Background: Macrosatellite repeats (MSRs), usually spanning hundreds of kilobases of genomic DNA, comprise a significant proportion of the human genome. Because of their highly polymorphic nature, MSRs represent an extreme example of copy number variation, but their structure and function is largely understudied. Here, we describe a detailed study of six autosomal and two X chromosomal MSRs among 270 HapMap individuals from Central Europe, Asia and Africa. Copy number variation, stability and genetic heterogeneity of the autosomal macrosatellite repeats RS447 (chromosome 4p), MSR5p (5p), FLJ40296 (13q), RNU2 (17q) and D4Z4 (4q and 10q) and X chromosomal DXZ4 and CT47 were investigated. Results: Repeat array size distribution analysis shows that all of these MSRs are highly polymorphic with the most genetic variation among Africans and the least among Asians. A mitotic mutation rate of 0.4-2.2% was observed, exceeding meiotic mutation rates and possibly explaining the large size variability found for these MSRs. By means of a novel Bayesian approach, statistical support for a distinct multimodal rather than a uniform allele size distribution was detected in seven out of eight MSRs, with evidence for equidistant intervals between the modes. Conclusions: The multimodal distributions with evidence for equidistant intervals, in combination with the observation of MSR-specific constraints on minimum array size, suggest that MSRs are limited in their configurations and that deviations thereof may cause disease, as is the case for facioscapulohumeral muscular dystrophy. However, at present we cannot exclude that there are mechanistic constraints for MSRs that are not directly disease-related. This study represents the first comprehensive study of MSRs in different human populations by applying novel statistical methods and identifies commonalities and differences in their organization and function in the human genome.

allele, African American, Asian, CT47 gene, Caucasian, D4Z4 gene, DXZ4 gene, FLJ40296 gene, MSR5p gene, RNU2 gene, RS447 gene, X chromosome, article, chromosome 10q, chromosome 13q, chromosome 17q, chromosome 4p, chromosome 4q, chromosome 5p, chromosome polymorphism, controlled study, copy number variation, ethnic difference, female, gene, gene location, genetic association, genetic stability, genetic variability, genome analysis, genomic instability, human, human cell, human genome, male, mutation rate, mutational analysis, nucleotide sequence, population size, short tandem repeat,
BMC Genomics
Erasmus MC: University Medical Center Rotterdam

Schaap, M, Lemmers, R.J.L.F, Maassen, R, van der Vliet, P.J, Hoogerheide, L.F, van Dijk, H.K, … van der Maarel, S.M. (2013). Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: Evidence for differences and commonalities in size distributions and size restrictions. BMC Genomics, 14(1). doi:10.1186/1471-2164-14-143