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- Title
Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation.
- Authors
Luijk, René; Wu, Haoyu; Ward-Caviness, Cavin K; Hannon, Eilis; Carnero-Montoro, Elena; Min, Josine L.; Mandaviya, Pooja; Müller-Nurasyid, Martina; Mei, Hailiang; van der Maarel, Silvere M.; BIOS Consortium; Relton, Caroline; Mill, Jonathan; Waldenberger, Melanie; Bell, Jordana T.; Jansen, Rick; Zhernakova, Alexandra; Franke, Lude; ‘t Hoen, Peter A. C.; Boomsma, Dorret I.
- Abstract
X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI. DNA methylation is critically involved in X chromosome inactivation (XCI) and dosage compensation, yet some X-chromosomal genes escape XCI. Here, Lujik et al. identify three autosomal genetic loci that associate with differential DNA methylation near genes that variably escape XCI in females.
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-05714-3