Bias towards large genes in autism

Journal name:
Nature
Volume:
512,
Pages:
E1–E2
Date published:
DOI:
doi:10.1038/nature13583
Received
Accepted
Published online

Arising from I. F. King et al. Nature 501, 5862 (2013); doi:10.1038/nature12504

In an important recent paper, King et al.1 reported that inhibition of TOP1 and other topoisomerases reduces the expression of extremely long genes. They also showed that the list of large genes affected by TOP1 inhibition is enriched with candidate genes for autism spectrum disorders (ASD); however, the list of candidate genes that was used contains many genes with limited evidence for association with ASD2. Here we demonstrate that the size of the genes among ASD candidate genes is biased towards extremely large genes only for genes identified to be disrupted by copy number variations (CNVs). Thus, our analysis suggests that the association between large genes and ASD is mainly driven by the method that implicated the genes in ASD. There is a Reply to this Brief Communication Arising by Zylka, M. J. et al. Nature 512, http://dx.doi.org/10.1038/nature13584 (2014).

References

  1. King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 5862 (2013)
  2. Abrahams, B. S. et al. SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol. Autism 4, 36 (2013)
  3. Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886897 (2011)
  4. Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863885 (2011)
  5. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285299 (2012)
  6. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242245 (2012)
  7. O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246250 (2012)
  8. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237241 (2012)
  9. Ben-David, E. et al. Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. Hum. Mol. Genet. 20, 36323641 (2011)

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Author information

Affiliations

  1. Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

    • Shahar Shohat &
    • Sagiv Shifman

Contributions

Both authors conceived the project, analysed the data and wrote the paper.

Competing financial interests

Competing Financial Interests Declared none.

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Comments

  1. Report this comment #63709

    Hugh Fletcher said:

    This wealth of information, while a triumph of genomics, could be distracting or confusing. It copies naturalists who quantify all the species present in a habitat as a prerequisite to understanding it without generating hypotheses or understanding. It suggests that brain development is chaotic, with 100+ loci typically each accounting for 0.5% of the effect combined with currently unknown environmental factors. No locus is necessary let alone sufficient. If the phenotypes of human brains were put into a heap, so ones near the middle would be normal, those at the edge would be abnormal, and the exact point around the heap, reflecting the location and extent of structural brain abnormality, would be expressed as a continuum of schizophrenia, OCD, autism, ADHD or whatever. Stone et al. (N Engl J Med 2014; 370:1209-1219March 27, 2014) have identified disrupted foci about 5mm diameter in cell layers near the cortical surface in autistics and one epileptic. These appear similar to healed viral plaques, and could easily result from removal of specific cells by the immune system, either attacking foreign proteins or autoimmune attack on particular cells. Notably, MHC is the most significant genetic predictor of mental disease (and diabetes!). This fact has been largely ignored because it is easier to study synaptic transmission and more profitable to treat symptoms by manipulating dopamine than to investigate the primary cause. This mimics the trend for Alzheimer?s studies to look at plaque precursor protein and ignore the main genetic component, APOE.

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