Studies of human genetic variation have found strong evidence for the action of natural selection

One of the most comprehensive studies of the forces that have shaped patterns of human genetic variation has found strong evidence for the action of natural selection, which may help explain why certain people are at risk for a variety of conditions and others are not.

The findings were published online this week for the journal Public Library of Science Biology in a paper titled "Population History and Natural Selection Shape Patterns of Genetic Variation in 132 Genes." For the paper, researchers studied the molecular evolution of 132 genes by comprehensively resequencing them in 24 African-Americans and 23 European-Americans. The results showed strong evidence for natural selection at eight genes in the European-American population, likely explained by the different environmental conditions people encountered as they moved into Europe sometime between 25,000 to 50,000 years ago.

"Our results suggest that the migration of humans out of Africa into new environments was accompanied by genetic adaptations to emergent selective forces," said Dr. Joshua Akey, lead author of the paper and an assistant professor in the Department of Genome Sciences at the University of Washington in Seattle.

If you were to compare the genomes of two randomly selected individuals you would find that they are not identical, but on average contain differences every 1,000 base pairs or so. The most common form of these differences is "single nucleotide polymorphisms," or SNPs (pronounced 'snips').

Occasionally, new SNPs arise that allow certain individuals in a population to be healthier and produce more offspring, and these variants become more frequent through the process of natural selection. Although there is considerable interest in finding regions of the human genome that have been targets of natural selection, the tools and resources needed to do so are only now becoming widely available.

In the paper, researchers describe the largest signature of natural selection discovered to date: a series of four contiguous genes on Chromosome 7 that appear to have been transformed as people in Europe began to drink more cow and goat milk. The result: people that inherited certain variations of these genes, known as alleles, are better able to absorb calcium into their bodies.

One of the genes involved is TRPV6 and has been implicated in the development or aggressiveness of prostate cancer. It and another gene in the region, TRPV5, are also involved in calcium absorption in the kidney, intestine and placenta. Scientists had previously found that genetic variation in a gene promoting lactose-tolerance in milk drinking European populations was selected for some 10,000 to 20,000 years ago. The latest discovery seems to complement that discovery, Akey said, because the body would not only need to be tolerant to lactose but also be able to absorb the calcium.

The lead author of the paper says that researchers worldwide are just beginning to understand evolution's contribution to our genetic risks for disease and the underlying genetic causes of illness.

"This paper provides compelling evidence that identifying regions of the human genome that have been the targets of natural selection will provide important insights into recent human evolutionary history – and may also help us understand and identify the genetic contribution to various complex diseases," Akey said.

The findings appear to provide support for a theory widely known as the 'thrifty gene hypothesis' that was originally proposed to explain the high prevalence of Type 2 diabetes. The thrifty gene hypothesis argues that genetic variation that encouraged people to eat and store lots of food was beneficial at one point in human history when resources were scarce, but is now detrimental and increases susceptibility to diseases such as diabetes and obesity.

"The environment of modern humans is dramatically different compared to our ancestors who lived just 10,000 years ago. Now we have unlimited access to fast food and super-sized versions of everything. Although the "thrifty gene hypothesis" may be overly simplistic, the basic idea that genetic variation that once helped us but is now working against us may indeed turn out to be true for some genes that increase susceptibility to complex diseases. If this is true, finding genes that have been affected by natural selection may also help us find complex disease genes," Akey said.

In the paper, Akey and colleagues describe several additional genes that have been affected by selection and show a connection to diseases such as high blood pressure, kidney disease, susceptibility to infection, asthma, and Alzheimer's disease.

He and colleagues used data from the Seattle SNPs project, led by Dr. Deborah Nickerson, a professor in the Department of Genome Sciences at UW, which is a large-scale study of genetic variation and how it may affect the function of human genes.

Akey performed the research as a postdoctoral research fellow in the laboratory of Dr. Leonid Kruglyak at the Fred Hutchinson Cancer Research Center's Human Biology Division. The project is part of the programs for genomic application funded by the National Heart, Lung, and Blood Institute (NHLBI).

The authors include Dr. Joshua Akey, Dr. Leonid Kruglyak, Dr. Deborah A. Nickerson, Dr. Michael A. Eberle of the Fred Hutchinson Cancer Research Center, Dr. Mark J. Rieder and Dr. Christopher S. Carlson of the UW Department of Genome Sciences, and Dr. Mark D. Shriver at the Pennsylvania State University, Department of Anthropology.

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