The monkey's perspective
© BioMed Central Ltd 2007
Published: 26 September 2007
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© BioMed Central Ltd 2007
Published: 26 September 2007
The sequencing of the genome of a female rhesus macaque (Macaca mulatta) of Indian origin will provide us with biomedical and evolutionary insights into both humans and Old World monkeys.
The recently published draft of the rhesus macaque (Macaca mulatta) genome from the Rhesus Macaque Genome Sequencing and Analysis Consortium  follows that of the chimpanzee  by only a year and a half, and now gives us three primate genome sequences, including our own. Of the 2.87 gigabases sequenced at 5.2-fold coverage, and containing approximately 20,000 predicted genetic loci, regions of the macaque genome that could be aligned to the human genome sequence were 93.5% identical (90.76% when small insertions and deletions are included). Compared with the human-chimpanzee difference of 98.77%, which sometimes gives sequences that are too similar to draw meaningful comparisons, and the human-mouse difference of 69.1%, which gives sequences often too divergent to be useful, the macaque sequences provide Goldilocks' 'just right' for many types of analyses.
Screens for positively selected changes between chimpanzees and humans using the mouse genome as an outgroup initially suggested that selected changes were more numerous in the human lineage than in the chimp lineage . Other studies found a possibly accelerated rate of change in conserved noncoding regions in the human lineage . These observations were readily accepted, in part because they supported our naturally anthropocentric view that humans are special and so there should be a molecular signature of our uniqueness. More recent analyses using the more closely related macaque as the outgroup suggest, however, that a greater number of positively selected changes has in fact occurred along the chimpanzee lineage, leaving humans as the more 'primitive' species from a genomic standpoint [5, 6]. This is somewhat surprising, given that overall the skeletons of our 5-6-million-year-old ancestors look remarkably chimpanzee-like. With respect to our extremely large and complex brain, studies using the mouse as outgroup proposed an accelerated rate of evolution in nervous-system genes in humans . But, perhaps no longer surprisingly, a recent study using the macaque genome for comparison showed that even genes expressed specifically in the brain were found to be under no greater selection in humans than in chimpanzees . Thus, we still do not know the molecular basis for the evolution of the uniquely large human brain.
The macaque genome has also benefited our understanding of the human genome in other ways. For example, the method called 'phylogenetic shadowing' involves the comparison of DNA sequences across multiple species to reveal conservative sequence blocks. Such conserved regions may be putative exons, regulatory elements, or otherwise functionally significant [9, 10]. By comparing sequences of closely related species (for example, between primates, rather than distinctly related animals), the rare changes within these 'least variable' regions may highlight the critical mutations that make a species unique.
It is important to recognize the relatively deep evolutionary history of macaques when planning or interpreting biomedical studies. The five species mentioned above make up the majority of macaques used in such studies, and diverged from each other up to 5 million years ago. This means that as far as evolutionary divergence goes, substituting one species for another is akin to substituting humans for chimps. It is therefore highly desirable that the genetic backgrounds of the macaque species used in research, and their differences from each other, should be fully assessed.
It is already known that different species and subspecies of macaques react differently and show different levels of pathogenesis with respect to two of the most widely studied human infectious diseases, AIDS and malaria. For instance, rhesus macaques of Indian origin (like the one whose genome was sequenced ) progress much more rapidly to simian AIDS upon infection with simian immunodeficiency virus (SIV) compared with rhesus macaques of Chinese origin [12, 13]. Rhesus macaques and mainland Malaysian populations of long-tailed macaques show greater susceptibility and pathogenesis to some strains of malaria than do long-tailed macaques from the Philippines, which are far less susceptible and do not get as sick . This correlates with the observation that mainland populations of long-tailed macaques are known to hybridize with rhesus macaques, as demonstrated by the lengths of their tails and molecular markers.
To investigate the diversity of these monkeys, nearly 1,500 single-nucleotide polymorphisms (SNPs) were typed in nine Chinese and 38 Indian rhesus macaques as part of the rhesus macaque genome project . The monkeys of Indian origin show much less variability than the Chinese animals, which again needs to be taken into account in any studies using macaques. Another interesting finding from the rhesus genome project is that a significant number of disease-causing or disease-associated alleles in humans are found in macaques or in the inferred common ancestor of chimpanzees and humans (when using the rhesus macaque as the outgroup). Since these alleles do not cause disease in macaques, we must be more cautious in using non-human primate models (and, obviously, non-primate models) in investigating human genetic diseases.
What is also clear from the studies so far is the importance of finished rather than draft genomes for detailed comparative analyses. Accurate sequences, and thus alignments, are critical when assessing polymorphism, the influence of selection and ancestral states. With a variety of other primate genomes currently being sequenced or in the planning stages - including gorilla, orangutan, gibbon, marmoset, tarsier, galago and mouse lemur - breakthroughs in understanding the evolutionary history and biology we share with our closest living relatives will continue to occur at an increasing pace.
We would like to thank Christina Bergey for assistance with the figures and Eleni Nikitopoulos for her comments on the manuscript.