Macaque genome sequence provides sideways look at human disease.
Rhesus macaques can't claim the distinction of being humanity's closest cousins, nor of ever having been popularized by Jane Goodall. But the newly completed analysis of the macaque's genome could prove just as important as that of the chimpanzee's, scientists say.
Macaca mulatta is the third primate genome to be sequenced, following those for humans (Homo sapiens) and chimpanzees (Pan troglodytes). Adding the macaque to that picture, scientists say, should allow researchers to make better sense of the other two genomes. And because the rhesus macaque is the main monkey model for many diseases, understanding its genome could help to clarify why some diseases develop, and why some treatments work differently in monkeys from in humans.
The macaque genome, published on 13 April in Science, is crucial for unravelling the evolutionary events that led to humanity. Ever since scientists released the chimp genome sequence in 2005 (see Nature 437, 69–87; 2005), they have been busily trying to dissect how it differs from our own — looking for clues to explain uniquely human traits.
But when a genetic difference is identified between humans and chimps, it is not always possible to tell which form of the DNA is older. Scientists can compare each sequence to those of distantly related animals, such as chickens and mice, but this technique fails when the genetic variant is so new that it is unique to primates. The macaque is therefore an ideal reference point, scientists say, because the evolutionary split between monkeys and apes (such as humans and chimps) occurred 25 million years ago, much earlier than the human–chimp divergence 6 million years ago.
“Now that we have a third primate, a large part of the focus is understanding the changes that happened in each primate lineage, and that is very important in understanding evolution,” says George Weinstock of the Baylor College of Medicine in Houston, Texas, a leader of the macaque sequencing effort. The project involved researchers from North America, Asia and Europe (Rhesus Macaque Genome Sequencing and Analysis Consortium Science 316, 222–234; 2007).
And the macaques could soon have company. Other primate genome sequences in progress include the gibbon (Nomascus leucogenys), orangutan (Pongo pygmaeus), gorilla (Gorilla gorilla) and marmoset (Callithrix jacchus).
The new analysis finds that where humans and macaques share genes, the DNA sequences in those genes are 97.5% identical. But the findings also highlight differences between the species' DNA. For instance, the scientists report that the 108 gene families shared between humans, macaques and chimps have evolved differently in the three species, and about 60% of those amplified in the macaque show signs of natural selection. Some of these genes probably explain differences between humans and monkeys — like our inability to swing through forest treetops and our revulsion to ingesting our own vomit.
The differences might also shed light on more medical issues. Macaques are often used as stand-ins for humans in experimental tests of drugs and medical treatments — especially for infectious diseases, such as HIV. But these monkey tests do not always accurately predict how the treatments behave in the human body.
The new analysis finds that macaques have many more copies of genes corresponding to those making up the human HLA system — a key part of the body's defence against diseases. Finding that the HLA system is genetically different in macaques could be a sign that the monkeys' immune systems don't work like our own. That information, in turn, could help researchers design more accurate preclinical tests in macaques.
“A lot of people use macaques as a model for the immune response, so the fact there are these differences is important,” says Evan Eichler of the University of Washington in Seattle, one of the leaders of the analysis portion of the macaque project.
And that, scientists say, means that the macaque genome should be analysed in even more detail. The current publication is only a 'draft' sequence — meaning it is not as complete as, for instance, the human genome.
But already, plenty of material is available to chew on. For instance, the analysis turned up hundreds of cases in which humans and macaques share a gene, but although the macaque version keeps the monkey healthy, the human one causes disease. Understanding the implications of this finding could take some time. But it may cause some scientists to rethink their approach to the nature of disease. Rather than being a recent glitch in our physiology, a disease-causing gene might actually be a holdover from our ancestral history that hasn't kept pace with the way our bodies or lifestyles have evolved, and has now become detrimental.
“We tend to think about disease very simplistically, that everything was fine until a new variant was introduced, and then things went awry,” Weinstock says. “But actually, it is much more complex than that.”