Lost and Found Genes

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Vive la différence. Extra (green) or missing (red) copies of genes can drive evolution.

Credit: Adapted from G. Perry et al., Genome Research (2008)

Lost and Found Genes

By Jon Cohen
ScienceNOW Daily News
7 November 2008

As close as humans are to chimpanzees, why do they dodge some diseases that afflict us? And why are we different on so many other levels? A new study that compares genomes from more humans and chimps than ever before suggests that these and other variations might stem from extra or missing copies of key genes.

Although small genetic mutations often receive top billing as the drivers of evolution, the new study focuses on entire genes that are deleted or duplicated, so-called copy number variants (CNVs). Humans and chimps carry two copies of most genes, but different individuals can be missing a gene altogether or have a dozen extra copies. Studies in humans have connected CNVs to myriad diseases, to how we metabolize food, and even to how much testosterone men make. These results led a group headed by molecular cytogeneticist Richard Redon of the Wellcome Trust Sanger Institute near Cambridge, U.K., to collect DNA from 30 chimps and 30 humans and compare regions in which stretches were deleted or copied. (For technical reasons, CNV regions, or CNVRs, are easier to identify than CNVs themselves.)

Earlier studies, like this one, included far fewer individuals, which made it difficult to draw firm conclusions, such as whether an extra gene in a human had evolutionary significance or was just a personal peculiarity, says Redon.

The researchers found several hundred CNVRs in each species, but a big evolutionary question loomed: How many of these are in all humans and all chimps and are thus "fixed" differences that denote evolutionary changes between the two species?

To answer this question, they compared CNVRs in a "reference" human to a reference chimp, which revealed more than 300 copy-number differences. With their data from the 60 other chimps and humans, they determined that 92 copy-number differences between the species were fixed. The team publishes its findings in this month's issue of Genome Research.

First author George Perry, a molecular anthropologist who recently moved from the University of Arizona, Tempe, to the University of Chicago, says some of these variants may help explain phenotypic differences between the species. "There are lots of examples from other species where there's gene duplication, and then one of the copied genes changes slightly and it results in physical innovations," he explains. Similarly, gene deletions can have profound effects.

As an example, Perry points to a gene involved in cholesterol metabolism called APOL1 that has been deleted in chimpanzees; in humans, it confers resistance to a parasite that causes sleeping sickness. Other fixed differences the team uncovered include genes for inflammatory responses and cell growth. The researchers also found evidence that questions whether a CNV that became famous for influencing human susceptibility to HIV, CCL3L1, evolved because of AIDS, as earlier studies asserted.

Geneticist Chris Ponting, who studies comparative genomics at the University of Oxford in the U.K., says the study provides "tantalizing clues." Yet Ponting and the authors caution that many more genomic comparisons of chimpanzees and humans--and finer tools than this study used--will be necessary to identify which CNVs evolved because of natural selection and truly have an impact. Still, Ponting says the study "has shown the way forward in how to approach this issue under an overarching evolutionary framework."