DOI: 10.1126/Science.1139247 , 222 (2007); 316 Science Et Al. Consortium, Rhesus Macaque Genome Sequencing and Analysis Rhesus M
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Evolutionary and Biomedical Insights from the Rhesus Macaque Genome Rhesus Macaque Genome Sequencing and Analysis Consortium, et al. Science 316, 222 (2007); DOI: 10.1126/science.1139247 The following resources related to this article are available online at www.sciencemag.org (this information is current as of April 13, 2007 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/cgi/content/full/316/5822/222 Supporting Online Material can be found at: http://www.sciencemag.org/cgi/content/full/316/5822/222/DC1 A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/cgi/content/full/316/5822/222#related-content This article cites 67 articles, 34 of which can be accessed for free: http://www.sciencemag.org/cgi/content/full/316/5822/222#otherarticles on April 13, 2007 This article has been cited by 3 articles hosted by HighWire Press; see: http://www.sciencemag.org/cgi/content/full/316/5822/222#otherarticles This article appears in the following subject collections: Genetics http://www.sciencemag.org/cgi/collection/genetics Information about obtaining reprints of this article or about obtaining permission to reproduce www.sciencemag.org this article in whole or in part can be found at: http://www.sciencemag.org/about/permissions.dtl Downloaded from Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright c 2007 by the American Association for the Advancement of Science; all rights reserved. The title SCIENCE is a registered trademark of AAAS. The Rhesus Macaque Genome ognized as a loss in the chimpanzee if it is RESEARCH ARTICLE present in the macaque, or it can be recognized as a gain in the human if it is absent in macaque. In principle, this three-way comparison should Evolutionary and Biomedical Insights make it possible to pinpoint many changes and identify specific underlying mutational mecha- from the Rhesus Macaque Genome nisms, which could have been critically impor- tant during the past 25 million years in shaping Rhesus Macaque Genome Sequencing and Analysis Consortium*† the biology of the three primate species. We examined the basic elements of the rhesus The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the macaque genome and undertook reconstruction ancestors of Homo sapiens about 25 million years ago. Because they are genetically and of the major changes in the human-chimpanzee– physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in rhesus macaque (HCR) trio. The regions of the basic and applied biomedical research. We determined the genome sequence of an Indian-origin genome that were duplicated in macaque were Macaca mulatta female and compared the data with chimpanzees and humans to reveal the then identified and correlated with other ge- structure of ancestral primate genomes and to identify evidence for positive selection and lineage- nome features. Individual macaque genes were specific expansions and contractions of gene families. A comparison of sequences from individual studied, and the orthologous genes in the HCR animals was used to investigate their underlying genetic diversity. The complete description of the trio were aligned to reveal evidence for the ac- macaque genome blueprint enhances the utility of this animal model for biomedical research and tion of selection on individual loci. Additional improves our understanding of the basic biology of the species. animals from other populations were also sampledbyDNAsequencingtostudytheir hesus macaques (Macaca mulatta)(1) to research, but the rhesus macaque has been genetic diversity. Throughout, complementary are one of the most frequently en- used most widely. Taxonomists recognize six methods were applied and the different results countered and thoroughly studied of all M. mulatta subspecies (1), which differ substan- combined in order to represent the most com- R on April 13, 2007 nonhuman primates (table S1.1). They have a tially in their geographical range, body size, and a plete picture of macaque biology. For a visual broad geographic distribution that reaches from variety of morphological, physiological, and be- representation of some of the insights gained Afghanistan and India across Asia to the havioral characteristics. North American research from the genome and more information about Chinese shore of the Pacific Ocean. As an Old colonies include animals representing both Indian the importance of the macaque as a model World monkey (superfamily Cercopithecoidea, and Chinese subspecies, although India ended the organism, see the poster in this issue (6). family Cercopithecidae), this species is closely exportation of these animals in the 1970s. related to humans and shares a last common With the advent of whole-genome sequenc- Sequencing the Genome ancestor from about 25 million years ago (Mya) ing, a highly accurate human genome sequence To generate a draft genome sequence for the (2). The two species often live in close associa- and a draft of the chimpanzee genome have rhesus macaque, whole-genome shotgun tion, and macaques exhibit complex and in- been generated and compared. The chimpanzee sequences were assembled. The bulk of the www.sciencemag.org tensely social behavioral repertoires. shared a common ancestor with humans ap- sequencing used DNA from a single M. mulatta The relationship between humans and ma- proximately 6 Mya (4, 5), and the major impact female, whereas DNA from an unrelated male caques is even more important because biomedical of the chimpanzee genome sequence data has was used to construct a bacterial artificial chro- research has come to depend on these primates been in their direct comparison with data from mosome (BAC) library to provide BAC end as animal models. Compared with rodents, which the human genome. However, the chimpanzee sequences and to aid in selective finishing. We are separated from humans by more than 70 data have major limitations. First, because the million years (2, 3), macaques exhibit greater alignable sequence is only 1 to 2% different Downloaded from similarity to human physiology, neurobiology, from that of the human, there is no informative HCR Ancestor and susceptibility to infectious and metabolic “signal” to distinguish conserved elements from diseases. Critical progress in biomedicine the overall high background level of conserva- 25 Mya attributed to macaques includes the identifica- tion. This is exacerbated by the fact that the 43 tion of the “rhesus factor” blood groups and chimpanzee genome was an incomplete draft, advances in neuroanatomy and neurophysiol- containing sequence errors that could potentially HC Ancestor ogy. Most important, their response to infectious mask true divergence. Second, the differences ~6 Mya agents related to human pathogens, including that are found between humans and chimpan- simian immunodeficiency virus and influenza, zees are difficult to assign as specific to either 5 14 has made macaques the preferred model for the chimpanzee or the human. As a result, the vaccine development. Lesser-known contribu- chimpanzee analyses have on their own provided tions of these animals include their early use in relatively few answers to the fundamental ques- humanchimpanzee macaque the U.S. space program—a rhesus monkey was tion of the nature of the specific molecular launched into space more than a dozen years changes that make us human. before any chimpanzee. By contrast, the genome of the rhesus ma- The cynomolgus macaque (M. fascicularis), caque has diverged farther from our own, with an pigtailed macaque (M. nemestrina), and Japa- average human-macaque sequence identity of Fig. 1. Evolutionary triangulation in the hu- nese macaque (M. fuscata) have all contributed ~93%. Figure 1 shows the inferred common an- man, chimpanzee and rhesus macaque lineages cestor for all three species, as well as a common (lineage-specific breaks), showing a summary of *To whom correspondence should be addressed. Richard A. Gibbs, E-mail: [email protected] ancestor that predated the human-chimpanzee chromosomal breakpoints on a microscopic scale †All authors with their contributions and affiliations appear divergence. A characteristic that is found in (Fig. 3) (7). Circled numbers indicate numbers of at the end of this paper. humans but not in the chimpanzee can be rec- lineage-specific breaks. 222 13 APRIL 2007 VOL 316 SCIENCE www.sciencemag.org SPECIALSECTION used several whole-genome shotgun libraries point. The human map was also used to help and the XY sex chromosomes. With the ex- with different insert sizes (~3.0, 10, 35, and place large merged scaffolds onto the ma- ception of 48 breakpoints (Fig. 1)—including 180 kb) to generate a total of 18.4 Gb of raw caque chromosomes (8, 9) [the chromosome three fusions, one fission, and breakpoints DNA sequence through standard fluorescent numbering of Rogers et al.(8) was used] at the induced by inversions that are each detectable Sanger sequencing technologies. Initial assemblies highest level of the assembly process. Given through chromosome staining, by radiation hy- to the intermediate scaffold stage were carried out that the human data were only used to split brid mapping, or by comparative linkage map- by