@article{guo_tsai_hardison_james_motsinger-reif_thames_stone_deng_piedrahita_2013, title={Differentially expressed microRNAs and affected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas}, volume={34}, ISSN={0143-4004}, url={http://dx.doi.org/10.1016/j.placenta.2013.04.007}, DOI={10.1016/j.placenta.2013.04.007}, abstractNote={This study focuses on the implementation of modulated modularity clustering (MMC) a new cluster algorithm for the identification of molecular signatures of preeclampsia and intrauterine growth restriction (IUGR), and the identification of affected microRNAs Eighty-six human placentas from normal (40), growth-restricted (27), and preeclamptic (19) term pregnancies were profiled using Illumina Human-6 Beadarrays. MMC was utilized to generate modules based on similarities in placental transcriptome. Gene Set Enrichment Analysis (GSEA) was used to predict affected microRNAs. Expression levels of these candidate microRNAs were investigated in seventy-one human term placentas as follows: control (29); IUGR (26); and preeclampsia (16). MMC identified two modules, one representing IUGR placentas and one representing preeclamptic placentas. 326 differentially expressed genes in the module representing IUGR and 889 differentially expressed genes in a module representing preeclampsia were identified. Functional analysis of molecular signatures associated with IUGR identified P13K/AKT, mTOR, p70S6K, apoptosis and IGF-1 signaling as being affected. Analysis of variance of GSEA-predicted microRNAs indicated that miR-194 was significantly down-regulated both in preeclampsia (p = 0.0001) and IUGR (p = 0.0304), and miR-149 was significantly down-regulated in preeclampsia (p = 0.0168). Implementation of MMC, allowed identification of genes disregulated in IUGR and preeclampsia. The reliability of MMC was validated by comparing to previous linear modeling analysis of preeclamptic placentas. MMC allowed the elucidation of a molecular signature associated with preeclampsia and a subset of IUGR samples. This allowed the identification of genes, pathways, and microRNAs affected in these diseases.}, number={7}, journal={Placenta}, publisher={Elsevier BV}, author={Guo, L. and Tsai, S.Q. and Hardison, N.E. and James, A.H. and Motsinger-Reif, A.A. and Thames, B. and Stone, E.A. and Deng, C. and Piedrahita, J.A.}, year={2013}, month={Jul}, pages={599–605} } @article{watson_hardison_harris_motsinger-reif_mcleod_2011, title={Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines}, volume={10}, ISSN={["1535-7163"]}, DOI={10.1158/1535-7163.mct-10-0872}, abstractNote={Abstract We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines. Mol Cancer Ther; 10(10); 1839–45. ©2011 AACR.}, number={10}, journal={MOLECULAR CANCER THERAPEUTICS}, author={Watson, Venita Gresham and Hardison, Nicholas E. and Harris, Tyndall and Motsinger-Reif, Alison and McLeod, Howard L.}, year={2011}, month={Oct}, pages={1839–1845} } @article{watson_motsinger-reif_hardison_peters_havener_everitt_auman_comins_mcleod_2011, title={Identification and replication of loci involved in camptothecin-induced cytotoxicity using CEPH pedigrees}, volume={6}, number={5}, journal={PLoS One}, author={Watson, V. G. and Motsinger-Reif, A. and Hardison, N. E. and Peters, E. J. and Havener, T. M. and Everitt, L. and Auman, J. T. and Comins, D. L. and McLeod, H. L.}, year={2011} } @article{peters_motsinger-reif_havener_everitt_hardison_watson_wagner_richards_province_mcleod_2011, title={Pharmacogenomic characterization of US FDA-approved cytotoxic drugs}, volume={12}, ISSN={["1462-2416"]}, DOI={10.2217/pgs.11.92}, abstractNote={ Aims: Individualization of cancer chemotherapy based on the patient’s genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown. Materials & methods: In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families. Results: The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of <0.15 for gemcitabine to >0.60 for epirubicin. Conclusion: Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation. Original submitted 6 April 2011; Revision submitted 1 July 2011 }, number={10}, journal={PHARMACOGENOMICS}, author={Peters, Eric J. and Motsinger-Reif, Alison and Havener, Tammy M. and Everitt, Lorraine and Hardison, Nicholas E. and Watson, Venita G. and Wagner, Michael and Richards, Kristy L. and Province, Mike A. and McLeod, Howard L.}, year={2011}, month={Oct}, pages={1407–1415} } @article{tsai_hardison_james_motsinger-reif_bischoff_thames_piedrahita_2011, title={Transcriptional profiling of human placentas from pregnancies complicated by preeclampsia reveals disregulation of sialic acid acetylesterase and immune signalling pathways}, volume={32}, ISSN={["1532-3102"]}, DOI={10.1016/j.placenta.2010.11.014}, abstractNote={The placenta plays an important role as a regulator of fetal nutrition and growth throughout development and placental factors contribute to gestational abnormalities such as preeclampsia. This study describes the genome-wide gene expression profiles of a large (n = 60) set of human placentas in order to uncover gene expression patterns associated with preeclampsia. In addition to confirming changes in expression of soluble factors associated with preeclampsia such as sFLT1 (soluble fms-like tyrosine kinase-1), sENG (soluble endoglin), and INHA (inhibin alpha), we also find changes in immune-associated signaling pathways, offering a potential upstream explanation for the shallow trophoblast invasion and inadequate uterine remodeling typically observed in pathogenesis of preeclampsia. Notably, we also find evidence of preeclampsia-associated placental upregulation of sialic acid acetylesterase (SIAE), a gene functionally associated with autoimmune diseases.}, number={2}, journal={PLACENTA}, author={Tsai, S. and Hardison, N. E. and James, A. H. and Motsinger-Reif, A. A. and Bischoff, S. R. and Thames, B. H. and Piedrahita, J. A.}, year={2011}, month={Feb}, pages={175–182} } @article{bischoff_tsai_hardison_motsinger-reif_freking_nonneman_rohrer_piedrahita_2009, title={Characterization of Conserved and Nonconserved Imprinted Genes in Swine}, volume={81}, ISSN={["1529-7268"]}, DOI={10.1095/biolreprod.109.078139}, abstractNote={To increase our understanding of imprinted genes in swine, we carried out a comprehensive analysis of this gene family using two complementary approaches: expression and phenotypic profiling of parthenogenetic fetuses, and analysis of imprinting by pyrosequencing. The parthenote placenta and fetus were smaller than those of controls but had no obvious morphological differences at Day 28 of gestation. By Day 30, however, the parthenote placentas had decreased chorioallantoic folding, decreased chorionic ruggae, and reduction of fetal-maternal interface surface in comparison with stage-matched control fetuses. Using Affymetrix Porcine GeneChip microarrays and/or semiquantitative PCR, brain, fibroblast, liver, and placenta of Day 30 fetuses were profiled, and 25 imprinted genes were identified as differentially expressed in at least one of the four tissue types: AMPD3, CDKN1C, COPG2, DHCR7, DIRAS3, IGF2 (isoform specific), IGF2AS, IGF2R, MEG3, MEST, NAP1L5, NDN, NNAT, OSBPL1A, PEG3, APEG3, PEG10, PLAGL1, PON2, PPP1R9A, SGCE, SLC38A4, SNORD107, SNRPN, and TFPI2. For DIRAS3, PLAGL1, SGCE, and SLC38A4, tissue-specific differences were detected. In addition, we examined the imprinting status of candidate genes by quantitative allelic pyrosequencing. Samples were collected from Day 30 pregnancies generated from reciprocal crosses of Meishan and White Composite breeds, and single-nucleotide polymorphisms were identified in candidate genes. Imprinting was confirmed for DIRAS3, DLK1, H19, IGF2AS, NNAT, MEST, PEG10, PHLDA2, PLAGL1, SGCE, and SNORD107. We also found no evidence of imprinting in ASB4, ASCL2, CD81, COMMD1, DCN, DLX5, and H13. Combined, these results represent the most comprehensive survey of imprinted genes in swine to date.}, number={5}, journal={BIOLOGY OF REPRODUCTION}, author={Bischoff, Steve R. and Tsai, Shengdar and Hardison, Nicholas and Motsinger-Reif, Alison A. and Freking, Brad A. and Nonneman, Dan and Rohrer, Gary and Piedrahita, Jorge A.}, year={2009}, month={Nov}, pages={906–920} } @article{bischoff_tsai_hardison_york_freking_nonneman_rohrer_piedrahita_2008, title={Identification of SNPs and INDELS in swine transcribed sequences using short oligonucleotide microarrays}, volume={9}, ISSN={1471-2164}, url={http://dx.doi.org/10.1186/1471-2164-9-252}, DOI={10.1186/1471-2164-9-252}, abstractNote={Abstract Background Genome-wide detection of single feature polymorphisms (SFP) in swine using transcriptome profiling of day 25 placental RNA by contrasting probe intensities from either Meishan or an occidental composite breed with Affymetrix porcine microarrays is presented. A linear mixed model analysis was used to identify significant breed-by-probe interactions. Results Gene specific linear mixed models were fit to each of the log2 transformed probe intensities on these arrays, using fixed effects for breed, probe, breed-by-probe interaction, and a random effect for array. After surveying the day 25 placental transcriptome, 857 probes with a q-value ≤ 0.05 and |fold change| ≥ 2 for the breed-by-probe interaction were identified as candidates containing SFP. To address the quality of the bioinformatics approach, universal pyrosequencing assays were designed from Affymetrix exemplar sequences to independently assess polymorphisms within a subset of probes for validation. Additionally probes were randomly selected for sequencing to determine an unbiased confirmation rate. In most cases, the 25-mer probe sequence printed on the microarray diverged from Meishan, not occidental crosses. This analysis was used to define a set of highly reliable predicted SFPs according to their probability scores. Conclusion By applying a SFP detection method to two mammalian breeds for the first time, we detected transition and transversion single nucleotide polymorphisms, as well as insertions/deletions which can be used to rapidly develop markers for genetic mapping and association analysis in species where high density genotyping platforms are otherwise unavailable. SNPs and INDELS discovered by this approach have been publicly deposited in NCBI's SNP repository dbSNP. This method is an attractive bioinformatics tool for uncovering breed-by-probe interactions, for rapidly identifying expressed SNPs, for investigating potential functional correlations between gene expression and breed polymorphisms, and is robust enough to be used on any Affymetrix gene expression platform. }, number={1}, journal={BMC Genomics}, publisher={Springer Nature}, author={Bischoff, Steve R and Tsai, Shengdar and Hardison, Nicholas E and York, Abby M and Freking, Brad A and Nonneman, Dan and Rohrer, Gary and Piedrahita, Jorge A}, year={2008}, pages={252} }