AGBT Talk: Tim Yu, Harvard Medical School

Title: Genome wide searches for autism.

Disclosure: work is his own, but was here as a guest of Complete Genomics.

Backround on neurodevelopmental brain disorders

  • Big question: How does brain form and work?
  • Recent work has been focused on autism.
    • Stats presented on autism (1:110 are autistic, using broad def of autism)
    • 8% recurrance risk for siblings.
  • Cognitive imparement in 50-60%
  • regression in 10-25% of cases
  • Challenges to gene discovery
    • difficult to make diagnoses (especially @ genetic level where 80-95% of cases)
  • Hypothesis: repressive burden
    • Nice slide: rate of cousin marriages corresponds to regions with higher birth defects and cognitive imparement.  (Mainly middle east and north Africa.)
    • over 200 pedigrees collected.
    • Focus on middle east, where cousin marriages are common and culturally appropriate.
  • use 500k snp chips
    • phase I: validation and CNV discovery
    • Phase II: targetted sequencing… which migrated to whole genome
  • Locus Heterogeneity
    • Many bands are implicated
    • Sequence region to identify candidate genes (mutations)
  • At this point, in comes Complete Genomics.
    • 40 individuals with autism sequenced
    • Analysis for non-complete genomics data set involved wading through forest of open source tools – complete genomics, tho, you just get hard drives and the data is ready to use.   (Big contrast)
    • Coverage: 63x coverage, 95.6% bases called
  • Variant calling: used rare gene model
    • 3.2M variants
    • 1k pathogenic  + novel
    • 100 pathogenic + novel + homozygous
    • 10 pathogenic + novel + homozygous + linked.
  • When compared to known autism genes, they were able to identify several individuals where it WAS the causative variant.
    • Most were still not obvious, however.
  • [Skipping clinical/patient data]
    • For this patient, a chr6 area identified.
      • from 3.2M snps, only 4 were consistent with recessive model, one was in PEX7.
    • All affected family members had mutation in PEX7
    • Absent in 700 controls.
  • 2nd example:
    • “Mutation in known gene with atypical presentation can be autism.”


  • There will be no “autism gene”
  • WGS will help us understand the disease
  • Not all genes identified will be new, and many will have known interventions.
  • There will new ones too.
  • Autism is complex, but some variations will be “low hanging fruit”, such as autosomal recessive presented here.

[All in all a neat talk – similar to cancer, wading into a complex genetic landscape.]

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