Since completing the sequencing of the chimpanzee genome last year, geneticists have spent many hours comparing human DNA sequences to those of our closest evolutionary relative, looking for the differences that distinguish the two species.
Now a team of researchers has found the human DNA sequence with the most dramatically increased rate of change.
The function of this region of DNA is still unknown, but it appears to be directly involved in the development of the human brain. "It's very exciting to use evolution to look at regions of our genome that haven't been explored yet," said Howard Hughes Medical Institute investigator David Haussler, the leader of the team that included scientists from the University of California, Santa Cruz, the University of California, Davis, the University of Brussels, and Universiti Claude Bernard in France.
Their article will be published in an advance online publication on August 16, 2006, in the journal Nature.
Haussler's group found the DNA region using a technique developed by Katherine Pollard, a former postdoctoral fellow in Haussler's lab who is now an assistant professor at the University of California, Davis. Pollard compared the DNA sequences of chimps, mice, and rats to find the regions that had remained largely unchanged over the 80 million years or so since the common ancestor of those organisms. She then examined the same regions in humans to identify those that had changed markedly in the 6 million years since humans and chimps diverged from a common ancestor.
"Some DNA regions have hardly changed at all over many millions of years in most species," said Pollard. "My twist was to look for the subset of these regions that have changed just in humans."
Forty-nine regions, which the team called human accelerated regions (HARs), rose to the top of the list. Surprisingly, only two of these regions code for proteins. Instead, the majority of the regions tend to be located near genes that are involved in regulating the function of genes. Furthermore, 12 of the regions are adjacent to genes involved in the development of the brain.
The Nature paper looks in depth at the region that has undergone the most change in the human lineage, which the researchers called HAR1 (for human accelerated region 1). Only two of the region's 118 bases changed in the 310 million years separating the evolutionary lineages of the chicken and the chimp. Incredibly, since the human lineage separated from that of the chimp, 18 of the 118 nucleotides have changed. This region "stood out," said Pollard.
But what does it do? To find out, Pollard began working with the wet lab, led by Sofie Salama. Haussler established the wet lab following his appointment as an HHMI investigator. After months of work, Salama and her lab mates determined that HAR1 is part of a larger DNA that is transcribed into RNA in the brain.
Then Salama got lucky. Pierre Vanderhaegen, a neuroscientist at the University of Brussels, was visiting Santa Cruz because he knew Salama's husband, who is also a neuroscientist. "I learned that Pierre was setting up to do in-situ hybridizations [at his lab in Brussels] to look at gene expression patterns in human embryonic brain samples," said Salama. "So I gave him a DNA probe from the HAR1 region and said, 'Try this.'"