low glucose concentrations and the latter higher concentrations (Özcan et al, 1996, 1998). Of course the primary metabolic enzymes of glycolysis, fermentation and respiration are ancient and widely distributed in yeasts (Blank et al, 2005), and the ability to ferment glucose under anaerobic conditions also predates WGD (Visser et al, 1990; Møller et al, 2001). These observations suggest that the yeast lineage leading to S. cerevisiae has been characterized by a long period of natural selection for rapid growth on substrates such as glucose. Several lines of evidence suggest that WGD may have played a role in this selection. A survey of over 40 yeast species both with and without the WGD indicates that the ability to grow anaerobically on minimal media, the presence of a Crabtree effect and the ability to generate petite mutants are all strongly associated with yeasts possessing the WGD (Merico et al, 2007). Another study also found a general, though weak, trend for higher rates of ethanol production in post-WGD yeasts (e.g., Saccharomyces exiguus and Saccharomyces servazzii) than in non-WGD yeasts (Blank et al, 2005). There is also an excess of energy metabolism genes surviving in duplicate from this event (Kuepfer et al, 2005). In this paper we propose that the WGD had an important impact on gene dosage and that this dosage change had a knock-on effect on how the lineage of post-WGD yeasts (including S. cerevisiae) uses glucose. We propose three linked hypotheses relating glucose metabolism to the yeast WGD. First, we suggest that the loss of duplicate copies of other genes after WGD increased the concentrations of glycolytic enzymes (which survived in duplicate). Second, we propose that the inherent kinetics of fermentation and respiration meant that this increase in enzyme concentration gave rise to an increased preference for fermentation in the partially polyploid yeast. Finally, we propose that this yeast had a selective advantage because it was able to use glucose more rapidly than its ancestors and hence out-compete other yeasts when glucose was in excess. In the sections below, we briefly introduce each hypothesis in turn. Hypothesis 1—WGD followed by gene loss raised glycolytic enzyme concentrations To increase flux through a metabolic pathway is a challenging problem for natural selection. In general, a slow succession of changes in enzyme concentrations (due either to independent gene duplications or to independent changes in gene expression) will be required to increase flux, as (roughly speaking) one reaction after another becomes rate-limiting (Kacser and Burns, 1973). Given that natural selection favors microorganisms with higher growth rates and that gene expression in these organisms can evolve rapidly (Dekel and Alon, 2005), it is not surprising that a laboratory attempt to increase growth rates in S. cerevisiae by overexpression of a single enzyme (pyruvate decarboxylase) was unsuccessful (van Hoek et al, 1998a). It is instead more likely that any increase in the rate of cell division would require more global changes in gene expression such as those seen in experimental evolution studies (Ferea et al, 1999). Duplicate gene pairs produced by WGD have the potential to produce precisely these simultaneous changes in enzyme concentrations, an idea attributable to Ohno (1970). An association between reactions with high flux and an increased frequency of iso-enzymes formed by gene duplication has been found in yeast (Papp et al, 2004), suggesting that duplication can help organisms to adapt their metabolic fluxes. However, that study did not partition the duplicate genes considered into single-gene duplicates and duplicates produced by WGD. We argue that the process of genome shrinkage following WGD eventually led to a bias in the expression of glycolysis enzymes. In support of this contention, we note that several duplicated genes in S. cerevisiae today have been maintained for reasons of increased gene dosage (Seoighe and Wolfe, 1999; Koszul et al, 2004). We have also previously shown that soon after WGD there was a very rapid loss of duplicate genes (Scannell et al, 2006). It is reasonable to argue this process of gene loss resulted in changes in relative levels of protein expression as part of the cell's protein ‘energy budget’ was redirected to the surviving duplicates. Hypothesis 2—higher enzyme concentrations increased the relative flux through fermentation If changes in relative gene dosages were able to increase flux through glycolysis, why was the result not simply an overall increase in metabolic rate? We propose that the fermentative and respiratory pathways responded differently to such changes. There are several reasons to think that changes in enzyme concentration should have relatively little impact on respiratory flux. First, respiration depends on the concentration of oxygen in the cell, which, unlike glucose, is difficult or impossible for the cell to alter. Second, because the copy number of the mitochondrial genome is unlikely to have been affected by the WGD, some respiratory proteins would not have seen an increase in concentration. Third, spatial factors such as the number and location of mitochondria may constrain the rate of respiration, as seen in studies of metabolic scaling (West et al, 1999). Although the fact that glycolytic enzymes are observed in association with the mitochondrial surface suggests that spatial constraints also affect glycolysis, not all copies of the requisite enzymes are so localized (Brandina et al, 2006), meaning that this constraint should be weaker for glycolysis than for respiration. Thus, increased dosage from such enzymes may generally increase their dissolved concentration and allow them to route increased flux. Indeed, computational analysis supports a role for increased dosage from duplicates for several reactions in glycolysis (Kuepfer et al, 2005). Glycolytic genes also increase in expression under anaerobic growth relative to aerobic growth in S. cerevisiae (Kwast et al, 2002), presumably because their concentrations are not rate-limiting under respiratory conditions. Moreover, experiments that simultaneously overexpressed several enzymes in the lower half of the glycolytic chain and in the fermentative pathway yielded yeast cells with higher fermentative rates (Smits et al, 2000). Finally, S. cerevisiae strains with mutations in the GCR1 and GCR2 transcription factors show both lowered expression of glycolytic genes and increased reliance on respiratory reactions (Sasaki and Uemura, 2005). Collectively, these points suggest that respiration and fermentation scale differently in yeast. It might seem surprising that the fermentation enzymes would be in place to route additional flux after an increase in the rate of glycolysis and the consequent saturation of the respiratory apparatus. However, Zeeman et al (1998) found that K. lactis will ferment aerobically after an artificial block of the respiratory apparatus. It thus appears that even before WGD, yeast species may have had some ability to use alcohol fermentation as an overflow pathway, a principle suggested by Käppelli (1986). At least part of S. cerevisiae's preference for fermentation is due to differences in the enzymes at the branch point between respiration and fermentation. Pyruvate decarboxylase (PDC) is the first step in fermentation, while pyruvate dehydrogenase (PDH, a multicomponent enzyme including PDA1, PDB1, LAT1 and LDP1 in Figure 1) converts pyruvate to acetyl-Coenzyme A as the first step in respiration. These two reactions, which compete for pyruvate as a substrate, differ in their kinetics. The concentration of pyruvate that gives half-maximal activity (Km) of PDH is lower than that for PDC (Kresze and Ronfit, 1981; van Urk et al, 1989). Moreover, PDC exhibits cooperativity (super linear scaling of reaction rate with substrate concentration; Boiteux and Hess, 1970; Hübner et al, 1978) with respect to pyruvate, and the maximal activity of PDC is greater than of PDH (van Urk et al, 1989; Pronk et al, 1996). The net result is to make flux through PDH favored at low pyruvate concentrations and flux through PDC favored at higher ones (Pronk et al, 1996). Thus, for S. cerevisiae, a more rapid rate of glucose consumption should be associated with the routing of an increased proportion of the resulting pyruvate into fermentation as opposed to respiration. Hypothesis 3—increased fermentation rate conferred a selective advantage The first two hypotheses do not themselves suggest that any particular changes in gene dosage were advantageous to the ancestors of S. cerevisiae. However, it is plausible that the appearance of fruit-bearing angiosperms opened an ecological niche to which yeasts such as S. cerevisiae were particularly well adapted due to their ability to consume glucose rapidly through fermentation (Ashburner, 1998; Piškur and Langkjær, 2004). Note that this advantage exists in spite of the fact that fermentation yields less ATP per gram of glucose than does respiration. Glucose resources are susceptible to a ‘tragedy of the commons’ often seen in competitive situations. In particular, when multiple genotypes compete for glucose, organisms with fast, inefficient metabolism are at a selective advantage relative to their more efficient but slower-growing competitors (Pfeiffer et al, 2001; Pfeiffer and Schuster, 2005; MacLean and Gudelj, 2006). Results The above hypotheses led us to examine the genome sequence and metabolic data available for S. cerevisiae and some of its close relatives to see if they showed evidence of selection for such metabolic changes. Hypothesis 1A—number of glycolytic genes retained in duplicate since WGD As previously described, it is possible to identify gene duplicates that owe their existence to the WGD by showing that a pair of duplicates lie in paired regions of shared gene order, as inferred by comparing that genome to those of yeast species without the genome duplication (Byrne and Wolfe, 2005). In Figure 1 we find that, of the 10 reactions of glycolysis, five of them maintain WGD duplicates in S. cerevisiae (two duplicate pairs in the case of the first reaction) and moreover that five of these six duplicate gene pairs (excluding the pair GPM2/GPM3) are preserved across four species examined (Saccharomyces cerevisiae, Saccharomyces bayanus, Candida glabrata and Saccharomyces castellii; Byrne and Wolfe, 2005). Given that 551 duplicate gene pairs have survived in S. cerevisiae since genome duplication, one can ask what the chances are that six such pairs would appear in a group of thirteen enzymes (including the ancient duplicate hexokinase, phosphoglycerate mutase and phosphofructokinase enzymes; Figure 1). The hypothesis that the glycolysis genes were preserved in duplicate at the same frequency as the reminder of the genome is rejected by Fisher's exact test (P=0.0014), in agreement with the excess of energy metabolism duplicate genes in S. cerevisiae previously seen (Conant and Wagner, 2002; Kuepfer et al, 2005). Moreover, given that 239 of the 551 S. cerevisiae duplicate pairs are also duplicated in the other three WGD species (taken from Byrne and Wolfe, 2005), we can ask what would be the chance of seeing as many duplicates preserved across all four species as are seen in glycolysis if that pathway were to follow the pattern of the remainder of the genome. Given than the proportion of WGD duplicate genes in S. cerevisiae that are also preserved in the other three species excluding glycolytic duplicates is (239–5)/(551–6)=0.43, the probability of seeing five or more duplicates preserved in glycolysis is P=0.056 by a binomial test. One could argue that these results simply reflect an overall preference for retaining duplicate genes of a particular functional class after WGD. To test this possibility, we retrieved all S. cerevisiae genes classified in Gene Ontology (The Gene Ontology Consortium, 2000) as being involved in the biological process ‘catabolism’. We compared the proportion of surviving WGD duplicates in this category excluding glycolysis enzymes to the proportion surviving among the glycolysis enzymes. Significantly more duplicates survive among the glycolytic enzymes (P=0.004, Fisher's exact test, see Supplementary methods for details). Hypothesis 1B—distribution of hexose transporters Pritchard and Kell (2002) have shown that hexose transport is the major rate-limiting step in glycolysis. Supporting this observation, Otterstedt et al (2004) found that an S. cerevisiae strain with very limited capacity to transport hexoses does not show a Crabtree effect and under aerobic conditions only respires. Moreover, yeast cells grown in conditions of glucose limitation have been observed to undergo spontaneous duplication of hexose transporters (Brown et al, 1998). This observation implies that the duplication of transporters confers a selective advantage in environments that are otherwise able to support higher growth rates but for which the cells are operating near their maximal glucose uptake rates. If the WGD was fixed in the population in order to allow increased flux through glycolysis, it follows that hexose transport should occur at higher rates in the post-WGD species. Given the lack of experimental data from many of the species studied here, we cannot make a quantitative comparison of hexose transport rates between post-WGD and non-WGD yeasts. However, as a first approximation, we examined the number of hexose transporter genes in these genomes (Table I; see Supplementary methods for details). In agreement with our hypothesis, all of the post-WGD species have at least twice as many hexose transporter genes as the three non-WGD species. Note that this difference is only partially due to WGD—S. cerevisiae in particular has several tandemly duplicated transporters that post-date the WGD (data not shown)—and probably reflects ongoing selection for increased rates of transport. Table 1. Number of hexose transport gene paralogs in five species of yeast Species Has WGD? Number of hexose transport genes S. cerevisiae Yes 18 S. bayanusa Yes 16 C. glabrata Yes 11 S. castelliib Yes 14 K. lactis No 2 S. kluyveri No 5 E. gosspyii No 5 a One identified Saccharomyces bayanus hexose transporter could not be aligned by GenomeHistory, and is hence omitted from this row. b Three sequences from Saccharomyces castellii could not be aligned by GenomeHistory, and are hence omitted from this row. Hypothesis 2A—effects of enzyme concentration changes on the relative fluxes through fermentation and respiration If our first hypothesis is correct, the yeast ancestor that existed at the time of WGD had lower concentrations of glycolytic enzymes than does the modern S. cerevisiae. To gain insight into how altered enzyme concentrations might change the patterns of carbon flux, we used previously published models of S. cerevisiae metabolism (Teusink et al, 2000; Pritchard and Kell, 2002) with the Jarnac/Jdesigner package (Sauro et al, 2003). We first considered the change in metabolic steady state concentrations that might have resulted from duplication. To a first approximation, reaction rates for an enzyme catalyzed reaction depend on two enzyme-specific parameters: Km, the substrate concentration that gives a half maximal reaction rate, which is essentially independent of enzyme concentration, and Vmax, the maximal reaction velocity. Vmax depends on factors such as the activation energy of the reaction and the concentration of the catalyzing enzyme. We modeled the effects of WGD on glycolysis by representing the implied ancestral enzyme concentrations for glycolysis and alcohol fermentation as uniform reductions in their Vmax values. As enzyme concentrations increase from 65 to 100% of their current levels (see Supplementary methods), the concentration of several metabolic intermediates increases, with pyruvate showing a 17% increase in concentration (Figure 2A). Perhaps even more significantly, the flux through the final reaction in glycolysis (i.e., pyruvate kinase, CDC19 and PYK2 in Figure 1) increases by a factor of two across the range of enzyme concentrations considered (red line in Figure 2A). Figure 2.(A) Changes in the concentration of key metabolites in response to overall decreases in the Vmax values for the reactions of glycolysis (blue, left axis scale), as well as the change in PYK flux over the same range (red, right axis scale). (B) Ratio of the flux through pyruvate decarboxylase (PDC, fermentative pathways) to the flux through pyruvate dehydrogenase (PDH, respiratory pathway) as a function of pyruvate concentration and the ratio of NAD+ to NADH concentration (because NAD+ and NADH are two oxidation states of the same molecule, their concentrations vary inversely and hence are constrained to sum to 8.01 in B; Theobald et al, 1997). (C) Effect of compartmentalization on the relative fluxes of the first reaction in respiration (PDH) and in fermentation (PDC). On the x-axis is the relative enzyme concentration modeling a change from a rough pre-duplication state of 0.65 to a post-duplicate value of 1.0 (see A). On the y-axis is given the ratio of the fluxes between the two reactions relative to the flux when [E] on the x-axis is equal to 1.0. Download figure Download PowerPoint We next studied the effect that changes in pyruvate concentration have on the competing reactions PDC and PDH, given the differing kinetics of these two enzymes (see Supplementary methods). Figure 2B shows the ratio of PDC flux over PDH flux. We plot the dependence of this ratio on the concentration of pyruvate and on the ratio of NAD+ to NADH in the mitochondria. Note that we are concerned here with how the inherent kinetics of these two enzymes differ: the relative contours of Figure 2B are independent of the actual concentrations of the two enzymes (so although those concentrations can be changed by regulatory interactions not included in our analysis, the relative behavior of the two enzymes cannot be so easily altered). Increasing the pyruvate concentration increases relative flux through PDC. In principle, this effect could be counteracted by the increased ratio of cytosolic NAD+ to NADH that is also seen when glycolytic enzyme concentrations increase (the slight increase in NAD+ concentration shown in Figure 2A as Vmax increases is matched by an equal decrease in the concentration of NADH). However, this counter effect is probably quite weak, both because the increase in NAD+ concentration seen is small and because the mitochondrial and cytosolic concentrations of these cofactors may not be in equilibrium (Bunoust et al, 2005). Hypothesis 2B—compartmentalization of respiration Alcoholic fermentation takes place in the cytosol, whereas respiration is carried out exclusively in the mitochondria of yeast cells. As a result, the ratio of the surface area of mitochondria}, number={1}, journal={Molecular Systems Biology}, publisher={EMBO}, author={Conant, Gavin C and Wolfe, Kenneth H}, year={2007}, month={Jan}, pages={129} }
 @article{scannell_frank_conant_byrne_woolfit_wolfe_2007, title={Independent sorting-out of thousands of duplicated gene pairs in two yeast species descended from a whole-genome duplication}, volume={104}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-34347209089&partnerID=MN8TOARS}, DOI={10.1073/pnas.0608218104}, abstractNote={
            Among yeasts that underwent whole-genome duplication (WGD),
            Kluyveromyces polysporus
            represents the lineage most distant from
            Saccharomyces cerevisiae
            . By sequencing the
            K. polysporus
            genome and comparing it with the
            S. cerevisiae
            genome using a likelihood model of gene loss, we show that these species diverged very soon after the WGD, when their common ancestor contained >9,000 genes. The two genomes subsequently converged onto similar current sizes (5,600 protein-coding genes each) and independently retained sets of duplicated genes that are strikingly similar. Almost half of their surviving single-copy genes are not orthologs but paralogs formed by WGD, as would be expected if most gene pairs were resolved independently. In addition, by comparing the pattern of gene loss among
            K. polysporus
            ,
            S. cerevisiae
            , and three other yeasts that diverged after the WGD, we show that the patterns of gene loss changed over time. Initially, both members of a duplicate pair were equally likely to be lost, but loss of the same gene copy in independent lineages was increasingly favored at later time points. This trend parallels an increasing restriction of reciprocal gene loss to more slowly evolving gene pairs over time and suggests that, as duplicate genes diverged, one gene copy became favored over the other. The apparent low initial sequence divergence of the gene pairs leads us to propose that the yeast WGD was probably an autopolyploidization.
          }, number={20}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Scannell, D.R. and Frank, A.C. and Conant, G.C. and Byrne, K.P. and Woolfit, M. and Wolfe, K.H.}, year={2007}, pages={8397–8402} }
 @article{conant_wagner_stadler_2007, title={Modeling amino acid substitution patterns in orthologous and paralogous genes}, volume={42}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-33750992513&partnerID=MN8TOARS}, DOI={10.1016/j.ympev.2006.07.006}, abstractNote={We study to what degree patterns of amino acid substitution vary between genes using two models of protein-coding gene evolution. The first divides the amino acids into groups, with one substitution rate for pairs of residues in the same group and a second for those in differing groups. Unlike previous applications of this model, the groups themselves are estimated from data by simulated annealing. The second model makes substitution rates a function of the physical and chemical similarity between two residues. Because we model the evolution of coding DNA sequences as opposed to protein sequences, artifacts arising from the differing numbers of nucleotide substitutions required to bring about various amino acid substitutions are avoided. Using 10 alignments of related sequences (five of orthologous genes and five gene families), we do find differences in substitution patterns. We also find that, although patterns of amino acid substitution vary temporally within the history of a gene, variation is not greater in paralogous than in orthologous genes. Improved understanding of such gene-specific variation in substitution patterns may have implications for applications such as sequence alignment and phylogenetic inference.}, number={2}, journal={Molecular Phylogenetics and Evolution}, author={Conant, G.C. and Wagner, G.P. and Stadler, P.F.}, year={2007}, pages={298–307} }
 @article{conant_wolfe_2006, title={Functional Partitioning of Yeast Co-Expression Networks after Genome Duplication}, volume={4}, ISSN={1545-7885}, url={http://dx.doi.org/10.1371/journal.pbio.0040109}, DOI={10.1371/journal.pbio.0040109}, abstractNote={Several species of yeast, including the baker's yeast Saccharomyces cerevisiae, underwent a genome duplication roughly 100 million years ago. We analyze genetic networks whose members were involved in this duplication. Many networks show detectable redundancy and strong asymmetry in their interactions. For networks of co-expressed genes, we find evidence for network partitioning whereby the paralogs appear to have formed two relatively independent subnetworks from the ancestral network. We simulate the degeneration of networks after duplication and find that a model wherein the rate of interaction loss depends on the “neighborliness” of the interacting genes produces networks with parameters similar to those seen in the real partitioned networks. We propose that the rationalization of network structure through the loss of pair-wise gene interactions after genome duplication provides a mechanism for the creation of semi-independent daughter networks through the division of ancestral functions between these daughter networks.}, number={4}, journal={PLoS Biology}, publisher={Public Library of Science (PLoS)}, author={Conant, Gavin C and Wolfe, Kenneth H}, editor={Hurst, LaurenceEditor}, year={2006}, month={Apr}, pages={e109} }
 @article{conant_wagner_2005, title={The rarity of gene shuffling in conserved genes.}, volume={6}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-33646556197&partnerID=MN8TOARS}, number={6}, journal={Genome biology}, author={Conant, G.C. and Wagner, A.}, year={2005} }
 @article{conant_wagner_2004, title={A fast algorithm for determining the best combination of local alignments to a query sequence}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-2942580944&partnerID=MN8TOARS}, DOI={10.1186/1471-2105-5-62}, abstractNote={Existing sequence alignment algorithms assume that similarities between DNA or amino acid sequences are linearly ordered. That is, stretches of similar nucleotides or amino acids are in the same order in both sequences. Recombination perturbs this order. An algorithm that can reconstruct sequence similarity despite rearrangement would be helpful for reconstructing the evolutionary history of recombined sequences.We propose a graph-based algorithm for combining multiple local alignments to a query sequence into the single combination of alignments that either covers the maximal portion of the query or results in the single highest alignment score to the query. This algorithm can help study the process of genome rearrangement, improve functional gene annotation, and reconstruct the evolutionary history of recombined proteins. The algorithm takes O(n2) time, where n is the number of local alignments considered.We discuss two example applications of the algorithm. The algorithm is able to provide useful reconstructions of the metazoan mitochondrial genome. It is also able to increase the percentage of a query sequence's amino acid residues for which similar stretches of amino acids can be found in sequence databases.}, journal={BMC Bioinformatics}, author={Conant, G.C. and Wagner, A.}, year={2004} }
 @book{babu_conant_eller_roberts_gowan_eisenbarth_fain_vardi_2004, title={A second-generation genome screen for linkage to type 1 diabetes in a Bedouin Arab family}, volume={1037}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-14544275567&partnerID=MN8TOARS}, DOI={10.1196/annals.1337.026}, abstractNote={Abstract:  IDDM17 on chromosome 10 was identified in an initial genome screen of 13 members (10 affected) of a large Bedouin Arab family that had 19 relatives affected with type 1 diabetes. Two more children have now been diagnosed with the disease. A second genome screen with 45 members (17 affected members, spouses, and offspring; 382 markers) was performed. A parallel version of Genehunter was used for parametric and nonparametric linkage analyses. The nonparametric linkage analysis (NPL) confirmed the IDDM17 locus (NPL = 3.79; P= 0.001) with a prominent LOD (logarithm of the odds = 2.38) peak. These results demonstrate the strong potential of genetically homogenous, extended families for mapping genes that contribute to a complex disease.}, journal={Annals of the New York Academy of Sciences}, author={Babu, S.R. and Conant, G.C. and Eller, E. and Roberts, C.M. and Gowan, K. and Eisenbarth, G.S. and Fain, P.R. and Vardi, P.}, year={2004}, pages={157–160} }
 @article{conant_wagner_2004, title={Duplicate genes and robustness to transient gene knock-downs in
            Caenorhabditis elegans}, volume={271}, ISSN={0962-8452 1471-2954}, url={http://dx.doi.org/10.1098/rspb.2003.2560}, DOI={10.1098/rspb.2003.2560}, abstractNote={We examine robustness to mutations in the nematode worm Caenorhabditis elegans and the role of single‐copy and duplicate genes in it. We do so by integrating complete genome sequence and microarray gene expression data with results from a genome‐scale study using RNA interference (RNAi) to temporarily eliminate the functions of more than 16 000 worm genes. We found that 89% of single‐copy and 96% of duplicate genes show no detectable phenotypic effect in an RNAi knock‐down experiment. We find that mutational robustness is greatest for closely related gene duplicates, large gene families and similarly expressed genes. We discuss the different causes of mutational robustness in single‐copy and duplicate genes, as well as its evolutionary origin.}, number={1534}, journal={Proceedings of the Royal Society of London. Series B: Biological Sciences}, publisher={The Royal Society}, author={Conant, Gavin C and Wagner, Andreas}, year={2004}, month={Jan}, pages={89–96} }
 @article{hahn_conant_wagner_2004, title={Molecular Evolution in Large Genetic Networks: Does Connectivity Equal Constraint?}, volume={58}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0842290925&partnerID=MN8TOARS}, DOI={10.1007/s00239-003-2544-0}, abstractNote={Genetic networks show a broad-tailed distribution of the number of interaction partners per protein, which is consistent with a power-law. It has been proposed that such broad-tailed distributions are observed because they confer robustness against mutations to the network. We evaluate this hypothesis for two genetic networks, that of the E. coli core intermediary metabolism and that of the yeast protein-interaction network. Specifically, we test the hypothesis through one of its key predictions: highly connected proteins should be more important to the cell and, thus, subject to more severe selective and evolutionary constraints. We find, however, that no correlation between highly connected proteins and evolutionary rate exists in the E. coli metabolic network and that there is only a weak correlation in the yeast protein-interaction network. Furthermore, we show that the observed correlation is function-specific within the protein-interaction network: only genes involved in the cell cycle and transcription show significant correlations. Our work sheds light on conflicting results by previous researchers by comparing data from multiple types of protein-interaction datasets and by using a closely related species as a reference taxon. The finding that highly connected proteins can tolerate just as many amino acid substitutions as other proteins leads us to conclude that power-laws in cellular networks do not reflect selection for mutational robustness.}, number={2}, journal={Journal of Molecular Evolution}, author={Hahn, M.W. and Conant, G.C. and Wagner, A.}, year={2004}, pages={203–211} }
 @article{conant_wagner_2003, title={Asymmetric sequence divergence of duplicate genes}, volume={13}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0141853996&partnerID=MN8TOARS}, DOI={10.1101/gr.1252603}, abstractNote={Much like humans, gene duplicates may be created equal, but they do not  stay that way for long. For four completely sequenced genomes we show that  20%–30% of duplicate gene pairs show asymmetric evolution in the amino  acid sequence of their protein products. That is, one of the duplicates  evolves much faster than the other. The greater this asymmetry, the greater  the ratio Ka/Ks of amino acid substitutions  (Ka) to silent substitutions (Ks) in a gene pair. This  indicates that most asymmetric divergence may be caused by relaxed selective  constraints on one of the duplicates. However, we also find some candidate  duplicates where positive (directional) selection of beneficial mutations  (Ka/Ks > 1) may play a role in asymmetric divergence.  Our analysis rests on a codon-based model of molecular evolution that allows a  test for asymmetric divergence in Ka. The method is also more  sensitive in detecting positive selection (Ka/Ks > 1)  than models relying only on pairwise gene comparisons.}, number={9}, journal={Genome Research}, author={Conant, G.C. and Wagner, A.}, year={2003}, pages={2052–2058} }
 @article{conant_wagner_2003, title={Convergent evolution of gene circuits}, volume={34}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0037743679&partnerID=MN8TOARS}, DOI={10.1038/ng1181}, abstractNote={Convergent evolution is a potent indicator of optimal design. We show here that convergent evolution occurs in genetic networks. Specifically, we show that multiple types of transcriptional regulation circuitry in Escherichia coli and the yeast Saccharomyces cerevisiae have evolved independently and not by duplication of one or a few ancestral circuits.}, number={3}, journal={Nature Genetics}, author={Conant, G.C. and Wagner, A.}, year={2003}, pages={264–266} }
 @article{conant_plimpton_old_wagner_fain_pacheco_heffelfinger_2003, title={Parallel genehunter: Implementation of linkage analysis package for distributed-memory architectures}, volume={63}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0142042382&partnerID=MN8TOARS}, DOI={10.1016/S0743-7315(03)00080-7}, abstractNote={We present a parallel algorithm for performing multipoint linkage analysis of genetic marker data on large family pedigrees. The algorithm effectively distributes both the computation and memory requirements of the analysis. We discuss an implementation of the algorithm in the Genehunter linkage analysis package (version 2.1), enabling Genehunter to run on distributed-memory platforms for the first time. Our preliminary benchmarks indicate reasonable scalability of the algorithm even for fixed-size problems, with parallel efficiencies of 75% or more on up to 128 processors. In addition, we have extended the hard-coded limit of 16 non-founding individuals in Genehunter 2.1 to a new limit of 32 non-founding individuals.}, number={7-8}, journal={Journal of Parallel and Distributed Computing}, author={Conant, G.C. and Plimpton, S.J. and Old, W. and Wagner, A. and Fain, P.R. and Pacheco, T.R. and Heffelfinger, G.}, year={2003}, pages={674–682} }
 @article{conant_wagner_2002, title={GenomeHistory: A software tool and its application to fully sequenced genomes}, volume={30}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0036682357&partnerID=MN8TOARS}, number={15}, journal={Nucleic Acids Research}, author={Conant, G.C. and Wagner, A.}, year={2002}, pages={3378–3386} }
 @inproceedings{conant_plimpton_old_wagner_fain_heffelfinger_2002, title={Parallel genehunter: Implementation of a linkage analysis package for distributed-memory architectures}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84966632851&partnerID=MN8TOARS}, DOI={10.1109/IPDPS.2002.1016586}, abstractNote={We present a parallel algorithm for performing multipoint linkage analysis of genetic marker data on large family pedigrees. The algorithm effectively distributes both the computation and memory requirements of the analysis. We discuss an implementation of the algorithm in the Genehunter linkage analysis package (version 2.1), enabling Genehunter to be run on distributed memory platforms for the first time. Our preliminary benchmarks indicate reasonable scalability of the algorithm for even small fixed-size problems, with parallel efficiencies of 75% or more on up to a few dozen processors.}, booktitle={Proceedings - International Parallel and Distributed Processing Symposium, IPDPS 2002}, author={Conant, G. and Plimpton, S. and Old, W. and Wagner, A. and Fain, P. and Heffelfinger, G.}, year={2002}, pages={184–191} }
 @article{conant_lewis_2001, title={Effects of nucleotide composition bias on the success of the parsimony criterion in phylogenetic inference}, volume={18}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-0034983477&partnerID=MN8TOARS}, number={6}, journal={Molecular Biology and Evolution}, author={Conant, G.C. and Lewis, P.O.}, year={2001}, pages={1024–1033} }