The burden of deleterious variants in a non-human primate biomedical model

Abstract

Genome sequencing studies of nonhuman primate (NHP) pedigree and population samples are discovering variants on a large and rapidly growing scale. These studies are increasing the utility of several NHP species as model systems for human disease. In particular, by identifying homozygous protein truncating variants (hPTVs) in genes hypothesized to play a role in causing human diseases, it may be possible to elucidate mechanisms for the phenotypic impact of such variants through investigations that are infeasible in humans. The Caribbean vervet (Chlorocebus aethiops sabaeus) is uniquely valuable for this purpose, as the dramatic expansion of its population following severe bottlenecks has enabled PTVs that passed through the bottleneck to attain a relatively high frequency. Using whole genome sequence (WGS) data from 719 monkeys of the Vervet Research Colony (VRC) extended pedigree, we found 2,802 protein-truncating alleles in 1,747 protein-coding genes present in homozygous state in at least one monkey. Polymorphic sites for 923 SNV hPTVs were also observed in natural Caribbean populations from which the VRC descends. The vervet genome browser (VGB) includes information on these PTVs, together with a catalog of phenotypes and biological samples available for monkeys who carry them. We describe initial explorations of the possible impact of vervet PTVs on early infant mortality.

Resources for functional genomic studies of health and development in nonhuman primates

“…To develop genetic resources for mapping quantitative phenotypes and to create a catalog of PTV knockouts with potential acute phenotypic effects in the VRC pedigree, a comprehensive genetic characterization based on genome sequencing has been conducted in more than 700 VRC vervets, representing the richest phenotypic collection or a large array of samples collected from internal tissues for various tissue‐specific assessments (Huang et al, ; Ramensky et al, ). From more than 4 million high‐quality sites segregating in the pedigree, genetic mapping panels comprising common SNPs selected according to linkage disequilibrium patterns have been developed for linkage analysis (~150,000 SNPs), association analysis (~500,000 SNPs), and associated genotype data (Huang et al, ).…”

“…Beyond the SNP marker panels for genetic mapping of quantitative traits, genetic variation in exonic regions of the genome has been extensively cataloged in the VRC vervets to discover candidate variants with rare, severe phenotypic traits. More than 1 million SNVs (including six missense variants matching human pathogenic mutations) and 241,648 short indels have been discovered in the exons (Ramensky et al, ). Among them, a list of 2,802 PTV knockouts (PTVs found in the pedigree in the homozygous state) is a promising resource for identification of the genetic basis of severe phenotypes.…”

“…For example, several PTV knockouts have been observed exclusively in mothers with high rates of early infant mortality and thus appear to be putative variants increasing the risk of infant death. Similarly to rhesus LoFs, vervet PTVs have been observed in genes implicated in cancers and neurodegenerative, neurodevelopment, and infectious diseases (Ramensky et al, ). Among the PTVs segregating in the VRC pedigree, 33% have also been observed in the Caribbean vervet populations from which the VRC pedigree was established (Svardal et al, ).…”

“…These new genetic resources focus on providing tools for the exploration of the phenotypic effects of genetic variants and have better utility for genotype–phenotype studies than initial SNP collections. The newly released large‐scale NHP databases—The Macaque Genotype and Phenotype Resource (mGAP) (mGAP The Macaque Genotype And Phenotype Resource, n.d.; Bimber, Yan, Peterson, & Ferguson, ) and The Vervet Genome Browser (VGB) (Ramensky et al, ; The Vervet Genome Browser, )—are specifically designed to help explore genetic variants in the context of their functional consequences and associated phenotypes, on the basis of variant and gene annotations. Most importantly, they provide genotype‐level information, which helps to link each variant to its carriers for further phenotypic investigations.…”

“…The VGB provides a genomic visualization of a catalog of 2,802 PTVs that have been observed in the homozygous state in at least one individual in the VRC and therefore may represent naturally occurring gene knockouts in the VRC (Ramensky et al, ; The Vervet Genome Browser, ). To facilitate genotype–phenotype investigations for each monkey carrying a PTV, the VGB provides information on the availability of live animals, their phenotypic and gene expression data, banked tissues, fibroblast cell cultures, DNA, and RNA.…”