Worldwide Population Analysis of the 4q and 10q Subtelomeres Identifies Only Four Discrete Interchromosomal Sequence Transfers in Human Evolution

Abstract

Subtelomeres are dynamic structures composed of blocks of homologous DNA sequences. These so-called duplicons are dispersed over many chromosome ends. We studied the human 4q and 10q subtelomeres, which contain the polymorphic macrosatellite repeat D4Z4 and which share high sequence similarity over a region of, on average, >200 kb. Sequence analysis of four polymorphic markers in the African, European, and Asian HAPMAP panels revealed 17 subtelomeric 4q and eight subtelomeric 10qter haplotypes. Haplotypes that are composed of a mixture of 4q and 10q sequences were detected at frequencies >10% in all three populations, seemingly supporting a mechanism of ongoing interchromosomal exchanges between these chromosomes. We constructed an evolutionary network of most haplotypes and identified the 4q haplotype ancestral to all 4q and 10q haplotypes. According to the network, all subtelomeres originate from only four discrete sequence-transfer events during human evolution, and haplotypes with mixtures of 4q- and 10q-specific sequences represent intermediate structures in the transition from 4q to 10q subtelomeres. Haplotype distribution studies on a large number of globally dispersed human DNA samples from the HGDP-CEPH panel supported our findings and show that all haplotypes were present before human migration out of Africa. D4Z4 repeat array contractions on the 4A161 haplotype cause Facioscapulohumeral muscular dystrophy (FSHD), whereas contractions on most other haplotypes are nonpathogenic. We propose that the limited occurrence of interchromosomal sequence transfers results in an accumulation of haplotype-specific polymorphisms that can explain the unique association of FSHD with D4Z4 contractions in a single 4q subtelomere.

Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population

“…As reported, all 4q subtelomeres originate from only four discrete interchromosomal sequence transfers during human evolu- tion, and haplotypes with mixtures of 4q-and 10q-specific sequences represent intermediate structures in the transition from 4q to 10q subtelomeres. 10 We also found that in this family, a 4qB variant resided on chromosome 10, confirming the same detection in other populations, 10 and further suggesting that the breakpoint of the D4Z4 repeat was distal to the 4qA and 4qB variants. The pathophysiological pathway from 4q35 deletion together with the 4qA variant to the clinical picture of FSHD is unclear.…”

“…[3][4][5] Furthermore, several reports have confirmed that there are 4qA and 4qB variants of the 4q subtelomere, and FSHD is uniquely associated with the 4qA variant. [6][7][8][9][10] These findings add to the diagnostic challenge and pathogenetic complexity. 11 Therefore, the correct diagnosis of FSHD depends on the ability to distinguish the 4qA and 4qB variants.…”

DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

“…Of note, the same haplotypes are also found in the duplicated FR-MAR present within the q26 region of human chromosome 10. [22][23][24] Consequently, any cell contains four copies and up to four haplotypes of the FR-MAR. All four copies of FR-MAR are attached to the NM in normal primary human myoblasts, as was previously demonstrated by in situ fluorescent hybridization on nuclear halos.…”

“…These 8nt þ haplotypes are generally not associated with the FSHD phenotype. [22][23][24] Next, we have analyzed the level of DNA methylation at four CpGs in the FR-MAR region in relation with NM attachment. One of the four CpGs, CpG 4 , was found to be 100% methylated in the NM fraction.…”

“…Indeed, several SSLPs have been identified that are specifically associated with FSHD. [22][23][24] Finally, the chromatin structure and DNA methylation level could also modify the FR-MAR binding to the NM. Other genetic and epigenetic abnormalities affecting the subtelomeric region of chromosome 4q have also been observed in various pathologies including the Rett and ICF syndromes, 25 as well as in several types of cancer.…”