Editors' ChoiceAutism

Big Genes Cause Big Problems

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Science Translational Medicine  25 Sep 2013:
Vol. 5, Issue 204, pp. 204ec158
DOI: 10.1126/scitranslmed.3007629

Gene length is evolutionarily constrained for several reasons. A longer gene and protein product increases the energy cost of biosynthesis and the risk for deleterious mutations and also reduces transcriptional and translational efficiency. As a consequence, gene length is very highly conserved in prokaryotes and eukaryotes, and the functional advantages of increasing gene length are weighed against the evolutionary costs. However, the idea that long genes may be especially linked to a human disease and require specific transcriptional mechanisms has received little attention. An exciting new study by King and colleagues describes the discovery that topoisomerases are required to facilitate the expression of genes longer than 67 kilobase (kb) in size and that long genes influenced by topoisomerase activity include many known autism-linked genes. Topoisomerases are a family of enzymes that modulate DNA topology by adding or removing DNA supercoils and tangles that arise because of DNA repair, replication events, or transcription.

The authors have previously found that topoisomerase inhibitors can activate expression of the silent paternal allele of the imprinted gene Ube3A, which is linked to a monogenic disease called Angelman Syndrome as well as to autism. In the current study, the authors demonstrate that a topoisomerase 1 (TOP1) inhibitor called topotecan has surprisingly specific effects on the expression of Ube3A compared with other imprinted genes, which were unaffected by this drug. The authors then used RNA sequencing and microarrays to evaluate the effects of topoisomerase inhibition on all genes expressed in cortical neurons. They discovered that genes longer than 67 kb (such as Ube3A) exhibit a significant decrease in expression after topotecan treatment, whereas genes shorter than 67 kb exhibit a modest increase. Different topoisomerase inhibitors and genetic strategies to reduce TOP1 or TOP2 expression by using short hairpin RNA–mediated gene knockdown had similar effects. Using chromatin immunoprecipitation sequencing for RNA polymerase II, the authors demonstrated that the inhibition of TOP1 results in an inhibition of transcriptional elongation for long genes. Last, topotecan was found to significantly change the expression of 183 genes in cultured cortical neurons. A disproportionate number of these genes (27%) have been previously linked to autism spectrum disorders (ASD). Overall, ASD-linked genes were found to be 3.7-fold longer than the average gene expressed in cortical neurons.

This study reveals that gene length is an Achilles heel in the genome. Recent studies have linked mutations in topoisomerase-related genes to ASDs, and future work should determine whether the expression of long genes is especially compromised in individuals with this diagnosis. It is also of interest to determine whether other diseases are affected by problems associated with gene length.

I. F. King et al., Topoisomerases facilitate transcription of long genes linked to autism. Nature, published online 28 August 2013 (10.1038/nature12504). [Full]

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