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Tracing our footsteps

How can we find out what changes specific mutating genes brought along for humans? Easy, use a time machine to go back and find out.

Since we don’t seem to have invented one yet, Pardis Sabeti, an Iranian-American scientist at Harvard University and the Broad Institute — a collaboration between Harvard and the Massachussetts Institute of Technology —has come up with an innovative solution. She and a team of international researchers have introduced a specific genetic variation — believed to have first surfaced in people living in China some 30,000 years ago — in mice to see what exactly the changes it leads to are.

This is the first time that mice, commonly used in disease research, have been used to study human evolution. This novel approach may prove a watershed in gaining deeper insights into human evolution as scientists could employ similar animal models to study other genetic variations.

It is fitting that Sabeti has come up with such an original way of tackling the problem for she is an unusual scientist. Apart from being a computational geneticist, Sabeti is the lead singer and bassist of the alternative rock band Thousand Days, which released four albums, including one last year.

From a tiny founding population that originated in Africa, humans went on to take over planet Earth in a span of 100,000 years. During each wave of migration, our forefathers encountered hostile environments and their survival hinged on adapting to newer surroundings. Evolutionary biologists have hypothesised — and proved in some cases — that aiding this adaptation were mutations in a number of human genes. Scientists have identified as many as 400 sites on the human genome that carry signatures of recent human evolution. Following up on them, scientists have elucidated DNA changes that occurred at some of these sites and even correlated them with the acquired traits.

Humans, just like all other living beings, evolve through a process of selection, which involves organisms with some traits thriving while those without that particular mutation die off. If a particular version of a gene has spread through a whole population, it means that at one time it boosted survival. How exactly? That’s where the mice come in.

The EDAR gene is found in vertebrates — including mice and zebra fish, apart from humans — and is believed to be involved in the development of skin, hair and scales in fish. While African and European populations carry the standard version of this gene, that found in East Asians is subtly different as one of its DNA units has mutated. This minor variation was first identified in 2007 by Sabeti’s team but they didn’t have any idea about the traits associated with it.

To trace the changes the mutant EDAR gene confers, Sabeti and her colleagues, together with their collaborators from across the globe, decided to transplant the gene variant in mice. The scientists discovered that the single mutation gave rise to several traits such as thicker hair shafts, increased sweat glands, smaller breasts and teeth which are characteristic of the present-day Han population in China. Some of these — thicker hair shafts and more sweat glands — were critically important to adapt to the humid climate.

Yana Kamberov works with colleague Sijia Wang in a Harvard lab

“There is an archaeological record hidden in our DNA that can help point us to the traits that have been critical in human survival, such as resistance to infectious diseases and new abilities to respond to different environments,” says 37-year-old Sabeti.

“This shows that single amino acid substitution alone can change multiple traits,” says Yana Kamberov, a Harvard Medical School research fellow, who is one of the two first authors of the paper.

This was one of two papers from Sabeti’s lab that appeared in Cell journal early this month. The other paper — to which an Indian scientist, Rameshwar Bamezai of the Jawaharlal Nehru University in New Delhi, has contributed — is equally significant. It uses data from the 1000 Genome Project to analyse DNA sequence variations across the entire human genome. Scientists who contributed to the paper identified hundreds of gene variants that potentially contributed to human evolutionary adaptation. One of these, a mutation in a gene called TLR5, changed the immune responses of cells exposed to bacterial proteins, suggesting that this variant could protect against bacterial infections.

Bamezai, as part of an international team of scientists, has earlier studied the genetic susceptibility of Mycobacterium leprae (leprosy-causing microbe). “We worked with him and his team to analyse signatures of natural selection linked to several genetic markers of resistance to leprosy,” Sabeti told KnowHow.