Abstract
Although the breast cancer susceptibility gene BRCA1 is one of the most extensively characterized genetic loci, much less is known about its upstream variable number tandem repeat element, the RNU2 locus. RNU2 encodes the U2 small nuclear RNA, an essential splicing element, but this locus is missing from the human genome assembly due to the inherent difficulty in the assembly of repetitive sequences. To fill the gap between RNU2 and BRCA1, we have reconstructed the physical map of this region by re-examining genomic clone sequences of public databases, which allowed us to precisely localize the RNU2 array 124 kb telomeric to BRCA1. We measured by performing FISH analyses on combed DNA for the first time the exact number of repeats carried by each of the two alleles in 41 individuals and found a range of 6-82 copies and a level of heterozygosity of 98%. The precise localisation of the RNU2 locus in the genome reference assembly and the implementation of a new technical tool to study it will make the detailed exploration of this locus possible. This recently neglected macrosatellite could be valuable for evaluating the potential role of structural variations in disease due to its location next to a major cancer susceptibility gene.
Highlights
Structural variation in the human genome has gained considerable attention in the recent years as it accounts for much of the variation between human genomes and may represent the main genetic basis of phenotypic differences
Precise Localisation of the RNU2 Array The organization of the RNU2-BRCA1 region as published in the literature is presented in Figure 1A: the genes described within this interval are NBR1, BRCA1P1 and NBR2 [16,19]
The distance between the RNU2 locus and D17S1322, a microsatellite located within BRCA1 intron 19, is reported to be,175 kb based on physical maps
Summary
Structural variation in the human genome has gained considerable attention in the recent years as it accounts for much of the variation between human genomes and may represent the main genetic basis of phenotypic differences. According to the high-resolution recent maps, most CNVs in the array-accessible regions of the genome are ancient bi-allelic polymorphisms that are in linkage disequilibrium (LD) with SNPs (Single Nucleotide Polymorphisms). This implies that the contribution of most common CNVs to human phenotypic variation was already detectable in genome-wide association studies (GWAS) as associations to nearby SNPs [5].
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