A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions

Abstract

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of $1 in 3,000 and $1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.

Common Threads: Aphidicolin-Inducible and Folate-Sensitive Fragile Sites in the Human Genome

“…In addition, folate stress induces MiDAS or γ-H2AX foci, a marker of DSBs, at many genomic loci in normal human cells ( Kumari et al, 2009 ; Garribba et al, 2020 ), suggesting that there are also several common folate-sensitive fragile sites that are as yet uncharacterized. Furthermore, a recent study of epigenetic variation in the human genome suggests the existence of at least 19 rare, long, and silenced CGG repeat tracts that could well also be fragile ( Garg et al, 2020 ).…”

Genetic basis of mitochondrial diseases

“…Finally, the cause of the disease may be outside the four base pair genetic code. Human disease can also be caused by rare epigenetic variation (epivariation, epimutations) [267], defined as an alteration in DNA methylation, irrespective of their underlying etiology (sporadic events such as imprinting anomalies [268] or sequence variation [269]). Although the contribution of epivariations to mitochondrial disorders remains unexplored, recent studies reported enrichment of de novo epivariation in congenital disorders and neurodevelopmental disorders, followed by altered gene expression [270,271].…”

Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases

“…This work suggests that epivariants may underlie a fraction of human disease that would be missed with purely genetic sequence-based approaches. This study provides a broad overview of rare epigenetic changes in the human genome, giving insight into the underlying origins and consequences of epivariations, potentially altering the methylation pattern related to human diseases [ 163 ]. In this light, it is important to distinguish the constitutional secondary epimutations that cause diseases from the common epigenetic variants, usually influenced by ethnicity and caused by non-pathogenic natural adaptive mechanisms in humans [ 164 ].…”