The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region [published erratum appears in Hum Mol Genet 1997 Mar;6(3):502]

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric chromosomes. Here, we examine two models for the role of this repeat in FSHD. First, because of the extensive similarity between the 3.2 kb repeats on 4q and those adjacent to rDNA on the acrocentric chromosomes, we investigated whether the FSHD region on 4q is involved in sub-nuclear localization, specifically to the nucleolus. The results likely exclude any involvement of nucleolar localization in the development of FSHD. Second, we investigated a model that suggests that a functional gene may be buried within the tandem array of 3.2 kb repeats. Toward this end, we evaluated the evolutionary conservation of the repeat and a double homeodomain sequence within the repeat in a variety of primate species. The genomic organization of the 3.2 kb repeat in humans, great apes and lower primates identified the FSHD-associated repeat on chromosome 4q as the likely ancestral copy. The sequence of the rhesus monkey double homeodomain reveals significant sequence identity with the human 4q sequence. These results strongly suggest a functional role for a component of the FSHD-associated repeat.

One in four individuals of African-American ancestry harbors a 5.5 kb deletion at chromosome 11q13.1

“…The 5.5kb sequence or the control probes (6.6kb HRAS probe localized to the short arm of chromosome 11 (11p15) and a 5kb probe, representing MLL gene at 11q23) were labelled and hybridized to metaphase spreads as previously described [2, 15]. Briefly, metaphase spreads were prepared by standard cytogenetic procedures.…”

A repetitive elements perspective in Polycomb epigenetics

“…Macrosatellites consist of arrays of 1–12 kb repeat units, with a number of repeats ranging from a few to over one hundred (Warburton et al, 2008; Moseley et al, 2012). They can be either chromosome specific, as DXZ4 at chromosome Xq23 (Giacalone et al, 1992) and ZAV at chromosome 9q32 (Tremblay et al, 2010) or they can be associated with two or more chromosomal locations, such as D4Z4, on chromosomes 4q35 and 10q26; (Deidda et al, 1995; Winokur et al, 1996) and RS447, on 4p15 and 18p23; (Gondo et al, 1998). …”

“…Interestingly, reduction of D4Z4 copy number below 11 units is associated with FSHD, one of the most important forms of muscular dystrophy (Wijmenga et al, 1992; Van Deutekom et al, 1993). D4Z4 belongs to a family of repeats with high sequence identity present also in human chromosomes 10q26, 1p12, and the p-arm of acrocentric chromosomes (Lyle et al, 1995; Winokur et al, 1996). This results in frequent exchanges between the 4q35 and 10q26 arrays, which share the highest identity (Van Deutekom et al, 1993).…”

YY1 associates with the macrosatellite DXZ4 on the inactive X chromosome and binds with CTCF to a hypomethylated form in some male carcinomas

“…They are composed of individual repeat units, typically >1 kb in size, that are arranged in tandem, often spanning hundreds of kilobases (5). Some are chromosome specific, such as ZAV at chromosome 9q32 (6) and DXZ4 at chromosome Xq23 (7,8), whereas others are found on at least two chromosomes, such as D4Z4 on chromosomes 4q35 and 10q26 (9,10) or RS447 on chromosome 4p15 and 18p23 (11). The macrosatellite about which most is known is D4Z4, because of its association with onset of facioscapulohumeral muscular dystrophy (FSHD) (12).…”