Jackson research team finds protein controlling chromosome recombination "hotspots"

Date: January 1, 2010
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Jackson Laboratory scientists have found that a protein, PDRM9, turns certain locations on chromosomes into "hotspots" of recombination activity during reproduction.

Genetic recombination, in which chromosomes "cross over" and essentially exchange segments during meiosis, is a fundamental part of sexual reproduction. It ensures greater genetic diversity and helps with the separation of chromosomes to ensure that eggs and sperm have only one copy of each chromosome, instead of the pairs found in almost all other kinds of cells.

Recombination is an extraordinarily precise process. The segments exchanged have to be exactly the same length, without even one extra base, so that they don't introduce disastrous "frame-shift" mutations (like skipping a button when putting on a shirt: all the rest of the buttons will be matched with the wrong holes).

Scientists have observed so-called hotspots on chromosomes, where recombination occurs most frequently, but lacked understanding of how they develop and operate. In a paper published in Science (online December 31, 2009), Jackson Laboratory Professor Ken Paigen and colleagues provide some of the first insights into what regulates recombination hotspots.

Paigen and coauthors in his laboratory, Research Scientist Petko Petkov and Postdoctoral Associate Emil Parvanov, identified an area on mouse chromosome 17 that apparently controls the activation of hotspots elsewhere in the genome. Using extensive crossing of mouse strains, Paigen's group narrowed the control region to a relatively small area with only four genes. Functionally, only one of the genes is a strong candidate.

The gene codes for a protein, PRDM9, that has DNA binding regions known as zinc fingers. The gene is expressed during early meiosis, and its absence causes sterility in both sexes. Moreover, the gene's known "job"--adding methyl groups to structural proteins known as histones in a very specific way within the DNA--precedes recombination at known hotspots: further evidence of PRDM9's role in establishing the hotspots.

PRDM9 is the first protein to be identified in the mammalian recombination hotspot control system. Further research will investigate whether PRDM9 controls the activation of all recombination hotspots or whether it is a member of a family of regulatory proteins and only regulates a subset of hotspots.

The paper is one of three separate studies published in Science implicating PRDM9 in regulating the locations of genomic hotspots in humans, chimpanzees and mice. The findings suggest that PRDM9 determines where the hotspots will accumulate on the genomes of various species and may provide a key for interpreting the genome differences between closely related species.

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.

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Parvanov et al.: PRDM9 controls activation of mammalian recombination hotspots. Science, February 12, 2010, published online 31 December 2009; 10.1126/science.1181495.

Drs. Paigen and Petkov write review on current understanding of genetic hotspots  

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