“CoRSIV” Writing: Jotting Down Interindividual Variation in DNA Methylation

From playwrights to poets, many writers take advantage of word processing software to keep their writing under control.  However, variety is the spice to life, and others swear that putting quill to parchment and writing out their epic tales in good old flowing cursive helps to get the creative juices flowing. As a testament to this variation amongst individuals, a talented team of researchers from the labs of Cristian Coarfa and Robert A. Waterland (Baylor College of Medicine, Texas, USA) demonstrate their preference for cursive, but in a slightly different form.

Their recent study sought to explore the DNA methylation variants written throughout the genome, specifically the ones that vary from person to person but remain consistent across different tissues. To this end, the team devised a clever algorithm to detect what they call “correlated regions of systemic interindividual variation” (“CoRSIV” for short) for DNA methylation in human tissues representative of the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). The team measured CpG methylation by deep whole-genome bisulfite sequencing (WGBS) of genomic DNA derived from tissues from ten donors from the National Institutes of Health Genotype-Tissue Expression (GTEx) program.

Here are just some of the musings that Gunasekara and colleagues jotted down in CoRSIV:

• Algorithmic analysis identified 9926 CoRSIVs, representing just 0.1% of the human genome
• Most CoRSIVs are only 200–300-bp long and include 5–10 CpGs, although the largest span several kb and involve hundreds of CpGs
• CoRSIV clustering occurs at the major histocompatibility locus on chromosome 6 and the pericentromeric region on the long arm of chromosome 20
• While genetic variation influences methylation at many CoRSIVs in cis, systemic interindividual epigenetic variation may be independent of genetic variation at some loci
• The authors note that CoRSIVs exhibit inter-correlations over long genomic distances, associate with transposable elements and subtelomeric regions, possess low amounts of CpG islands and transcription factor binding sites, and display both conservation across diverse human ethnic groups and sensitivity to periconceptional environment
  • The detection of positively intercorrelated CoRSIV pairs spanning large genomic distances led to the identification of superCoRSIVs within topologically associated domains enriched for CTCF binding sites
• Importantly, CoRSIVs also associate with genes implicated in a range of human disorders/phenotypes
  • Analysis of a database encompassing 1319 “epigenome-wide association studies” (EWASdb) demonstrates that CoRSIVs associate with deletion or duplication of chromosome 7q11.23, immunodeficiency, centromeric instability and facial abnormalities (ICF) syndrome, asthma, down syndrome, and human immunodeficiency virus
  • However, CoRSIV-associated genes also include those implicated in neoplasms, mental disorders, digestive, nervous system, and cardiovascular diseases with SPATC1L in male infertility, PM20D1 in Alzheimer’s disease, and DUSP22 in lymphoma provided as examples

Co-senior author Cristian Coarfa shares, “Recent studies are already showing that methylation at these regions is associated with a range of human diseases including obesity, cancer, autism, Alzheimer’s disease and cleft palate”. Co-senior author Robert Waterland concludes, “Because epigenetic marking has the power to stably silence or stably activate genes, any disease that has a genetic basis could equally likely have an epigenetic basis. There is incredible potential for us to understand disease processes from an epigenetic perspective. CoRSIVs are the entryway to that.”

For more on how CoRSIV epigenetic writing could help us to understand the epigenetic etiologies of disease, see Genome Biology, June 2019.