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.
Highlights
In the human, as well as in other eukaryotes, sites of recombination are not randomly distributed along the chromosomes because of the presence of numerous hot-spots and cold-spots of recombination [1]
We used a combination of fine-structure meiotic mapping, haplotype analysis, and linkage disequilibrium (LD) mapping to examine rates of recombination in imprinted regions of the human genome
Our fine-structure meiotic mapping results in the Chromosome 11p15.5–imprinted region agree with the studies of Paldi et al [5] and Lercher and Hurst [8] that this region is a hot-spot of recombination in male meiosis
Summary
As well as in other eukaryotes, sites of recombination are not randomly distributed along the chromosomes because of the presence of numerous hot-spots and cold-spots of recombination [1]. Sex-specific recombination hot-spots have been identified in the vicinity of two human imprinted regions: 11p15.5 and 15q11–q13 [5,6], as well as around the Igf locus in sheep [7]. Lercher and Hurst [8] have shown that most, if not all, imprinted chromosomal regions in the human genome have unusually high (and possibly sex-specific) recombination rates. These last authors used meiotic mapping data from the deCODE map [9] which has a resolution of about 1 cM. This window is considerably larger than most of the chromosomal regions containing imprinted genes, and the limited resolution of the map with respect to the size of imprinted regions has the potential to make their findings conservative
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