Sequencing the rhesus macaque provides new insights into genetic diversity and selection

The sequencing of the genome of an Old World monkey the rhesus macaque in 2007 further advanced our ability to look for evidence of positive selection (Box 10.2) (Gibbs et al. 2007). Divergence between the macaque lineage and the human-chimp common ancestor is thought to have occurred some 25 million years ago, in contrast to the human and chimpanzee lineages which diverged an estimated 6 million years ago (Fig 6.5) (Kumar and Hedges 1998; Chen and Li 2001; Patterson et al. 2006). This increased divergence was reflected in the 93.54% sequence identity observed between the human and macaque genomes, considerably lower than that observed between human and chimpanzee (Gibbs et al. 2007). For analysis of putative effects of selection, increased divergence offers more opportunity to detect differences. A further major advance made possible through having an additional primate genome sequence was the ability to define the ancestral state of human and chimpanzee nucleotide diversity using the macaque as an 'outgroup':

a nucleotide difference between human and chimpanzee could now been resolved as a gain or loss depending on its absence or presence in the macaque, respectively.

Comparing orthologous genes between the human and chimpanzee genome showed on average three nonsynonymous and five synonymous substitutions per gene; for human-macaque comparisons this was found to increase to 12 and 22, respectively (Gibbs et al. 2007). Gibbs and colleagues analysed 10 376 genes for which orthologous counterparts could be identified among the three genomes, human, chimpanzee, and macaque. Looking at the ratio of nonsynonymous to synonymous changes, the mean rate (0.247) was similar to that previously found on comparing human and chimpanzee (0.23) (CSAC 2005); 2.8% of genes had a ratio greater than one indicating positive selection with enrichment among genes involved in the immune response. Extending the comparison to include the mouse and dog, analysis of 5286 orthologous genes showed ratios were significantly higher among the two primate species (0.169 in humans, 0.175 in chimpanzee) suggesting reduced purifying (negative) selection (rates of 0.124 in macaques, 0.104 in mice, and 0.111 in dogs).

Box 10.2 Sequencing the macaque genome

A draft sequence for the rhesus macaque was published by the Rhesus Macaque Genome Sequencing and Analysis Consortium in 2007 (Gibbs et al. 2007). The majority of sequence came from a single female of Indian origin; a whole genome shotgun sequencing approach was used with 5.2-fold coverage for a genome assembly of 2.87 Gb representing 98% of the available genome. A total of 26 479 single base differences were also resolved by sequencing an additional eight Chinese and eight Indian rhesus macaques (equalling 26.2 Mb of sequence). The macaque genome differs from the human one in having only 20 autosomes, and in containing more acrocentric chromosomes. Extensive structural variation was apparent at a microscopic and submicroscopic scale, with 43 microscopically visible breakpoints and more than 820 submicroscopic rearrangement induced breakpoints seen between the reconstructed human-chimp ancestor and macaque genomes (Gibbs et al. 2007). The extent of segmental duplication was considerably lower than for the chimpanzee or human genomes with a lower bound estimate of 2.3%; expansion of gene families could also be resolved with 108 gene families identified among primates (Section 6.2.5). Macaque-specific expansions included HLA-related genes and a further immune-related gene cluster, immunoglobulin lambda-like (IGL): more than half of macaque-specific gene expansions also showed evidence of positive selection based on analysis of coding DNA. As with the chimpanzee genome, sequencing of the macaque genome revealed further insights into the biology and nature of mobile DNA elements (Chapter 8).

Among primates, genes with significantly higher Ka/Ks ratios included those with an involvement in the perception of taste and smell, and transcriptional regulation. Genome-wide analysis among human, chimpanzee, and macaque orthologous genes revealed 178 out of 10 376 genes showed evidence of positive selection using a variety of measures. Enrichment among different functional categories was broadly similar to earlier studies, including defence and immunity, signal transduction, fertilization, and cell adhesion; other gene categories included iron binding and hair shaft formation (Gibbs et al. 2007).

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