Geography and History Shape Genetic Differences in Humans

http://www.hhmi.org/news/pritchard20090605.html

• In recent years, geneticists have identified a handful of genes that have helped human populations adapt to new environments within just a few thousand years—a strikingly short timescale in evolutionary terms. Other factors -- the movements of humans within and among continents, the expansions and contractions of populations, and the vagaries of genetic chance – have heavily influenced the distribution of genetic variations in populations around the world.

• The research was carried out by Jonathan Pritchard, a Howard Hughes Medical Institute investigator at the University of Chicago, and a team of colleagues including Graham Coop at the University of California, Davis; Joseph Pickrell at the University of Chicago; and Marcus Feldman, Richard Myers, and Luca Cavalli-Sforza at Stanford University. The team found that for most genes, it can take at least 50,000-100,000 years for natural selection to spread favorable traits through a human population.

• Natural selection occurs when a particular genetic difference – which researchers call a variant -- gives an individual a greater opportunity to have children and pass on his or her genes to future generations. These genetic differences, which arise by mutation and then are inherited from parent to child, might confer a survival advantage in a given environment, such as being able to survive malaria or digest milk from animals. As individuals thrive and pass on their genes to their offspring, the variant can become more common in a population. This natural selection of advantageous genes—the raw material of evolution—leaves signals in our DNA that can be detected when researchers compare human genomes.

• Pritchard and his colleagues published the results of their analysis on June 5, 2009, in Public Library of Science (PLoS) Genetics.

• Pritchard says the genetic variants responsible for light skin are good examples of the effects of natural selection. Modern humans evolved in Africa more than 150,000 years ago and then spread throughout Africa and the rest of the world. As these humans moved into northern latitudes, natural selection favored traits that helped them survive in their new environment. Dark skin became a disadvantage, possibly because it blocked too much of the sunlight that humans need to synthesize vitamin D for healthy bones. People with genetic variants that produced lighter skin therefore tended to be healthier and had more children, and today those variants are common in people of European and northern Asian ancestry.

• Selection may also play a role in determining susceptibility to several common diseases. This is another reason why geneticists would like to identify genes that have undergone selection. For example, the “thrifty gene” hypothesis holds that natural selection favored being able to put weight on quickly when food was abundant to tide humans through periods of scarcity. Now that humans in many areas of the world have access to virtually unlimited amounts of food, genetic variants associated with this trait may be contributing to an epidemic of obesity and diabetes.

• Pritchard and his colleagues set out to answer a fundamental question facing human geneticists: Is it possible to determine which genetic variants have increased because of selection and which have increased because of population changes or genetic chance? New data that became available last year from the Human Genome Diversity Project at Stanford University provided a much denser sampling of worldwide genetic differences than was previously available. Pritchard and his colleagues used this resource to carry out a new and more rigorous test for selection.

• To determine whether the frequency of a particular variant resulted from natural selection, Pritchard and his colleagues compared the distribution of variants in parts of the genome that affect the structure and regulation of proteins to the distribution of variants in parts of the genome that do not affect proteins. Since these neutral parts of the genome are less likely to be affected by natural selection, they reasoned that studying variants in these regions should reflect the demographic history of populations. Genetic variants that have been influenced by selection, in contrast, should show different patterns of distribution.

• Their analysis immediately identified known examples of selection, including those involved in determining skin pigmentation, resistance to pathogens, and the ability to digest milk as an adult, the last is a trait that arose in Europe, the Middle East, and Africa following the domestication of dairy animals. The study also revealed several genes of unknown function that appear to have been under strong selective pressures. “We’re keen to learn what these genes are and how they work,” says Coop, who was the lead author on the PLoS Genetics paper.

• In the next few years, a wealth of new data will become available to investigate these questions. For example, the 1000 Genomes Project, supported by the Wellcome Trust Sanger Institute and the National Human Genome Research Institute, is seeking to produce the complete DNA sequences of more than a thousand people from around the world.