CMT 1A Reps - genetic hotspots news

[Guest guest]

Am J Hum Genet. 2006 Nov;79(5):890-902.

A chromosomal rearrangement hotspot can be identified from

population genetic variation and is coincident with a hotspot for

allelic recombination.

SJ, Khajavi M, Lupski JR, Hurles ME.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,

Hinxton, Cambridge, CB10 1SA, United Kingdom.

Insights into the origins of structural variation and the mutational

mechanisms underlying genomic disorders would be greatly improved by

a genomewide map of hotspots of nonallelic homologous recombination

(NAHR). Moreover, our understanding of sequence variation within the

duplicated sequences that are substrates for NAHR lags far behind

that of sequence variation within the single-copy portion of the

genome. Perhaps the best-characterized NAHR hotspot lies within the

24-kb-long Charcot-Marie-Tooth disease type 1A (CMT1A)-repeats

(REPs) that sponsor deletions and duplications that cause peripheral

neuropathies. We investigated structural and sequence diversity

within the CMT1A-REPs, both within and between species. We

discovered a high frequency of retroelement insertions, accelerated

sequence evolution after duplication, extensive paralogous gene

conversion, and a greater than twofold enrichment of SNPs in humans

relative to the genome average. We identified an allelic

recombination hotspot underlying the known NAHR hotspot, which

suggests that the two processes are intimately related. Finally, we

used our data to develop a novel method for inferring the location

of an NAHR hotspot from sequence variation within segmental

duplications and applied it to identify a putative NAHR hotspot

within the LCR22 repeats that sponsor velocardiofacial syndrome

deletions. We propose that a large-scale project to map sequence

variation within segmental duplications would reveal a wealth of

novel chromosomal-rearrangement hotspots.