Haplotype Structure, LD Blocks, and Uneven Recombination Within the LRP5 Gene
Twells RCJ., Mein CA., Phillips MS., Hess JF., Veijola R., Gilbey M., Bright M., Metzker M., Lie BA., Kingsnorth A., Gregory E., Nakagawa Y., Snook H., Wang WYS., Masters J., Johnson G., Eaves I., Howson JMM., Clayton D., Cordell HJ., Nutland S., Rance H., Carr P., Todd JA.
Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in “LD blocks,” interspersed by apparent “hot spots” of recombination. Previously, we cloned and physically characterized thelow-density lipoprotein-receptor-related protein 5(LRP5) gene. Here, we have extensively analysed bothLRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. ForLRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.[Supplementary material: primers are available from our Web site:http://www-gene.cimr.cam.ac.uk/todd/human_data.shtml.]