Structural disruption of genomic regions containing ultraconserved elements is associated with neurodevelopmental phenotypes

The development of the human brain and nervous system can be affected by genetic or environmental factors. Here we focus on characterizing the genetic perturbations that accompany and may contribute to neurodevelopmental phenotypes. Specifically, we examine two types of structural variants, namely, copy number variation and balanced chromosome rearrangements, discovered in subjects with neurodevelopmental disorders and related phenotypes. We find that a feature uniting these types of genetic aberrations is a proximity to ultraconserved elements (UCEs), which are sequences that are perfectly conserved between the reference genomes of distantly related species. In particular, while UCEs are generally depleted from copy number variant regions in healthy individuals, they are, on the whole, enriched in genomic regions disrupted by copy number variants or breakpoints of balanced rearrangements in affected individuals. Additionally, while genes associated with neurodevelopmental disorders are enriched in UCEs, this does not account for the excess of UCEs either in copy number variants or close to the breakpoints of balanced rearrangements in affected individuals. Indeed, our data are consistent with some manifestations of neurodevelopmental disorders resulting from a disruption of genome integrity in the vicinity of UCEs.