While an escape from the zoo sounds newsworthy on its own, the addition of X-chromosome inactivation (XCI) makes it irresistible for our news crew. An exciting new epigenetic effort has captured the exceptional XCI escape artists across eutherian mammals.
XCI is a dosage compensation mechanism in females that results in the inactivation of one of the two X chromosomes in females. Interestingly, not every gene gets inactivated, and the proportion of genes that escape varies between species. Despite being known for their calico cat mascot, the XCI experts in the lab of Carolyn Brown (University of British Columbia, Canada) have taken a trip to the zoo to expose exceptions between species.
In this research, they leveraged several publicly available datasets. First, whole-genome sequencing and RNA-seq were used to find the ratio of inactive X (Xi) to active X (Xa) expression (Xi/Xa) for X-linked genes in humans and mice. Next, the excited examiners established a DNAm threshold for calling XCI status of X-linked genes with CpG islands for 12 species based on whole-genome bisulfite sequencing (WGBS) (humans, chimps, mice, cows, sheep, goats, and pigs), reduced representation bisulfite sequencing (RRBS) (horses) and 450k arrays (humans, chimps, bonobos, gorillas, orangutans, and dogs). Here are the extraordinary details:
- In most species, 80-90% of X-linked genes are subject to XCI
- Mice are an exception: they have the highest proportion of XCI genes (95%)
- 16 genes display discordant XCI status, with XCI escape in some species but not others
- 4 genes (RPS4X, CDK16, EIF1AX, and GEMIN8) show primate-specific XCI escape
- XCI escape for one gene, KDM5C, is specific to Artiodactyla (cows, sheep, goats, and pigs)
- Most genes that escape XCI cluster closely together and are located on the short arm of the X chromosome
- Genes that escape XCI have species-specific differences in the number of nearby repeats:
- Increased LTR repeats (humans, chimps, horses)
- Decreased LINE repeats (chimps, mice, sheep, horses)
- Decreased DNA repeats (mice, cows, sheep)
- Genes that escape XCI have increased CTCF binding sites (chimps, bonobos, gorillas, and horses) and increased chromatin accessibility (ATAC-seq) (humans, mice, and pigs)
First author Bradley Balaton shares, “These differences follow evolutionary lines and genes escape X-chromosome inactivation when the Y chromosome homologues are conserved, and then are subject to inactivation when the Y homologue no longer exists. This opens an evolutionary aspect of the control of how genes that escape X-chromosome inactivation are regulated, and we do see some common features associated with X-chromosome inactivation status conserved across species. We also hope that our X-chromosome inactivation calls across species will be useful to researchers working with these other mammalian species.”
Check out this zoo escape in Epigenetics & Chromatin, February 2021.