Human Recombination Hotspots Research Articles

High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot.

Little is known about the nature of recombination hotspots in the human genome and the relationship between crossover activity and patterns of linkage disequilibrium. We have therefore used both haplotype analysis and direct detection of crossovers in sperm to characterize a putative recombination hotspot in the TAP2 gene within the class II region of the MHC. Haplotype diversity provided evidence for a localized hotspot within intron 2 of this gene. Sperm DNA typing using allele-specific PCR primers to selectively amplify recombinant TAP2 molecules revealed a highly localized meiotic crossover hotspot approximately 1.2 kb long, unusually abundant in sequence polymorphisms and flanked by DNA much less active in recombination. Sperm crossover appeared to be fully reciprocal, and almost all crossover products were simple, involving a single exchange between adjacent heterozygous markers. This hotspot appears to be much more active in female than male meiosis. No primary sequence similarities could be found between any of the very few well defined crossover hotspots in the human genome, all of which show recombinationally active domains 1-2 kb long. Direct comparison of recombination frequency and haplotype diversity in TAP2 showed that linkage disequilibrium measures were a poor predictor of crossover frequency in this region, with non-recombining markers sometimes in free association and with examples of pairs of markers spanning the recombination hotspot showing substantial or even absolute linkage disequilibrium.

Fine-Mapping of a Region of Variation in Recombination Rate on BTA23 to the D23S22–D23S23 Interval Using Sperm Typing and Meiotic Breakpoint Analysis

Meiotic recombination rate (θ) within chromosome segments of similar physical size is known to vary widely throughout the genome. This variation has a genetic component, occurring between the sexes and among individuals of the same sex. We reported previously the existence of variation in θ between males in the DYA–PRL interval on bovine chromosome 23 (BTA23). This region contains the bovine major histocompatibility complex and has been shown to contain recombination hotspots in humans and mice. The aim of this study was to map more finely the interval(s) on BTA23 where variation in θ occurs using sperm typing and meiotic breakpoint analysis. By adding a marker (DRB3) between DYA and PRL, the DYA–PRL interval was subdivided into two adjacent intervals, thus permitting evaluation and comparison of θ among five bulls. Significant variation in θ was found for both intervals; θDYA–DRB3 ranged from 13.2 to 28.1%, and θDRB3–PRL ranged from 2.4 to 13.0%. The variation in θ was individual- and region-specific. A meiotic breakpoint strategy employing PCR amplification products from recombinant sperm was then used to refine the chromosomal location associated with variation in θ within the DYA–DRB3 interval. The subinterval D23S22–D23S23 exhibited the greatest degree of variation among bulls having high and low θ within the DYA–DRB3 interval. To confirm this result, θD23S22–D23S23 was directly evaluated in three additional randomly chosen bulls using sperm typing. The region showing variation in θ was narrowed to the D23S22–D23S23 subinterval, ranging from 4.6 to 9.2%. Identification of the molecular basis for variation in θ may be useful for map-dependent applications, such as marker-assisted selection and positional cloning of genes affecting physiologically important traits.