The rhesus macaque is three times as diverse but more closely equivalent in damaging coding variation as compared to the human

Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA.
BMC Genetics (Impact Factor: 2.4). 06/2012; 13(1):52. DOI: 10.1186/1471-2156-13-52
Source: PubMed


As a model organism in biomedicine, the rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates.
We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences) the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs) per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction) in the macaque is more closely equivalent to that of the human.
This large panel of newly identified macaque SNPs enriched for functionally significant regions considerably expands our knowledge of genetic variation in the rhesus macaque. Comparative analysis reveals that this widespread, highly adaptable species is approximately three times as diverse as the human but more closely equivalent in damaging variation.

Download full-text


Available from: Juan Francisco Lopez, Mar 30, 2014
1 Follower
27 Reads
  • Source
    • "2a, the nearly identical profiles for the two killer whales compared in fig. 2b), and only the rhesus monkey has a second peak reflecting more diverse regions (and overall higher diversity, despite possible undersampling of heterozygotes due to the relatively low 6Â coverage [Yuan et al. 2012], see Materials and Methods). Each plot reflects the genomic diversity of just one individual. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ecosystem function and resilience is determined by the interactions and independent contributions of individual species. Apex predators play a disproportionately determinant role through their influence and dependence on the dynamics of prey species. Their demographic fluctuations are thus likely to reflect changes in their respective ecological communities and habitat. Here we investigate the historical population dynamics of the killer whale based on draft nuclear genome data for the Northern Hemisphere and mtDNA data worldwide. We infer a relatively stable population size throughout most of the Pleistocene, followed by an order of magnitude decline and bottleneck during the Weichselian glacial period. Global mtDNA data indicates that while most populations declined, at least one population retained diversity in a stable, productive ecosystem off southern Africa. We conclude that environmental changes during the last glacial period promoted the decline of a top ocean predator, that these events contributed to the pattern of diversity among extant populations, and that the relatively high diversity of a population currently in productive, stable habitat off South Africa suggests a role for ocean productivity in the widespread decline.
    Molecular Biology and Evolution 02/2014; 31(5). DOI:10.1093/molbev/msu058 · 9.11 Impact Factor
  • Source
    • "In our 5-HTTLPR epigenetic study, not only did we identify 3 SNPs within the core promoter for the rhesus SLC6A4 gene (despite sampling a limited number of subjects), but there also appears to be increased diversity in this region in humans, with 25 SNPs within the 1 KB 5 0 of the SLC6A4 transcription start site. This was approximately 109 higher than we had previously reported for variation in human intergenic regions (Yuan et al. 2012). These findings demonstrate how genetic and environmental effects may interact and how genetic variability could be driven by disruptive and/or balancing selection at genes known to moderate aggressive behavior. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aggressive behavior can have adaptive value in certain environmental contexts, but when extreme or executed inappropriately, can also lead to maladaptive outcomes. Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity, impulsivity, and anxiety can contribute to individual differences in aggressive behavior. Genetic polymorphisms in the coding or promoter regions of the Mu-Opioid Receptor (OPRM1), Corticotropin Releasing Hormone (CRH), Monoamine Oxidase A (MAOA), Dopamine D4 Receptor (DRD4), and Serotonin Transporter (SLC6A4) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression. This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology.
    Current Topics in Behavioral Neurosciences 12/2013; 17. DOI:10.1007/7854_2013_267
  • Source
    • "A combination of transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation enriched sequencing (ChIP-seq) was recently used to selectively sequence gene-linked genomic regions in rhesus macaques. This approach yielded at least one SNP in each of the 16,797 annotated rhesus macaque genes and a total of 462,802 SNPs in all 14 individuals investigated (Yuan et al. 2012). Alternatively, we and others have found that humanbased exon capture designs can recover 80–95% of the macaque-equivalent exons (Jin et al. 2012; Vallender et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Complex diseases (e.g., cardiovascular disease and type 2 diabetes, among many others) pose the biggest threat to human health worldwide and are among the most challenging to investigate. Susceptibility to complex disease may be caused by multiple genetic variants (GVs) and their interaction, by environmental factors, and by interaction between GVs and environment, and large study cohorts with substantial analytical power are typically required to elucidate these individual contributions. Here, we discuss the advantages of both power and feasibility afforded by the use of extended pedigrees of rhesus macaques (Macaca mulatta) for genetic studies of complex human disease based on next-generation sequence data. We present these advantages in the context of previous research conducted in rhesus macaques for several representative complex diseases. We also describe a single, multigeneration pedigree of Indian-origin rhesus macaques and a sample biobank we have developed for genetic analysis of complex disease, including power of this pedigree to detect causal GVs using either genetic linkage or association methods in a variance decomposition approach. Finally, we summarize findings of significant heritability for a number of quantitative traits that demonstrate that genetic contributions to risk factors for complex disease can be detected and measured in this pedigree. We conclude that the development and application of an extended pedigree to analysis of complex disease traits in the rhesus macaque have shown promising early success and that genome-wide genetic and higher order -omics studies in this pedigree are likely to yield useful insights into the architecture of complex human disease.
    ILAR journal / National Research Council, Institute of Laboratory Animal Resources 11/2013; 54(2):91-105. DOI:10.1093/ilar/ilt041 · 2.39 Impact Factor
Show more