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DNAAbout 5 percent of mammals' genetic makeup has remained virtually unchanged by evolution. Surprisingly, less than a third of these "conserved" portions of the genome contain genes that code for proteins. The rest, known as conserved noncoding sequences (CNCs), is of growing interest to scientists: there's growing suspicion that these areas aren't just filler, but contain functional bits of genetic sequence whose variation may contribute to human disease.

Seeking to prove this suspicion, researchers led by Joel Hirschhorn, MD, PhD, of Boston Children's Divisions of Genetics and Endocrinology and Program in Genomics, and also an associate member of the Broad Institute, combined a list of CNCs with two large databases: the recently released HapMap database and the chimpanzee genome sequence. The HapMap project catalogued places where people's genomes vary and measured how frequent each variant is in the population. By comparing these data with the chimpanzee genome, the researchers identified which variants were new mutations--appearing in humans, but not in chimps.

They then compared the pattern of new mutations in the CNCs versus the rest of the genome. They reasoned that if the CNCs had a preponderance of rare mutations, and fewer mutations common to many individuals, that would indicate that some of the mutations in CNCs were harmful, and that natural selection was weeding them out. And that is what their computational analysis showed, providing the most direct evidence to date that CNCs perform important functions in the genome. Jared Drake and James Nemesh were key contributors to the work, a collaboration with the Sanger Institute in England. The study appeared in the December 25th, 2005 online edition of Nature Genetics.