Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: evidence for differences and commonalities in size distributions and size restrictions

Abstract

BackgroundMacrosatellite 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.ResultsRepeat 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.ConclusionsThe 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.

Characterization of the ICCE Repeat in Mammals Reveals an Evolutionary Relationship with the DXZ4 Macrosatellite through Conserved CTCF Binding Motifs

“…1 D ), which likely reflects repeat unit copy number variation typical of large tandem repeats (Tremblay et al. 2010; Schaap et al. 2013) and has been observed for DXZ4 in the great apes (McLaughlin and Chadwick 2011).…”

Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy

“…The predominant form of the disease, FSHD1 (OMIM 158900), represents >95% of reported cases and results from large DNA deletions within the 4q35 D4Z4 repeat array [16, 17]. Healthy, genetically unaffected individuals are typically defined as having more than 10 D4Z4 repeat units (RUs) on both 4q chromosome arms (generally 25–35 RUs and as high as 120 RUs per array [18, 19]), whereas individuals with genetic FSHD1 have a contracted D4Z4 array in the range of 1 to 10 D4Z4 RUs on one 4q chromosome arm, consistent with an autosomal dominant mode of inheritance (Fig. 1) [20].…”

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

“…Each D4Z4 repeat in the macrosatellite consists of *3300 bp of DNA ( > 15 nucleosomes); in the healthy population, the tandem arrayed copies number from 11 to more than 100 repeats, but on average 25-35 copies on both 4q arms (130,138). Thus, FSHD1-sized D4Z4 contractions result in the absence of hundreds of nucleosomes containing GC-rich repetitive sequence, which significantly alters the chromatin content of 4q35 and likely affects establishment of the proper epigenetic state during development.…”