TY - JOUR
T1 - A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions
AU - Garg, Paras
AU - Jadhav, Bharati
AU - Rodriguez, Oscar L.
AU - Patel, Nihir
AU - Martin-Trujillo, Alejandro
AU - Jain, Miten
AU - Metsu, Sofie
AU - Olsen, Hugh
AU - Paten, Benedict
AU - Ritz, Beate
AU - Kooy, R. Frank
AU - Gecz, Jozef
AU - Sharp, Andrew J.
N1 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - DNA methylation
KW - epimutation
KW - epivariation
KW - folate-sensitive fragile site
KW - repeat expansion
UR - http://www.scopus.com/inward/record.url?scp=85091662642&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.08.019
DO - 10.1016/j.ajhg.2020.08.019
M3 - Article
C2 - 32937144
AN - SCOPUS:85091662642
SN - 0002-9297
VL - 107
SP - 654
EP - 669
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -