@article{watowich_costa_chiou_goldman_petersen_patterson_martinez_sterner_horvath_montague_et al._2024, title={Immune gene regulation is associated with age and environmental adversity in a nonhuman primate}, ISSN={["1365-294X"]}, DOI={10.1111/mec.17445}, abstractNote={Abstract Phenotypic aging is ubiquitous across mammalian species, suggesting shared underlying mechanisms of aging. Aging is linked to molecular changes to DNA methylation and gene expression, and environmental factors, such as severe external challenges or adversities, can moderate these age‐related changes. Yet, it remains unclear whether environmental adversities affect gene regulation via the same molecular pathways as chronological, or ‘primary’, aging. Investigating molecular aging in naturalistic animal populations can fill this gap by providing insight into shared molecular mechanisms of aging and the effects of a greater diversity of environmental adversities – particularly those that can be challenging to study in humans or laboratory organisms. Here, we characterised molecular aging – specifically, CpG methylation – in a sample of free‐ranging rhesus macaques living off the coast of Puerto Rico ( n samples = 571, n individuals = 499), which endured a major hurricane during our study. Age was associated with methylation at 78,661 sites (31% of all sites tested). Age‐associated hypermethylation occurred more frequently in areas of active gene regulation, while hypomethylation was enriched in regions that show less activity in immune cells, suggesting these regions may become de‐repressed in older individuals. Age‐associated hypomethylation also co‐occurred with increased chromatin accessibility while hypermethylation showed the opposite trend, hinting at a coordinated, multi‐level loss of epigenetic stability during aging. We detected 32,048 CpG sites significantly associated with exposure to a hurricane, and these sites overlapped age‐associated sites, most strongly in regulatory regions and most weakly in quiescent regions. Together, our results suggest that environmental adversity may contribute to aging‐related molecular phenotypes in regions of active gene transcription, but that primary aging has specific signatures in non‐regulatory regions.}, journal={MOLECULAR ECOLOGY}, author={Watowich, Marina M. and Costa, Christina E. and Chiou, Kenneth L. and Goldman, Elisabeth A. and Petersen, Rachel M. and Patterson, Sam and Martinez, Melween I. and Sterner, Kirstin N. and Horvath, Julie E. and Montague, Michael J. and et al.}, year={2024}, month={Jul} }
 @article{kuderna_gao_janiak_kuhlwilm_orkin_bataillon_manu_valenzuela_bergman_rousselle_et al._2023, title={A global catalog of whole-genome diversity from 233 primate species}, volume={380}, ISSN={["1095-9203"]}, DOI={10.1126/science.abn7829}, abstractNote={The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.}, number={6648}, journal={SCIENCE}, author={Kuderna, Lukas F. K. and Gao, Hong and Janiak, Mareike C. and Kuhlwilm, Martin and Orkin, Joseph D. and Bataillon, Thomas and Manu, Shivakumara and Valenzuela, Alejandro and Bergman, Juraj and Rousselle, Marjolaine and et al.}, year={2023}, month={Jun}, pages={906–912} }
 @article{watowich_chiou_graves_montague_brent_higham_horvath_lu_martinez_platt_et al._2023, title={Best practices for genotype imputation from low-coverage sequencing data in natural populations}, ISSN={["1755-0998"]}, DOI={10.1111/1755-0998.13854}, abstractNote={AbstractMonitoring genetic diversity in wild populations is a central goal of ecological and evolutionary genetics and is critical for conservation biology. However, genetic studies of nonmodel organisms generally lack access to species‐specific genotyping methods (e.g. array‐based genotyping) and must instead use sequencing‐based approaches. Although costs are decreasing, high‐coverage whole‐genome sequencing (WGS), which produces the highest confidence genotypes, remains expensive. More economical reduced representation sequencing approaches fail to capture much of the genome, which can hinder downstream inference. Low‐coverage WGS combined with imputation using a high‐confidence reference panel is a cost‐effective alternative, but the accuracy of genotyping using low‐coverage WGS and imputation in nonmodel populations is still largely uncharacterized. Here, we empirically tested the accuracy of low‐coverage sequencing (0.1–10×) and imputation in two natural populations, one with a large (n = 741) reference panel, rhesus macaques (Macaca mulatta), and one with a smaller (n = 68) reference panel, gelada monkeys (Theropithecus gelada). Using samples sequenced to coverage as low as 0.5×, we could impute genotypes at >95% of the sites in the reference panel with high accuracy (median r2 ≥ 0.92). We show that low‐coverage imputed genotypes can reliably calculate genetic relatedness and population structure. Based on these data, we also provide best practices and recommendations for researchers who wish to deploy this approach in other populations, with all code available on GitHub (https://github.com/mwatowich/LoCSI‐for‐non‐model‐species). Our results endorse accurate and effective genotype imputation from low‐coverage sequencing, enabling the cost‐effective generation of population‐scale genetic datasets necessary for tackling many pressing challenges of wildlife conservation.}, journal={MOLECULAR ECOLOGY RESOURCES}, author={Watowich, Marina M. and Chiou, Kenneth L. and Graves, Brian and Montague, Michael J. and Brent, Lauren J. N. and Higham, James P. and Horvath, Julie E. and Lu, Amy and Martinez, Melween I. and Platt, Michael L. and et al.}, year={2023}, month={Aug} }
 @article{kuderna_ulirsch_rashid_ameen_sundaram_hickey_cox_gao_kumar_aguet_et al._2023, title={Identification of constrained sequence elements across 239 primate genomes}, ISSN={["1476-4687"]}, DOI={10.1038/s41586-023-06798-8}, abstractNote={AbstractNoncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.}, journal={NATURE}, author={Kuderna, Lukas F. K. and Ulirsch, Jacob C. and Rashid, Sabrina and Ameen, Mohamed and Sundaram, Laksshman and Hickey, Glenn and Cox, Anthony J. and Gao, Hong and Kumar, Arvind and Aguet, Francois and et al.}, year={2023}, month={Nov} }
 @article{gao_hamp_ede_schraiber_mcrae_singer-berk_yang_dietrich_fiziev_kuderna_et al._2023, title={The landscape of tolerated genetic variation in humans and primates}, volume={380}, ISSN={["1095-9203"]}, DOI={10.1126/science.abn8197}, abstractNote={Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.}, number={6648}, journal={SCIENCE}, author={Gao, Hong and Hamp, Tobias and Ede, Jeffrey and Schraiber, Joshua G. and McRae, Jeremy and Singer-Berk, Moriel and Yang, Yanshen and Dietrich, Anastasia S. D. and Fiziev, Petko P. and Kuderna, Lukas F. K. and et al.}, year={2023}, month={Jun}, pages={929-+} }
 @article{roche_montague_wang_dickey_ruiz-lambides_brent_platt_horvath_2023, title={Yearly variation coupled with social interactions shape the skin microbiome in free-ranging rhesus macaques}, volume={11}, ISSN={["2165-0497"]}, DOI={10.1128/spectrum.02974-23}, abstractNote={ABSTRACT
          While skin microbes are known to mediate human health and disease, there has been minimal research on the interactions between skin microbiota, social behavior, and year-to-year effects in non-human primates—important animal models for translational biomedical research. To examine these relationships, we analyzed skin microbes from 78 rhesus macaques living on Cayo Santiago Island, Puerto Rico. We considered age, sex, and social group membership, and characterized social behavior by assessing dominance rank and patterns of grooming as compared to nonsocial behaviors. To measure the effects of a shifting environment, we sampled skin microbiota (based on sequence analysis of the 16S rRNA V4 region) and assessed weather across sampling periods between 2013 and 2015. We hypothesized that, first, monkeys with similar social behavior and/or in the same social group would possess similar skin microbial composition due, in part, to physical contact, and, second, microbial diversity would differ across sampling periods. We found significant phylum-level differences between social groups in the core microbiome as well as an association between total grooming rates and alpha diversity in the complete microbiome, but no association between microbial diversity and measures of rank or other nonsocial behaviors. We also identified alpha and beta diversity differences in microbiota and differential taxa abundance across two sampling periods. Our findings indicate that social dynamics interact with yearly environmental changes to shape the skin microbiota in rhesus macaques, with potential implications for understanding the factors affecting the microbiome in humans, which share many biological and social characteristics with these animals.
          
            IMPORTANCE
            Primate studies are valuable for translational and evolutionary insights into the human microbiome. The majority of primate microbiome studies focus on the gut, so less is known about the factors impacting the microbes on skin and how their links affect health and behavior. Here, we probe the impact of social interactions and the yearly environmental changes on food-provisioned, free-ranging monkeys living on a small island. We expected animals that lived together and groomed each other would have more similar microbes on their skin, but surprisingly found that the external environment was a stronger influence on skin microbiome composition. These findings have implications for our understanding of the human skin microbiome, including potential manipulations to improve health and treat disease.
          }, number={5}, journal={MICROBIOLOGY SPECTRUM}, author={Roche, Christina E. and Montague, Michael J. and Wang, JiCi and Dickey, Allison N. and Ruiz-Lambides, Angelina and Brent, Lauren J. N. and Platt, Michael L. and Horvath, Julie E.}, year={2023} }
 @article{kuthyar_watson_huang_brent_platt_horvath_gonzalez-martinez_martinez_godoy-vitorino_knight_et al._2022, title={Limited microbiome differences in captive and semi-wild primate populations consuming similar diets}, volume={98}, ISSN={["1574-6941"]}, DOI={10.1093/femsec/fiac098}, abstractNote={Abstract
               Gut microbial communities are shaped by a myriad of extrinsic factors, including diet and the environment. Although distinct human populations consistently exhibit different gut microbiome compositions, variation in diet and environmental factors are almost always coupled, making it difficult to disentangle their relative contributions to shaping the gut microbiota. Data from discrete animal populations with similar diets can help reduce confounds. Here, we assessed the gut microbiota of free-ranging and captive rhesus macaques with at least 80% diet similarity to test the hypothesis that hosts in difference environments will have different gut microbiomes despite a shared diet. Although we found that location was a significant predictor of gut microbial composition, the magnitude of observed differences was relatively small. These patterns suggest that a shared diet may limit the typical influence of environmental microbial exposure on the gut microbiota.}, number={10}, journal={FEMS MICROBIOLOGY ECOLOGY}, author={Kuthyar, Sahana and Watson, Karli and Huang, Shi and Brent, Lauren J. N. and Platt, Michael and Horvath, Julie and Gonzalez-Martinez, Janis and Martinez, Melween and Godoy-Vitorino, Filipa and Knight, Rob and et al.}, year={2022}, month={Oct} }
 @article{watowich_chiou_montague_simons_horvath_ruiz-lambides_martinez_higham_brent_platt_et al._2022, title={Natural disaster and immunological aging in a nonhuman primate}, volume={119}, ISSN={["1091-6490"]}, DOI={10.1073/pnas.2121663119}, abstractNote={Significance
          Survivors of extreme adverse events, including natural disasters, often exhibit chronic inflammation and early onset of age-related diseases. Adversity may therefore accelerate aging via the immune system, which is sensitive to lived experiences. We tested if experiencing a hurricane was associated with immune gene expression in a population of free-ranging macaques. Exposure to Hurricane Maria broadly recapitulated age-associated molecular changes, including disruptions of protein folding genes, greater inflammatory immune cell marker gene expression, and older biological aging by an average of 2 y—approximately 7 to 8 y of the human lifespan. Together, our findings suggest that experiencing an extreme hurricane is associated with alterations in immune cell gene regulation similar to aging, potentially accelerating aspects of the aging process.}, number={8}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Watowich, Marina M. and Chiou, Kenneth L. and Montague, Michael J. and Simons, Noah D. and Horvath, Julie E. and Ruiz-Lambides, Angelina V and Martinez, Melween I and Higham, James P. and Brent, Lauren J. N. and Platt, Michael L. and et al.}, year={2022}, month={Feb} }
 @article{testard_brent_andersson_chiou_negron-del valle_decasien_acevedo-ithier_stock_anton_gonzalez_et al._2022, title={Social connections predict brain structure in a multidimensional free-ranging primate society}, volume={8}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.abl5794}, abstractNote={Reproduction and survival in most primate species reflects management of both competitive and cooperative relationships. Here, we investigated the links between neuroanatomy and sociality in free-ranging rhesus macaques. In adults, the number of social partners predicted the volume of the mid–superior temporal sulcus and ventral-dysgranular insula, implicated in social decision-making and empathy, respectively. We found no link between brain structure and other key social variables such as social status or indirect connectedness in adults, nor between maternal social networks or status and dependent infant brain structure. Our findings demonstrate that the size of specific brain structures varies with the number of direct affiliative social connections and suggest that this relationship may arise during development. These results reinforce proposed links between social network size, biological success, and the expansion of specific brain circuits.}, number={15}, journal={SCIENCE ADVANCES}, author={Testard, Camille and Brent, Lauren J. N. and Andersson, Jesper and Chiou, Kenneth L. and Negron-Del Valle, Josue E. and DeCasien, Alex R. and Acevedo-Ithier, Arianna and Stock, Michala K. and Anton, Susan C. and Gonzalez, Olga and et al.}, year={2022}, month={Apr} }
 @article{melin_orkin_janiak_valenzuela_kuderna_marrone_ramangason_horvath_roos_kitchener_et al._2021, title={Variation in predicted COVID-19 risk among lemurs and lorises}, volume={83}, ISSN={["1098-2345"]}, DOI={10.1002/ajp.23255}, abstractNote={AbstractThe novel coronavirus SARS‐CoV‐2, which in humans leads to the disease COVID‐19, has caused global disruption and more than 2 million fatalities since it first emerged in late 2019. As we write, infection rates are at their highest point globally and are rising extremely rapidly in some areas due to more infectious variants. The primary target of SARS‐CoV‐2 is the cellular receptor angiotensin‐converting enzyme‐2 (ACE2). Recent sequence analyses of the ACE2 gene predict that many nonhuman primates are also likely to be highly susceptible to infection. However, the anticipated risk is not equal across the Order. Furthermore, some taxonomic groups show high ACE2 amino acid conservation, while others exhibit high variability at this locus. As an example of the latter, analyses of strepsirrhine primate ACE2 sequences to date indicate large variation among lemurs and lorises compared to other primate clades despite low sampling effort. Here, we report ACE2 gene and protein sequences for 71 individual strepsirrhines, spanning 51 species and 19 genera. Our study reinforces previous results while finding additional variability in other strepsirrhine species, and suggests several clades of lemurs have high potential susceptibility to SARS‐CoV‐2 infection. Troublingly, some species, including the rare and endangered aye‐aye (Daubentonia madagascariensis), as well as those in the genera Avahi and Propithecus, may be at high risk. Given that lemurs are endemic to Madagascar and among the primates at highest risk of extinction globally, further understanding of the potential threat of COVID‐19 to their health should be a conservation priority. All feasible actions should be taken to limit their exposure to SARS‐CoV‐2.}, number={6}, journal={AMERICAN JOURNAL OF PRIMATOLOGY}, author={Melin, Amanda D. and Orkin, Joseph D. and Janiak, Mareike C. and Valenzuela, Alejandro and Kuderna, Lukas and Marrone, Frank, III and Ramangason, Hasinala and Horvath, Julie E. and Roos, Christian and Kitchener, Andrew C. and et al.}, year={2021}, month={Jun} }
 @misc{chiou_montague_goldman_watowich_sams_song_horvath_sterner_ruiz-lambides_martinez_et al._2020, title={Rhesus macaques as a tractable physiological model of human ageing}, volume={375}, ISSN={["1471-2970"]}, DOI={10.1098/rstb.2019.0612}, abstractNote={Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.
          This article is part of the theme issue ‘Evolution of the primate ageing process’.}, number={1811}, journal={PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES}, author={Chiou, Kenneth L. and Montague, Michael J. and Goldman, Elisabeth A. and Watowich, Marina M. and Sams, Sierra N. and Song, Jeff and Horvath, Julie E. and Sterner, Kirstin N. and Ruiz-Lambides, Angelina V. and Martinez, Melween I. and et al.}, year={2020}, month={Nov} }