Evolutionary Breakpoints in the Gibbon Suggest Association between Cytosine Methylation and Karyotype Evolution

Abstract

Gibbon species have accumulated an unusually high number of chromosomal changes since diverging from the common hominoid ancestor 15–18 million years ago. The cause of this increased rate of chromosomal rearrangements is not known, nor is it known if genome architecture has a role. To address this question, we analyzed sequences spanning 57 breaks of synteny between northern white-cheeked gibbons (Nomascus l. leucogenys) and humans. We find that the breakpoint regions are enriched in segmental duplications and repeats, with Alu elements being the most abundant. Alus located near the gibbon breakpoints (<150 bp) have a higher CpG content than other Alus. Bisulphite allelic sequencing reveals that these gibbon Alus have a lower average density of methylated cytosine that their human orthologues. The finding of higher CpG content and lower average CpG methylation suggests that the gibbon Alu elements are epigenetically distinct from their human orthologues. The association between undermethylation and chromosomal rearrangement in gibbons suggests a correlation between epigenetic state and structural genome variation in evolution.

A comprehensive molecular cytogenetic analysis of chromosome rearrangements in gibbons

“…Such association had already been reported for NLE (Carbone et al 2009b) and it seems to extend to the breakpoints shared by the four genera. The association between breakpoint regions and genes is surprising since breakage of coding and/or regulatory regions can be supposed to negatively affect the fitness.…”

“…The association between breakpoint regions and genes is surprising since breakage of coding and/or regulatory regions can be supposed to negatively affect the fitness. This effect seems to be somehow mitigated in gibbons in which the rearranged chromosomes were selected despite their falling in gene-dense regions (Carbone et al 2009b). In evaluating these results, however, it is worth noting that they were obtained using the human sequence as a reference.…”

Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas

“…It is possible that increased rates of aberrant methylation in sporadic VS may account for the reduced detection rate of NF2 point mutations in sporadic VS in comparison with NF2 tumours. As a reduction in the levels of methylation has also been proposed as a mechanism of increased occurrence of genomic recombination events (Carbone et al, 2009), it is also possible that an increased incidence of methylation in certain tumours would reduce the likelihood of MR involvement. Further work is necessary to test this hypothesis.…”

Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease

“…This idea differs from Lamarckian inheritance, in that in our model the genetic change is inherited, and this change leads to increased epigenetic variation. It also differs from the likely role of epigenetics in modifying mutation rate, both through C to T transition due to deamination of methylcytosine and through modified rates of chromosomal rearrangement (12,13). As a proof of principle, we revisited previously generated data sets (14) of genome-scale analysis of DNA methylation in human and mouse tissues and explored them in two new ways.…”