Low load for disruptive mutations in autism genes and their biased transmission

Ivan Iossifov, Dan Levy, Jeremy Allen, Kenny Ye, Michael Ronemus, Yoon Ha Lee, Boris Yamrom, Michael Wigler

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in wholeexome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.

Original languageEnglish (US)
Pages (from-to)E5600-E5607
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number41
DOIs
StatePublished - Oct 13 2015

Keywords

  • Autism genes
  • Autism spectrum disorder
  • Biased transmission
  • Disruptive mutations
  • Gene vulnerability

ASJC Scopus subject areas

  • General

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