In the genetic material of rhesus macaque monkeys of Indian origin, Cornell biologist Carlos Bustamante has discovered signals of a cataclysmic macaque population decline in the sub-continent tens of thousands of years ago.

Around the time that the first modern humans were exploring and populating India 51,000 years ago, his studies suggest that rhesus macaque monkeys suffered an abrupt drop in numbers, eventually shrinking to a quarter of their original population.

The reason for such a population contraction is still not clear but scientists believe that it has turned the genetic material of today’s Indian macaques especially useful in the hunt for genes associated with human diseases.

Bustamante and his colleagues have used genetic material of macaques of Indian origin to piece together the demographic history of macaques in India. Their findings are among the earliest results to spring from studies on the genome of the rhesus macaque which recently became the third primate species to have had its genome sequenced after humans in 2001 and chimpanzees in 2005.

The rhesus macaque genome is expected to provide fresh insights into differences between humans and other primates as well as emerge as a powerful new tool in biomedical research.

“It will be possible to use macaques to map the genetic basis of complex traits, including human diseases that involve both genetic and environmental components, such as cancer, heart disease, or diabetes,” said Bustamante, the leader of the team at the department of biological statistics and computational biology, Cornell University.

While chimpanzees and humans diverged from their common ancestor six million years ago, rhesus macaques are much older, having diverged from a common ancestor much earlier, 25 million years ago. And while humans share about 98.5 per cent of their genome with chimpanzees, the macaque genome is only 93 per cent identical to the human genome.

A comparison of the three genomes will allow scientists to determine whether differences are mere errors or represent key genetic elements that differentiate humans from other primates.

“Because the macaque is further away from us in evolution than is the chimpanzee, it provides good contrast when the three genomes are compared,” said Richard Gibbs, director of the Baylor College of Medicine Human Genome Sequencing Centre, US, and leader of a global consortium of 170 scientists from seven countries who sequenced the macaque genome.

The macaque genome has already thrown up surprises. Scientists have found instances in which the normal form of the macaque protein looks very similar to a corresponding protein associated with disease in humans. For example, healthy macaques have a protein associated with a condition called phenylketonuria in humans which causes brain damage and mental retardation.

These findings suggest that macaques can tolerate these mutations through as yet unknown mechanisms — something that allows their bodies to compensate for the defective proteins. “It shows the great sensitivity of different genes and proteins to small changes — a change in humans may be devastating, while the same change in macaque is fine,” Gibbs told KnowHow.

There are two possibilities to explain the presence of defective proteins in healthy macaques, said Ryan Hernandez, a Cornell University researcher and a member of the population genetics team.

“Another mutation somewhere else in the macaque genome has compensated for the disease state such that they do not get the disease, or alternatively, some mutations that cause disease in humans actually appear to be an ancestral state — what are now disease-causing mutations in humans used to be carried by all primates,” Hernandez told KnowHow.

The population genetics studies on Indian macaques may help resolve the mystery. The Cornell researchers and their colleagues in the US and Denmark have shown that macaques split into Indian and Chinese subgroups 162,000 years ago.

Their studies on nine Chinese macaques and 38 macaques of Indian origin indicate that since that split, the Indian macaque population has decreased four-fold, while the Chinese macaque population has increased three times. “The population spurt in China and the decline in India provides the two subgroups complementary roles in the hunt for genes,” said Hernandez.

What caused the population expansion in China and contraction in India remains unclear, but researchers believe the steep population decline in India coincided with an ice age about 51,000 years ago — about 10,000 years after the first modern humans trudging out of Africa arrived in India.

Scientists believe macaques from India and China would fit into a two-tiered strategy to look for genes associated with specific diseases or susceptibility to diseases. The Indian rhesus macaque may be first used to identify large genetic regions of interest, followed by the use of the Chinese rhesus macaque to focus on a narrower genetic window, Hernandez said.

“The physiological differences between the two groups are important in the design of studies to map genes,” said Bustamante. Previous studies have suggested that Indian and Chinese macaques appear to respond to diseases in different ways. When infected with the simian immunodeficiency virus — a cousin of HIV — Indian macaques develop symptoms faster than Chinese macaques.

“We’d like to follow up through more detailed analysis of the genetic diversity of macaques in India,” Bustamante told KnowHow. “We look forward to collaborating with biologists there who have similar interests.”

India imposed a ban on the export of macaques in the 1970s, and the Indian macaques used in the population studies were born in the US, the progeny of monkeys imported from India decades ago.