What makes us human? Comparing the human genome to the genomes of great apes and other species can provide a window into the molecular changes that may ultimately answer this question. In a new study in the premier open-access international journal PLoS Biology, Peter Keightley and colleagues compare the regulatory regions in the chimp and human genome with those of mouse and rat--and make a startling discovery. Compared with rodents, deleterious mutations have apparently accumulated in the hominid lineages, racking up an estimated additional 140,000 harmful mutations since humans and chimps diverged, mutations that have been selectively eliminated in mouse and rat.

The authors compared the conservation of DNA sequences making up the bulk of gene-regulating elements and found marked conservation in the regulatory regions between mice and rats, but nearly none between humans and chimps. This result suggests that the gene-regulating elements of hominids are subject to nearly unfettered mutation accumulation. Keightley and colleagues propose that selection is ineffective against mildly unfavorable mutations in the gene-regulating regions of hominids because of the small effective population size in their evolutionary history.

What do these results suggest for the future of human evolution? It's unlikely that the regulatory gatekeepers of our genome will allow mutations to spin out of control. Even if the number of unwanted mutations were to increase, stronger natural selection against them is likely to develop in parallel, Keightley and colleagues explain, protecting our fitness from a downward spiral. The authors' results, however, support the notion that population size exerts a powerful influence on evolutionary changes at the molecular level. With each new sequenced genome added to the comparative genomics lexicon, scientists are becoming increasingly conversant in the grammar and syntax of gene sequences--and filling in more and more gap
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Contact: Paul Ocampo
pocampo@plos.org
1-415-624-1224
Public Library of Science
24-Jan-2005

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