A comparison of genome sequences from various species has identified a gene that has evolved at an accelerated pace in humans and which may be one of the major differences between our species and chimps. The gene, whose function is unknown, could be involved in development of the cerebral cortex and might have been crucial in evolution of the human brain.
A ‘gene’ has for a long time been defined as a DNA sequence which encodes a single protein. The human genome was found to contain approximately 30,000 genes, but these coding sequences comprise only about 2% of the genome. A major proportion of the human genome is now known to consist of viral DNA sequences; the coding sequences of some genes overlap with, or are contained entirely within, those of others; coding sequences of individual gene products can be spread out across the genome, seperated by vast distances; and large sections of the genome encode RNA molecules of unknown function. In light of this, the definition of a gene has had to be reconsidered.
In the new study, which was published online in Nature earlier this week, Pollard, et al describe 49 DNA sequences which have undergone very little mutation in all the species compared in the study, except for humans, in which they appear to have rapidly evolved. The researchers have consequently named these sequences human accelerated regions (HARs). Most of the HAR sequences identified are not genes in the conventional sense of the word. Most lie near regulatory genes, and 12 of them are adjacent to genes involved in neural development, but only two of the sequences actually code for proteins.
One of the sequences, HAR1, has mutated more rapidly in humans than in any of the others studied so far; all other species have an almost identical version of the gene. The region consists of 118 base pairs; in chimps and chicks, which are seperated by more than 300 million years of evolution, HAR1 is almost identical, with only two nucleotides differing.
A comparison of the sequences in chimps and humans showed that 18 of the 118 nucleotides differ (left, top and bottom, respectively). This, says Pollard, is “an incredible amount of change,” because chimps and humans diverged from a common ancestor about 6 million years ago.
Further analysis of the sequence revealed that HAR1 lies in an overlapping region of two genes that are transcribed in opposite directions. Both the overlapping genes encode RNA molecules which are not translated into proteins, and whose functions are unknown.
The HAR1 gene encodes an RNA molecule which forms a stable structure called a ‘hairpin.’ This structure is formed by complementary base paring, the same type of bonding that occurs between DNA strands; other RNA molecules which form these structures can interact with protein molecules and DNA to regulate function, and it is possible that this is what HAR1 does.
HAR1 is expressed in Cajal-Retzius cells during 7-19 weeks of gestation. Cajal-Retzius cells (left) are involved in corticogenesis; they provide a transient scaffold, spanning the radius of the developing cortex, over which cortical cells migrate, then die after cortical development is complete. In these cells, HAR1 is co-expressed with reelin, which is required for the specification of the six layers of the developing cerebral cortex; HAR1 may have a role in the regulation of genes such as reelin during development of the neocortex.
“We don’t know what it does, and we don’t know if it interacts with reelin. But the evidence is very suggestive that this gene is important in the development of the cerebral cortex, and that’s exciting because the human cortex is three times as large as it was in our predecessors,” says David Haussler, director of the University of California’s Center for Biomolecular Science and Engineering, where much of the research took place.
Although the function of HAR1 is unknown, it is tempting to think that it is involved in the evolution and development of the cortical circuitry underlying cognition. The gene is, however, also known to be expressed in the ovaries and testes of adult humans; genes involved in human reproduction are also known to have evolved rapidly, so the possibility that HAR1 evolved for a reproductive function cannot be ruled out.