Primate genome architecture influences structural variation mechanisms and functional consequences

Abstract

Although nucleotide resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact of phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing, we constructed fine-resolution genomic structural variation maps in five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, which are comprised of thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques compared with great apes. By comparison, nonallelic homologous recombination is specifically active in the great apes, which is correlated with architectural differences between the genomes of great apes and macaque. Transcriptome analyses across nonhuman primates and humans revealed effects of species-specific whole-gene duplication on gene expression. We identified 13 gene duplications coinciding with the species-specific gain of tissue-specific gene expression in keeping with a role of gene duplication in the promotion of diversification and the acquisition of unique functions. Differences in the present day activity of SV formation mechanisms that our study revealed may contribute to ongoing diversification and adaptation of great ape and Old World monkey lineages. genome evolution | retrotransposons | neofunctionalization | copy-number variation G enomic structural variants (SVs), including copy number variants and balanced SV forms (such as inversions), are a major source of human genetic variation (1, 2). The development of massively parallel sequencing (MPS) to characterize SVs (3-5) has enabled comprehensive analyses of origin and functional impact of SVs in humans (3, 6). Although SVs are presumed to play a major role in primate evolution and phenotypic variation (7) as well, empirical evidence showing such a role remains scarce (8). Comparative analyses of reference genome assemblies of the chimpanzee (9), orang-utan (10), and rhesus macaque (11) have provided some initial insights into large-scale structural changes in primate genome evolution (12). Microarray technology-based surveys have provided additional glimpses of the abundance of polymorphic unbalanced SVs (i.e., copy number variants) in different primate species, enabling the construction of SV maps at a resolution of tens to hundreds of kilobases (13-16).Thus far, despite ongoing progress in assessing SNP variation in primates (10,(17)(18)(19), no study has leveraged MPS technology for ascertaining inter-and intraspecies SVs in different primates. We, therefore, performed MPS-based genome analyses in five individuals from each of these primate species, Pan troglodytes (chimpanzee), Pongo abelii (orang-utan), and Macaca mulatta (rhesus macaque), to construct comprehensive SV maps in these species. Our analyses have revealed marked differences in SV formation mechanism activities and further yielded a complex relationship between genomic copy number and gene expression patterns, with several gen...

The genome of the vervet (Chlorocebus aethiops sabaeus)

“…Among rare autosomal deletions (observed in a single vervet) that perturb exon sequences, we found very few in homozygous states (only six in a total of 77 genes containing such deletions), and most of these are in pseudogenes, presumably not subject to purifying selection. This finding is consistent with the suggestion of Gokcumen et al (2013) that purifying selection has contributed little to the SV differences observed among primates.…”

“…Furthermore, we uncovered 38 rapid expansions within hierarchical gene families for oxidative stress, a correlate also relevant to human health. As also seen in previous characterizations of SDs among primates, we observed substantial variation in their span and copy number (Gokcumen et al 2013;Prado-Martinez et al 2013;Sudmant et al 2013); such variation could have broad evolutionary implications, either through its stimulation of regional de-stabilization or through its role in propagating adaptive gene families. Understanding vervet population genetic history, including the genetic relationships among vervet subspecies, is essential for identifying loci that may contribute to susceptibility or resistance to a vast array of viral, microbial, and parasitic pathogens.…”

“…Few prior studies have used sequence data to extensively evaluate copy number variation in NHP populations (Gokcumen et al 2013;Sudmant et al 2013). Sudmant et al (2013) have reported that, in the common chimpanzee/bonobo ancestor, 57 genes likely experienced exonic deletions; similar to our observations in vervets, they found that these genes were enriched for immune and olfactory functions .…”

Geographic Distribution and Adaptive Significance of Genomic Structural Variants: An Anthropological Genetics Perspective

“…Indeed, several studies have further scrutinized the phenotypic impact of SVs through genome-wide association studies linking SVs to diseases such as autism (Sebat et al 2007), schizophrenia (Stefansson et al 2008), psoriasis (de Cid et al 2009), obesity (Falchi et al 2014Jacquemont et al 2011) and Crohn's disease (McCarroll et al 2008), among others. Other studies have unearthed important evolutionary trends that are shaped by genomic 8 structural differences between primate species (McLean et al 2011;Charrier et al 2012;Iskow et al 2012a;Gokcumen et al 2013a). Moreover, especially by the efforts of the 1000 Genomes Project Consortium, several complementary computational and experimental approaches were integrated to identify and analyze different types of SVs (Mills et al 2011;1000Genomes Project Consortium 2012.…”

Recent Advances in Studying of Copy Number Variation and Gene Expression

“…Using NGS-based CNV maps, Gokcumen et al showed that the lineage-specific formation rates of NAHR and Alu repeats resulted in markedly different CNV landscapes in chimpanzee, orangutan, and macaque. 81 They further described several gene duplications, which led to evolutionary innovation through the gain of gene expression in new tissues.…”