mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease

Abstract

Background: Non-human primates (NHPs), particularly macaques, serve as critical and highly relevant pre-clinical models of human disease. The similarity in human and macaque natural disease susceptibility, along with parallel genetic risk alleles, underscores the value of macaques in the development of effective treatment strategies. Nonetheless, there are limited genomic resources available to support the exploration and discovery of macaque models of inherited disease. Notably, there are few public databases tailored to searching NHP sequence variants, and no other database making use of centralized variant calling, or providing genotype-level data and predicted pathogenic effects for each variant.

Results: The macaque Genotype And Phenotype (mGAP) resource is the first public website providing searchable, annotated macaque variant data. The mGAP resource includes a catalog of high confidence variants, derived from whole genome sequence (WGS). The current mGAP release at time of publication (1.7) contains 17,087,212 variants based on the sequence analysis of 293 rhesus macaques. A custom pipeline was developed to enable annotation of the macaque variants, leveraging human data sources that include regulatory elements (ENCODE, RegulomeDB), known disease- or phenotype-associated variants (GRASP), predicted impact (SIFT, PolyPhen2), and sequence conservation (Phylop, PhastCons). Currently mGAP includes 2767 variants that are identical to alleles listed in the human ClinVar database, of which 276 variants, spanning 258 genes, are identified as pathogenic. An additional 12,472 variants are predicted as high impact (SnpEff) and 13,129 are predicted as damaging (PolyPhen2). In total, these variants are predicted to be associated with more than 2000 human disease or phenotype entries reported in OMIM (Online Mendelian Inheritance in Man). Importantly, mGAP also provides genotype-level data for all subjects, allowing identification of specific individuals harboring alleles of interest.

Conclusions: The mGAP resource provides variant and genotype data from hundreds of rhesus macaques, processed in a consistent manner across all subjects ( https://mgap.ohsu.edu ). Together with the extensive variant annotations, mGAP presents unprecedented opportunity to investigate potential genetic associations with currently characterized disease models, and to uncover new macaque models based on parallels with human risk alleles.

Keywords: Animal model; Database; Genome; Indian-origin; Macaca mulatta; Nonhuman primate; Rhesus; SNP.

Fig. 1

Summary of variant catalog. a Table listing the number of total variants and variants by type. b Chart showing the distribution of variants relative to gene regions. For each category, the first percentage indicates the fraction of variants of this type. The second percentage indicates the fraction of the genome of this category (when excluding repetitive regions, which are masked from mGAP variant calling). The categories Downstream Gene and Upstream Gene are defined as within 5000 bp of the gene start or end, respectively. c The derived allele frequency spectrum of variants in the mGAP database

Fig. 2

Variant annotation strategy. Macaque variant data are first lifted to the human genome (GRCh37), and annotated against multiple sources. The resulting variants are translated back to the original rhesus macaque coordinates (MMul8.0.1), and merged with the non-lifted variants

Fig. 3

Overview of mGAP website navigation. The front page of the mGAP site contains an overview of the current release, description of the resources, and links to commonly used pages. The website has additional tabs, providing detail on the variant catalog, phenotypes and macaque models, demographics data from the mGAP cohort and access to raw sequence data

Fig. 4

The mGAP genome browser. Variants of interest may be searched by chromosome position or gene name in the search bar. Diamonds indicate SNVs and bars indicate indels, with colors indicating predicted impact on protein coding (red = high, yellow = moderate, blue = low). Clicking a variant provides a detailed pop-up with summary and annotations. The provided information includes predicted function, regulatory data, species conservation, phenotypic data, allele frequencies, and genotypes by animal