Tracking genetic traits over time

first_imgFossils may providetantalizing clues to human history, but they also lack some vital information,such as revealing which pieces of human DNA have been favored by evolutionbecause they confer beneficial traits — resistance to infection or the abilityto digest milk, for example. These signs can only be revealed through geneticstudies of modern humans and other related species, though the task has provendifficult. Now, in a paper appearing in today’s edition of Science Express, Harvard and Broad Institute researchersdescribe a method for pinpointing these preferred regions within the humangenome that offers greater precision and resolution than ever before, and thepossibility of deeply understanding both our genetic past and present. “It’s clear that positive natural selection has been a critical force inshaping the human genome, but there are remarkably few examples that have beenclearly identified,” said senior author Pardis Sabeti, an associate memberof the Broad Institute of Harvard and MIT and an assistant professor of in Harvard’s department of organismic and evolutionary biology. “The methodwe’ve developed makes it possible to zero in on individual genes as well as thespecific changes within them that are driving important evolutionarychanges.”Positive natural selection is a process in which advantageous traits becomemore common in a population. That is because these traits boost an individual’schances of survival and reproduction, so they are readily passed on to futuregenerations. Identifying such traits — and the genes underlying them — is acornerstone of current efforts to dissect the biological history of the humanspecies as well as the diseases that threaten human health today. “In the human genome, positive natural selection leaves behind verydistinctive signals,” said co-first author Sharon Grossman, a researchassistant at Harvard’s FAS Center for Systems Biology and at the Broad Institute. Yet earlier methodsfor detecting these signals are limited, highlighting relatively large chunksof the genome that are hundreds of thousands to millions of genetic letters or“bases” in length, and that can contain many genes. Of the hundreds of these large genomic regions thought to be under positivenatural selection in humans, only a handful have so far been winnowed to aprecise genetic change.  “Finding the specific genetic changes that are under selection can be likelooking for a needle in a haystack,” said Grossman. Sabeti, Grossman, and their colleagues wondered if there might be a way toenhance this genomic search. Because existing methods for detecting naturalselection individually measure distinct genomic features, the researcherspredicted that an approach that combines them could yield even better results. After some initial simulations to test their new method, the research teamapplied it to more than 180 regions of the human genome that are thought to beunder recent positive selection, yet, in most cases, the specific gene orgenetic variant under selection is unknown. The researchers’ method, called “Composite of Multiple Signals” orCMS, enabled them to dramatically narrow the size of the candidate regions,reducing them from an average of eight genes per region to one. Moreover thenumber of candidate genetic changes was reduced from thousands to just a handful,helping the researchers to tease out the needles from the haystack. “The list of genes and genetic loci we identified includes many intriguingcandidates to follow up,” said co-first author Ilya Shlyakhter, acomputational biologist in Harvard’s department of organismic and evolutionary biology and at the Broad Institute.“For example, a number of genes identified are involved in metabolism,skin pigmentation, and the immune system.” In some cases, the researchers were able to identify a specific genetic changethat is the likely focal point of natural selection. For example, a variationin a gene called protocadherin 15, which functions in sensory perception,including hearing and vision, appears to be under selection in some East Asianpopulations. Several other genes involved in sensory perception also appear tobe under selection in Asia. In addition, the team uncovered strong evidence ofselection in East Asians at a specific point within the leptin receptor gene,which is linked to blood pressure, body mass index, and other important metabolicfunctions. The researchers also localized signals to regions outside of genes, suggestingthat they function not by altering gene structure per se, but by changing how certain genes are turned on and off. While the findings in the Science paper offer a deep glimpse of evolution’shandiwork, the researchers emphasize that further studies of individual geneticvariations, involving experiments that explore how certain genetic changesinfluence biological function, are necessary to fully dissect the role ofnatural selection and its impact on human biology. “This method allows us to trace evolution’s footprints with a much finerlevel of granularity than before, but it’s one piece of a much largerpuzzle,” said Sabeti. “As more data on human genetic variationbecomes available in the coming years, an even more detailed evolutionarypicture should emerge.”last_img