A map of recent positive selection in the human genome

Mar 13 2006

By scanning the entire human genome in search of genetic variations that may signal recent evolution, University of Chicago researchers found more than 700 genetic variants that may be targets of recent natural positive selection during the past 10,000 years of human evolution.

In one of the first comprehensive genome scans for selection, published in the Public Library of Science-Biology in a paper, titled "A Map of Recent Positive Selection in the Human Genome," the researchers found widespread evidence of evolution in all of the populations studied.

"This approach allows us to take a broad prospective to see what kinds of biological systems are undergoing adaptation," said Jonathan Pritchard, professor of human genetics and corresponding author of the paper. "There have been a lot of recent changes-the advent of agriculture, shifts in diet, new habitats, climatic conditions-over the past 10,000 years, and we're using these data to look for those signals of very recent adaptation."

The data analyzed here were collected by the International HapMap Project and consist of genetic data from 209 unrelated individuals who are grouped into three distinct populations: 89 East Asians, 60 Europeans and 60 Yorubans from Nigeria. The researchers found roughly the same number of signals of positive selection within each population. They also found that each population shares about one fifth of the signals with one or both of the other groups.

Among the more than 700 signals the team found were previously known sites of recent adaptation, such as the salt-sensitive hypertension gene and the lactase gene-the strongest signal in the genome hunt. The lactase mutation, which enables the digestion of milk to continue into adulthood, appeared in approximately 90 percent of Europeans.

"Presumably," Pritchard said, "a few thousand years from now, if selection pressure remains the same, everyone will have [the selected mutation]."

The team used the PANTHER (Protein ANalysis THrough Evolutionary Relationships) Classification System to classify all the genes in the genome by their biological functions into 222 categories.

In the paper, the researchers listed the top 16 categories that had the strongest signals, including olfaction (the sense of smell), reproduction-related processes and carbohydrate metabolism, which includes the lactase gene.

Other processes that show signals of selection include genes related to metabolism of foreign compounds, brain development and morphology. For example, the researchers found five genes involved in skin pigmentation that show evidence of positive selection in Europeans.

"The idea that skin pigmentation is under strong selection in general is sort of accepted," Pritchard said, "but only one of these five signals was known before." They also found signals in genes involved in hair formation and patterning.

Reproductive selection and sexual competition are systems that undergo adaptive evolution in many organisms, including throughout primate evolution, and signals of selection were found in all three populations, according to Pritchard.

"Many of the signals, however, seem to be more specific to modern human adaptation," he said, "like skin pigmentation, which may respond to changes in habitat, or metabolism genes, like lactase, which may respond to changes in agriculture."

Among East Asians, the researchers found a strong signal of selection in the alcohol dehydrogenase (ADH) cluster, the enzymes that break down alcohol. It's widely known that many East Asians have a mutation in a related gene that renders this pathway nonfunctional.

"That's why a lot of East Asians can't metabolize alcohol," Pritchard said, "but mutations in this pathway must have some additional positive effect that has been favored by natural selection."

One important facet of human evolution to modern diets may be in how food is used and stored in the body. The "thrifty gene" theory suggests some genes encourage efficient storage of food, which leads to rapid weight gain in times of abundant supply. Prior to modern agriculture, it was very important for the body to keep extra resources, but in today's environment, those genes have been linked to obesity. The researchers found signals of selection in several of these genes, including the leptin receptor that is responsible for regulating fat deposits.

In the past, scientists would pick a candidate gene-such as those implicated in brain development or diabetes-and closely analyze how the gene might be associated with evolution or disease. In this study, the researchers looked for signals in the evolutionary data to steer them toward new candidate genes.

Evolutionary theory predicts what patterns of genetic variation should look like around a positively selected allele. The frequency of that allele increases so rapidly that there's no time for recombination-the shuffling of nearby genes-to take place. This process produces a characteristic signal of unusual homogeneity among the chromosomes that carry the selected allele. For this project, the scientists scanned through the data for genomic regions that fit this pattern.

"We found many of the strongest signals in the genomes, but there may be many more that we've missed," Pritchard admitted, which is why the researchers now are looking more closely at the data, as well as within each population.

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