Analysis of Rhesus Monkey Genome Uncovers Differences with Humans, Chimps

An international consortium of scientists including Penn State researchers analyzed the draft genome sequence of the rhesus macaque monkey, the second nonhuman primate, after the chimpanzee, to have its genome sequenced.

Credit: Gopinath Sricandane - For image reprints, contact the photographer at: gopi@photoessays.net

The rhesus genome shares about 93 percent of its sequence with both the human and the chimpanzee genome. As the most distant of the three species, the rhesus provides an ideal reference point for comparisons among the three closely related primates. The study appeared recently in the journal Science, together with four companion papers that also relied on the genome sequence.

The rhesus is widely recognized as the best animal model for human immunodeficiency virus (HIV) infection. It also serves as a valuable model for studying other human infectious diseases and for vaccine research. The rhesus macaque genome sequence enhances essential research in neuroscience, behavioral biology, reproductive physiology, endocrinology and cardiovascular studies.

Other important findings of the overall study include extensive sub-microscopic chromosome changes that have occurred relative to humans and chimpanzees. There are also many small duplications within the genome that are different between the species. These rearrangements are a key feature of primate evolution.

Chimpanzee and human genes are 99 percent similar, while the rhesus macaque genes have an average of 97.5 percent identity to each. The added divergence of macaque allows for the detection of about 200 genes likely to be under positive selection in primates, that are potential key players in determining the differences between the species. These include keratin genes, for hair formation. Ongoing studies will examine the roles of these genes in the evolution of other species.

The sequencing of the rhesus genome was conducted at the Baylor College of Medicine Human Genome Sequencing Center in Houston, the Genome Sequencing Center at Washington University in St. Louis and at the J. Craig Venter Institute in Rockville, Md. The DNA sample for the sequencing came from a female rhesus macaque at the Southwest Foundation for Biomedical Research in San Antonio. Approximately 18 million DNA sequence reads were generated throughout 2005. The rhesus DNA fingerprint database from the Michael Smith Genome Sciences Center at the British Columbia Cancer Agency in Vancouver also was used. Independent assemblies of the rhesus genome data carried out at each of the three sequencing centers and these were joined into a "melded assembly" and the availability of the data was announced at the end of 2005.

"The rhesus macaque is physiologically very similar to humans and occupies a key point in the evolutionary tree," said Richard Gibbs, director of the BCM-HGSC and overall coordinator of the project "this has made for an exciting study."

A Rhesus Macaque Genome Sequence and Analysis Consortium comprising more than 170 scientists from 35 Institutions was established in May 2006, to analyze and interpret the sequence. The group studied chromosome and DNA changes through evolution, as well as gene changes and the relationship between the 'normal' macaque and examples of human disease mutations. As an added part of the study, genetic variation within the species was studied by DNA sequencing in additional animals.

In some cases whole families of genes are radically different between the species, with increases and decreases in different branches of the evolutionary tree. These include important immune related genes, as well as genes for which the function is either not known or is so far difficult to interpret. Overall the study showed that gene gains and losses occur at a higher rate in primates than in rodents.

Penn State researchers from the Center for Comparative Genomics and Bioinformatics were involved in the analysis of the rhesus macaque genome:

• Kateryna Makova , assistant professor of biology, led the study of sex chromosome evolution. The new results support a correlation between male mutation bias and generation times, which lends strong support to the role of replication in generating mutations.
• Webb Miller, professor of biology and computer science, participated in many aspects of the analysis, based on sequence alignment methodologies that he and his colleagues have pioneered. Among these are studies on the ancestral genome, segmental duplications, and analysis of a highly expanded PRAME gene family. Richard Burhans, John Karro, Ian Schenk, and Jian Ma in the CCGB also participated in these studies.
• Graduate students Charles Addo-Quaye and Heather Lawson participated in the identification of homologous genes between macaque and other primates, which was critical for the studies that led to the discovery of genes that are undergoing adaptive evolution in primates.
• Ross Hardison, the T. Ming Chu professor of biochemistry and molecular biology, along with Miller, Arthur Lesk, professor of biochemistry and molecular biology, and Belinda Giardine, examined the genes in macaque that are homologous to human disease genes. This study revealed more than 200 cases in which the disease-associated allele in humans was the same as the normal allele in other primates. These may reveal cases in which the ancestral genotype was adapted to a life-style (such as low caloric intake and high activity) quite different from the current conditions, and which can lead to pathologies now.