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Vol. LVII, No. 16
August 12, 2005

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Insights from Comparing Genomes

You can learn a lot by looking at a genome, the full set of genes in an organism. You can learn even more by looking at several at once — a field called comparative genomics. Among the more interesting work coming out in July were two NIH-funded comparative genomics studies, both published in Science a week apart. One compared 8 mammalian genomes; the other, those of 3 deadly protozoan parasites.

The mammalian study, funded in part by NHGRI and NCI, aimed to explore mammalian chromosome evolution by aligning and comparing the human, mouse, rat, cow, pig, dog, cat and horse genomes. In an impressive feat, the researchers reconstructed the genomes of long-extinct mammals and determined the rates of mammalian chromosome evolution. They found that rates dramatically accelerated around 65 million years ago, a period of mass extinction (most notably, of the dinosaurs) that marked the end of the age of reptiles and the arrival of the age of mammals. These results might be expected, given the rapid expansion of mammals into new ecological niches.

A more surprising finding was that chromosome rearrangements tended to occur in the same regions. Researchers had long thought that mammalian chromosomes evolved through random breaks, but this study found that nearly 20 percent of breakpoint regions were reused. These "hotspots" tend to have a high gene density. They also seem to be associated with the more frequent cancer-associated chromosome abnormalities. Rearrangements near these breakage hotspots might activate genes that trigger cancer or inactivate genes suppressing it. As more genomes become available, these relationships will become clearer.

The other research came in the form of a set of studies, partly supported by NIAID, that decoded the genomes of 3 trypanosomatids. These parasites, which cause leishmaniasis, Chagas' disease and "sleeping sickness," collectively cause disease and death in millions of people, primarily in developing countries. There are no vaccines for these diseases and no ideal drugs for dealing with them.

Although the 3 parasites share many general characteristics, each is transmitted by a different insect, targets different tissues, has distinct disease pathogenesis and uses different immune-evasion strategies. Nevertheless, comparative genome analysis revealed a core of about 6,200 common genes. A drug designed to target such conserved core processes could potentially be useful against all trypanosomatids. These studies also revealed a plethora of unique potential drug targets. This research will hopefully now spur the development of better diagnostics and therapeutics for these deadly diseases.