Format

Send to

Choose Destination
Cell. 2017 Oct 19;171(3):710-722.e12. doi: 10.1016/j.cell.2017.08.047. Epub 2017 Sep 28.

Genomic Patterns of De Novo Mutation in Simplex Autism.

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
2
Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
New York Genome Center, New York, NY 10013, USA.
4
Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA 95817, USA.
5
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
6
Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA.
7
New York Genome Center, New York, NY 10013, USA; Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
8
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: eee@gs.washington.edu.

Abstract

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3), suggesting a path forward for genetically characterizing more complex cases of autism.

KEYWORDS:

attributable fraction; autism; de novo mutation; genome sequencing; mechanisms of disease; multifactorial genetics; noncoding; oligogenic; regulatory

PMID:
28965761
PMCID:
PMC5679715
DOI:
10.1016/j.cell.2017.08.047
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center