by Klaus Schmitz and Kyriacos Markianos

More than 98% of the human genome is made up of non‐coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Together with colleagues we have had to grapple with this problem while investigating the effect of double deletions in Autism Spectrum disorder (ASD).

We studied a unique ASD cohort, 187 families selected for consanguinity in collaboration with the lab of Christopher A. Walsh, our colleague at Boston Children’s Hospital. Typically, these families had first cousin marriages. In consanguineous mating there is a high probability to inherit two copies of the same gene from a common ancestor, thus observation of two copies of the same deletion is much more frequent is such families than in the general population. We found, as expected, a higher rate of homozygous deletions among affected individuals relative to their unaffected siblings. However, most deletions did not disrupt coding sequence.

We relied on the findings of the Epigenome Roadmap project to characterize the effect of double deletions. This project is a large-scale effort to catalog the tissue specific location of epigenetic DNA modifications influencing gene expression. Assaying modifications like DNA acetylation in multiple tissue types is beyond the capabilities of any individual research lab.

When we cross referenced the location of epigenetic marks with the observed deletions in affected and unaffected individuals, we observed a statistically significant enrichment/depletion among affected/unaffected individuals. This enrichment/depletion pattern was more pronounced for epigenetic marks observed in neuronal tissue–as might be expected for ASD.

Noncoding deletions identified in medically relevant phenotypes such as ASD may provide an important foothold to begin to understand the role of patterned gene activation/regulation in cognitive and social function. Upon neuronal depolarization, neurons are known to show rapid and reversible changes in the levels of expression of a large number of activity-regulated genes, and this temporally regulated transcriptional program is known to be essential for the functional changes that underlie memory formation and learning. Biallelic noncoding mutations may provide mechanistic insights into the cis-regulatory mechanisms by which dosage alterations lead to ASD.

Klaus Schmitz-Abe performed this work in the lab of Kyriacos Markianos at Boston Children’s Hospital, in collaboration with the lab of Christopher A. Walsh and Timothy Yu, also at Boston Children’s. The team also collaborated with the labs of Michael E. Greenberg (Harvard Medical School) and Eric Morrow (Brown University.)

Learn more in the original research article:
Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder.
Schmitz-Abe K, Sanchez-Schmitz G, Doan RN, Hill RS, Chahrour MH, Mehta BK, Servattalab S, Ataman B, Lam AN, Morrow EM, Greenberg ME, Yu TW, Walsh CA, Markianos K. Sci Rep. 2020 Aug 20;10(1):14045. doi: 10.1038/s41598-020-70656-0.