title: Low load for disruptive mutations in autism genes and their biased transmission.
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 whole-exome 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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; New York Genome Center, New York, NY 10013; iossifov@cshl.edu wigler@cshl.edu.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allen
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Kenny
authors.initials: K
authors.lastname: Ye
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0003-0237-3540
authors.initials: M
authors.lastname: Ronemus
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Yoon-Ha
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
authors.forename: Boris
authors.initials: B
authors.lastname: Yamrom
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; New York Genome Center, New York, NY 10013; iossifov@cshl.edu wigler@cshl.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005788:Gene Pool; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation
keywords: autism genes; autism spectrum disorder; biased transmission; disruptive mutations; gene vulnerability