Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX

Crossover between the human sex chromosomes during male meiosis is restricted to the terminal pseudoautosomal pairing regions. An obligatory exchange occurs in PAR1, an Xp/Yp pseudoautosomal region of 2.6 Mb, which creates a male-specific recombination 'hot domain' with a recombination rate that is about 20 times higher than the genome average. Low-resolution analysis of PAR1 suggests that crossovers are distributed fairly randomly. By contrast, linkage disequilibrium (LD) and sperm crossover analyses indicate that crossovers in autosomal regions tend to cluster into 'hot spots' of 1-2 kb that lie between islands of disequilibrium of tens to hundreds of kilobases. To determine whether at high resolution this autosomal pattern also applies to PAR1, we have examined linkage disequilibrium over an interval of 43 kb around the gene SHOX. Here we show that in northern European populations, disequilibrium decays rapidly with physical distance, which is consistent with this interval of PAR1 being recombinationally active in male meiosis. Analysis of a subregion of 9.9 kb in sperm shows, however, that crossovers are not distributed randomly, but instead cluster into an intense recombination hot spot that is very similar in morphology to autosomal hot spots. Thus, PAR1 crossover activity may be influenced by male-specific hot spots that are highly suitable for characterization by sperm DNA analysis.     

Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot

Human DNA diversity arises ultimately from germline mutation that creates new haplotypes that can be reshuffled by meiotic recombination. Reciprocal crossover generates recombinant haplotypes but should not influence the frequencies of alleles in a population. We demonstrate crossover asymmetry at a recombination hot spot in the major histocompatibility complex, whereby reciprocal exchanges in sperm map to different locations in the hot spot. We identify a single-nucleotide polymorphism at the center of the hot spot and show that, when heterozygous, it seems sufficient to cause this asymmetry, apparently by influencing the efficiency of highly localized crossover initiation. As a consequence, crossovers in heterozygotes are accompanied by biased gene conversion, most likely occurring by gap repair, that can also affect nearby polymorphisms through repair of an extended gap. The result is substantial over-transmission of the recombination-suppressing allele and neighboring markers to crossover products. Computer simulations show that this meiotic drive, although weak at the population level, is sufficient to favor eventual fixation of the recombination-suppressing variant. These findings provide an explanation for the relatively uniform widths of human crossover hot spots and suggest that hot spots may be generally prone to extinction by meiotic drive.     

Deletion of genes on chromosome 1 in endocrine neoplasia

Recent studies have identified normal cellular DNA sequences which are lost in the development of embryonal and adult tumours. These tumours are thought to arise after a primary mutation in one allele of such a sequence is followed by loss of its normal homologue. In familial cases, the primary mutation is transmitted in the germ line. The secondary mutation may involve a substantial loss of chromosomal material and thus lead to identification of the site of the inherited mutation. We have examined constitutional and tumour genotypes of medullary thyroid carcinomas and phaeochromocytomas which develop in the dominantly inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2) to locate the predisposing gene in this syndrome. We observed deletion of a hypervariable region of DNA on the short arm of chromosome 1 in seven out of fourteen tumours. Analysis of the parental origin of the deleted allele in two families showed that it was derived from the affected parent in one case, which suggests that the deletion does not reflect the site of the inherited mutation in MEN2. The deleted region is distal to the breakpoint commonly detected in neuroblastomas, which share with the tumours of MEN2 embryological origin from neuroectoderm.