Genomic Patterns of De Novo Mutation in Simplex Autism

Tychele N. Turner, Bradley P. Coe, Diane E. Dickel, Kendra Hoekzema, Bradley J. Nelson, Michael C. Zody, Zev N. Kronenberg, Fereydoun Hormozdiari, Archana Raja, Len A. Pennacchio, Robert B. Darnell, Evan E. Eichler

Research output: Contribution to journalArticle

72 Citations (Scopus)

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. Genomic analysis of 516 families with an autistic child and an unaffected sibling suggests that simplex autism results from de novo mutation and is oligogenic.

Original languageEnglish (US)
Pages (from-to)710-722.e12
JournalCell
Volume171
Issue number3
DOIs
StatePublished - Oct 19 2017

Fingerprint

Autistic Disorder
Genes
Mutation
Nucleotides
Mutation Rate
Siblings
Corpus Striatum
Stem cells
Gene Dosage
Neurons
Missense Mutation
Brain
Embryonic Stem Cells
Genome
DNA

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Turner, T. N., Coe, B. P., Dickel, D. E., Hoekzema, K., Nelson, B. J., Zody, M. C., ... Eichler, E. E. (2017). Genomic Patterns of De Novo Mutation in Simplex Autism. Cell, 171(3), 710-722.e12. https://doi.org/10.1016/j.cell.2017.08.047

Genomic Patterns of De Novo Mutation in Simplex Autism. / Turner, Tychele N.; Coe, Bradley P.; Dickel, Diane E.; Hoekzema, Kendra; Nelson, Bradley J.; Zody, Michael C.; Kronenberg, Zev N.; Hormozdiari, Fereydoun; Raja, Archana; Pennacchio, Len A.; Darnell, Robert B.; Eichler, Evan E.

In: Cell, Vol. 171, No. 3, 19.10.2017, p. 710-722.e12.

Research output: Contribution to journalArticle

Turner, TN, Coe, BP, Dickel, DE, Hoekzema, K, Nelson, BJ, Zody, MC, Kronenberg, ZN, Hormozdiari, F, Raja, A, Pennacchio, LA, Darnell, RB & Eichler, EE 2017, 'Genomic Patterns of De Novo Mutation in Simplex Autism', Cell, vol. 171, no. 3, pp. 710-722.e12. https://doi.org/10.1016/j.cell.2017.08.047
Turner TN, Coe BP, Dickel DE, Hoekzema K, Nelson BJ, Zody MC et al. Genomic Patterns of De Novo Mutation in Simplex Autism. Cell. 2017 Oct 19;171(3):710-722.e12. https://doi.org/10.1016/j.cell.2017.08.047
Turner, Tychele N. ; Coe, Bradley P. ; Dickel, Diane E. ; Hoekzema, Kendra ; Nelson, Bradley J. ; Zody, Michael C. ; Kronenberg, Zev N. ; Hormozdiari, Fereydoun ; Raja, Archana ; Pennacchio, Len A. ; Darnell, Robert B. ; Eichler, Evan E. / Genomic Patterns of De Novo Mutation in Simplex Autism. In: Cell. 2017 ; Vol. 171, No. 3. pp. 710-722.e12.
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