Statistical enrichment of epigenetic states around triplet repeats that undergo expansions

Abstract

More than 30 human genetic diseases are linked to tri-nucleotide repeatexpansions. There is no known mechanism that explains repeat expansions in full,but changes in the epigenetic state of the associated locus has beenimplicated in the disease pathology for a growing number ofexamples. A comprehensive comparative analysis of the genomic features associated with diverse repeat expansions has been lacking.Here, in an effort to decipher the propensity of repeats to undergo expansionand result in a disease state, we determine the genomic coordinates oftri-nucleotide repeat tracts at base pair resolution and computationallyestablish epigenetic profiles around them. Using three complementary statisticaltests, we reveal that several epigenetic states are enriched around repeats thatare associated with disease, even in cells that do not harbour expansion,relative to a carefully stratified background. Analysis of over one hundredcell types reveals that epigenetic states generally tend to vary widely betweengenic regions and cell types. However, there is qualified consistency in the epigeneticsignatures of repeats associated with disease suggesting that changes to thechromatin and the DNA around an expanding repeat locus are likely to be similar.These epigenetic signatures may be exploited further to develop modelsthat could explain the propensity of repeats to undergo expansions