Use of genome-wide heterospecific single-nucleotide polymorphisms to estimate linkage disequilibrium in rhesus and cynomolgus macaques

Abstract

Rhesus and cynomolgus macaques are frequently used in biomedical research, and the availability of their reference genomes now provides for their use in genome-wide association studies. However, little is known about linkage disequilibrium (LD) in their genomes, which can affect the design and success of such studies. Here we studied LD by using 1781 conserved single-nucleotide polymorphisms (SNPs) in 183 rhesus macaques (Macaca mulatta), including 97 purebred Chinese and 86 purebred Indian animals, and 96 cynomolgus macaques (M. fascicularis fascicularis). Correlation between loci pairs decayed to 0.02 at 1146.83, 2197.92, and 3955.83 kb for Chinese rhesus, Indian rhesus, and cynomolgus macaques, respectively. Differences between the observed heterozygosity and minor allele frequency (MAF) of pairs of these 3 taxa were highly statistically significant. These 3 nonhuman primate taxa have significantly different genetic diversities (heterozygosity and MAF) and rates of LD decay. Our study confirms a much lower rate of LD decay in Indian than in Chinese rhesus macaques relative to that previously reported. In contrast, the especially low rate of LD decay in cynomolgus macaques suggests the particular usefulness of this species in genome-wide association studies. Although conserved markers, such as those used here, are required for valid LD comparisons among taxa, LD can be assessed with less bias by using species-specific markers, because conserved SNPs may be ancestral and therefore not informative for LD.

Figure 1.

Principal component analysis identifying the population structure and outliers in each population. The majority of the variance in the data (90.8%) is explained by the first 2 components, and their respective percentages are given on the axes. Ellipses indicate 95% of the total variance of each study population, and grid intervals show the coordinates of each individual (points) in ±5 units in relation to 0 (black grid lines).

Figure 2.

Histograms of observed heterozygosity (OH) for both Macaca species. Mean heterozygosities are significantly different (P < 0.01).

Figure 3.

(A) Average minor allele frequency (MAF) values in each species. The differences between mean MAF are significant (P < 0.01). (B) MAF distributions for each 0.1-MAF bin in each species.

Figure 4.

LD marker pair distance distributions for all populations.

Figure 5.

LD r² plotted against physical distance (kb), with nonlinear least-squares regression lines for the rhesus and cynomolgus macaque populations.