Abstract
BackgroundAgeing displays clear sexual dimorphism, evident in both morbidity and mortality. Ageing is also associated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. Here, we sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14–92 years.ResultsIn total, we identified 46 age-associated CpG sites in the male Y, 1327 age-associated CpG sites in the male X, and 325 age-associated CpG sites in the female X. The X chromosomal age-associated CpGs showed significant overlap between females and males, with 122 CpGs identified as age-associated in both sexes. Age-associated X chromosomal CpGs in both sexes were enriched in CpG islands and depleted from gene bodies and showed no strong trend towards hypermethylation nor hypomethylation. In contrast, the Y chromosomal age-associated CpGs were enriched in gene bodies, and showed a clear trend towards hypermethylation with age.ConclusionsSignificant overlap in X chromosomal age-associated CpGs identified in males and females and their shared features suggest that despite the uneven chromosomal dosage, differences in ageing-associated DNA methylation changes in the X chromosome are unlikely to be a major contributor of sex dimorphism in ageing. While age-associated CpGs showed good replication across datasets in the present study, only a limited set of previously reported age-associated CpGs were replicated. One contributor to the limited overlap are differences in the age range of individuals included in each data set. Further study is needed to identify biologically significant age-associated CpGs in the sex chromosomes.
Highlights
Ageing displays clear sexual dimorphism, evident in both morbidity and mortality
Sex chromosomes are one of the biological factors contributing to sexual dimorphism in humans and other mammals [6]
Dosage compensation between XX females and XY males is achieved via X chromosome inactivation (XCI) in females, where one of the X chromosomes is packaged as heterochromatin and is nearly fully methylated
Summary
Ageing is associated with changes in DNA methylation, but very little focus has been on the sex chromosomes, potential biological contributors to the observed sexual dimorphism. We sought to identify DNA methylation changes associated with ageing in the Y and X chromosomes, by utilizing datasets available in data repositories, comprising in total of 1240 males and 1191 females, aged 14–92 years. Epidemiology, pathophysiology, and symptoms of ageingassociated diseases, such as cardiometabolic diseases, cancer, and neurodegenerative diseases, can differ between males and females [3]. The mechanisms underlying this sexual dimorphism remain poorly understood, but contributing factors include both biological as well as behavioral and societal [1, 3, 5]. A proportion of X chromosomal genes escape XCI [6]
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