Human Imprinted Chromosomal Regions are Historical Hot-Spots of Recombination

Carmen Sapienza
Fels Institute for Cancer Research; Temple University Medical School

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 cross-over 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. 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/Mb at imprinted regions is not associated with any significant enrichment for any particular sequence class, more than 50% of the variance in recombination rate between imprinted and control regions can be ascribed to CpG dinucleotides. Interestingly, fine-mapping of recombination events within the most male meiosis-specific recombination hot-spot of chromosome 11p15.5 indicates that many events 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.