Darwin's studies of finches in the Galapagos Islands revealed that the birds' beak length affected their survival, a finding that spawned his famous survival-of-the-fittest theory known as natural selection. A new study from the Human Biology Division finds evidence that natural selection had a strong influence on shaping the DNA differences associated with different racial or ethnic groups. The finding could speed the search for genes that affect an individual's risk of cancer and other diseases.
Researchers analyzed the evolution of 132 genes by sequencing them in 24 African-Americans and 23 European-Americans, and detected DNA changes indicative of natural selection in eight of the genes in the European-American population. The scientists speculate that these changes originally evolved as a way to survive in the new environmental conditions people encountered as they moved into Europe from Africa between 25,000 to 50,000 years ago.
Since populations that once benefited from certain genetic changes may live under very different environmental conditions today, some relics of natural selection may no longer provide a survival advantage and could even put carriers at increased risk for disease. Studying the legacy of natural selection could be of enormous benefit to scientists who hope to pinpoint the sets of genes that underlie cancer, heart disease and other so-called complex diseases, said Dr. Leonid Kruglyak, whose laboratory led the analysis.
"Although it remains to be demonstrated conclusively, there are strong arguments to support the idea that genes that have undergone natural selection are likely to be involved in disease susceptibility," he said.
The study, published in the October issue of the journal Public Library of Science Biology, was led by Dr. Joshua Akey, who conducted the work while a postdoc in Kruglyak's lab and is now an assistant professor of genome sciences at the University of Washington. Other co-authors included Dr. Michael Eberle, a research scientist in the Kruglyak lab, Dr. Deborah Nickerson and colleagues at UW and collaborators at Pennsylvania State University.
Small changes in the DNA sequence of genes have occurred randomly during the course of evolution, which is what makes the DNA from any two individuals unique. Many variants occur at high frequency in the population as a result of random demographic events. Other variants may become prevalent — that is, undergo natural selection — because offspring who inherit them gain a survival advantage. Genes that have been shaped by natural selection have been difficult to find because the majority of genetic changes that have occurred during thousands of years of evolution are thought to confer no appreciable survival advantage, Kruglyak said.
Chromosome 7, milk and prostate cancer
"The way to identify genes that have been the target of natural selection is to look at variation in many different genes within the genomes of many individuals from different racial or ethnic backgrounds," he said. "Then we look for genes that have undergone much more change than would be expected to have occurred if the changes had a neutral effect on fitness. The tools for doing this have only recently become available, which made this study possible."
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 researchers hypothesize that people who inherited certain variations of these genes may be better able to absorb calcium into their bodies, an idea Akey intends to explore in future studies.
One of the genes, called TRPV6, 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 involved in metabolism of lactose in European populations, which enables carriers to digest milk, conferred as survival advantage to carriers 10,000-20,000 years ago. The new finding seems to complement that discovery because the body would not only need to be tolerant to lactose but also be able to absorb the calcium.
The researchers also describe 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.
The findings are reminiscent of 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," Akey said. "For example, 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."