Crossovers between chromosomes are essential for correct chromosomal segregation during meiosis, and errors in crossover during recom-bination can result in aneuploidy, which has severe developmental con-sequences. Although the distribution and frequency of crossovers is known to be non-random — for example, recombination ‘hot spots’ are found in many species — the molecular and genetic mechanisms of crossover reg-ulation remain poorly characterized. Three recent studies each add an extra piece to the regulation puzzle.

Working in Caenorhabditis elegans, Mets and Meyer found that mutations in a novel condensin-containing protein complex — con-densin I — disrupt the distribution of crossovers and increase their number. Condensin is involved in

chromosome compaction, and the authors found that the mutation of any component of condensin I caused meiotic chromosomes to have a more elongated structure and also caused a shift in the position of DNA double-strand breaks (DSBs). DSBs are necessary for crossover, and the shift in position correlated with the change in crossover distribution. The authors suggest that condensin I regulates DSB formation, and thereby crossover distribution, via an effect on chromosome structure. Furthermore, their quantification of all DSBs indicated that an active mechanism ensures that each homologue pair has at least one DSB, which is essential for the obligate crossover that promotes accurate chromosome segregation.

Not only are crossover events non-random along chromosomes, but in humans there are substantial inter-individual differences in the number of recombination events that resolve into crossovers during meiosis, and there is a particularly notable difference between males and females. Cheung and colleagues treated the number of these recom-bination events as a quantitative phenotype and performed a genome-wide association study using SNP data from over 2,300 individuals and their offspring. They identified three loci in each sex that influence the recombination phenotype, and two of the six loci had been previ-ously implicated in recombination. Although these genetic variants

explain only a small proportion of variation in the sex-specific recom-bination pattern, they provide new leads for identifying regulators of recombination.

But how stringently are crossovers regulated? In another study using human SNP data, Fledel-Alon and colleagues mapped crossover distri-butions in a large set of pedigrees. They found that regulation seems to be controlled at the chromosome level, with a minimum of one cross-over per chromosome. Intriguingly, in females chromosome 21 frequently seems to segregate properly without a crossover, which suggests that humans have a ‘back-up’ mechanism for segregation in the absence of a crossover. Inefficiency in this mecha-nism might contribute to the risk of trisomy 21 in offspring.

These three studies provide evidence that recombination is regulated at a chromosomal scale and that there are likely to be many steps in regulation. Such regulation might have evolved to ensure both the persistence of genetic diversity and correct segregation.

Mary Muers

ORIGINAL RESEARCH PAPERS Mets, D. G. & Meyer, B. J. Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure. Cell 24 Sep 2009 (doi:10.1016/j.cell.2009.07.035) | Chowdhury, R., Bois, P. R., Feingold, E., Sherman, S. L. & Cheung, V. G. Genetic analysis of variation in human meiotic recombination. PLoS Genet. 5, e1000648 (2009) | Fledel-Alon, A. et al. Broad-scale recombination patterns underlying proper disjunction in humans. PLoS Genet. 5, e1000658 (2009)

R E C O m b I N At I O N

Piecing regulation together

R e s e a R c h h i g h l i g h t s

NATure revIeWS | Genetics voluMe 10 | NoveMBer 2009

Nature Reviews Genetics | AoP, published online 7 october 2009; doi:10.1038/nrg2685

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