Ageing-associated changes in DNA methylation in X and Y chromosomes

Abstract

Background: Ageing 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.

Results: In 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.

Conclusions: Significant 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.

Keywords: Ageing; DNA methylation; Sex chromosomes; X chromosome; Y chromosome.

Fig. 1

Characteristics of the study populations used and number of age-CpGs identified. Age distributions in the datasets are also visualized as histograms in Additional file 5: Fig. S1. Notably, the number of age-CpGs identified in each dataset was associated with the age range in the dataset. The data sets are shown in ranked order according the age interquartile range (IQR). Number of identified age-CpGs in each data set in males and females and in X (A) and Y chromosome (B) is visualized as bars. The number was higher in the X chromosome, as compared to the Y chromosome, reflecting the number of probes available for each chromosome on the Illumina 450 K array (11648 X chromosomal probes, 416 Y chromosomal probes). n = number of individuals in the data set