Human Imprinted Chromosomal Regions Are Historical Hot-Spots of Recombination

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Abstract
Human recombination rates vary along the chromosomes as well as between the two sexes. There is growing evidence that epigenetic factors may have an important influence on recombination rates, as well as on crossover position. Using both public database analysis and wet-bench approaches, we revisited the relationship between increased rates of meiotic recombination and genome imprinting. We constructed metric linkage disequilibrium (LD) maps for all human chromosomal regions known to contain one or more imprinted genes. We show that imprinted regions contain significantly more LD units (LDU) and have significantly more haplotype blocks of smaller sizes than flanking nonimprinted regions. There is also an excess of hot-spots of recombination at imprinted regions, and this is likely to do with the presence of imprinted genes, per se. These findings indicate that imprinted chromosomal regions are historical “hot-spots” of recombination. We also demonstrate, by direct segregation analysis at the 11p15.5 imprinted region, that there is remarkable agreement between sites of meiotic recombination and steps in LD maps. Although the increase in LDU/Megabase at imprinted regions is not associated with any significant enrichment for any particular sequence class, major sequence determinants of recombination rates seem to differ between imprinted and control regions. Interestingly, fine-mapping of recombination events within the most male meiosis–specific recombination hot-spot of Chromosome 11p15.5 indicates that many events may occur within or directly adjacent to regions that are differentially methylated in somatic cells. Taken together, these findings support the involvement of a combination of specific DNA sequences and epigenetic factors as major determinants of hot-spots of recombination at imprinted chromosomal regions. Now that the finished reference sequence of the human genome is available, focus has shifted towards understanding fundamental aspects of its functions. Meiotic recombination between maternal and paternal chromosomes serves an important mechanistic and evolutionary role in the transmission of the genome. Although significant progress has been made towards fine-mapping meiotic recombination events along human chromosomes, the characterization of factors that influence the position and frequency of crossovers remains a challenge. These authors have used data generated by the International HapMap Project as well as experimental analysis of a collection of three-generation Centre d'Etude du Polymorphisme Humain (CEPH) families, to show that chromosomal regions containing imprinted genes (i.e., genes transcribed only from one allele in a parent-of-origin–specific manner) exhibit higher rates of meiotic recombination than nonimprinted chromosomal regions. This characteristic is common for all major human populations. The major sequence determinants of recombination rates are likely to be different at imprinted and nonimprinted regions. Moreover, epigenetic modifications associated with imprinted regions may play an important role in increasing the frequency of meiotic crossovers and determining their position. Taken together these results suggest that a complex series of factors control meiotic recombination in the human.