A non-human primate system for large-scale genetic studies of complex traits

Abstract

Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n = 8) and suggestive (n = 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation.

Figure 1.

Vervet population history from Africa to the VRC. The African vervet meta-population (Chlorocebus aethiops) consists of five major sub-species, with estimated ranges as shown: sabaeus (red), tantalus (purple), aethiops (yellow), cynosurus (green) and pygerythrus (blue). Facial images (, adapted from 36) represent African subspecies. The current Caribbean vervet population [inhabiting the islands of Saint Kitts, Nevis, and Barbados (red frame)] has expanded more than 100-fold from a bottleneck that occurred about 80–100 generations ago when a small number of African vervets (believed to be West African sabaeus monkeys) were transported to these islands. The growth of the VRC pedigree (from Caribbean 57 founders to a current size of > 450 monkeys) represents a more recent expansion from a bottleneck.

Figure 2.

A putative master trans-regulator locus on vervet chromosome 9. The peak LOD scores observed for transcripts sited on several different vervet chromosomes map to a single region on vervet chromosome 9 (syntenic to human chromosome 10), suggesting the location of a master trans-regulator locus. The linked microsatellites span a region of ∼22cM from D10S1677–D10S564. Two of the linked transcripts are located on chromosome 9 (PRFDC1 and TSPAN14) while five other linked transcripts (SLC25A23, TMEM57, RAB5A, MTMR3 and DEDD2) are located on other vervet chromosomes. Interpretation of the linkage results to this region is complicated by the sparseness of the microsatellite-based vervet genetic map and by an inversion in the human genome (relative to the vervet and macaque genomes) that includes the four markers demonstrating maximal linkage to the transcript measures. Marker order in human and vervet chromosomes is shown in units of genetic distance (Kosambi centiMorgans, cM). Approximate gene locations (blue stars) are shown based on their known physical location in the human genome relative to microsatellite markers.

Figure 3.

Genetic investigation of populations of feral Caribbean vervets. The wild-born animals (n = 279) used in the fine-mapping association study presented here were sampled from several sites on St Kitts. Pin size corresponds to the number of animals trapped from a given location.

Figure 4.

Biomaterial repository established from vervet population samples in the Caribbean and Africa. Animals have been sampled for skin biopsy specimens (to establish fibroblast cell lines), blood, cerebrospinal fluid, hair and specimens for assaying the natural microbiome populating the gastro-intestinal tract, reproductive system and oro-nasal cavity (including nasopharyngeal, NPS; oropharyngeal, OPS). Wild monkeys have been assigned unique identifiers using a microchip injected subcutaneously to enable long-term follow-up studies of each monkey. Global positioning coordinates for all monkeys will be available online at http://www.genomequebec.mcgill.ca/compgen/vervet_research/animal_resources/.