期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 92, 期 3, 页码 375-386出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.02.006
关键词
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资金
- Natural Science Foundation of China [81100841]
- Beijing Science and Technology Fund for Chinese Returned Oversea Scientist
- Shanghai Science and Technology Commission [11dz1950300]
- National Basic Research Program of China [2011CBA00401, 2012CB944600]
- Ministry-of Science and Technology of China for the National 973 Program on Population and Health [2010CB529601]
- Nature Science Fund of Shanghai [09JC1402400, 09ZR1404500]
- NIH [GM061354, HD065286]
- Autism Speaks grant [2042]
- National Institute of Mental Health (NIMH) National Research Service Award [MH087123]
- Mass General Hospital Executive Committee on Research Fund for Medical Discovery award
NRXN1 microdeletions occur at a relatively high frequency and confer increased risk for neurodevelopmental and neurobehavioral abnormalities. The mechanism that makes NRXN1 a deletion hotspot is unknown. Here, we identified deletions of the NRXN1 region in affected cohorts, confirming a strong association with the autism spectrum and other neurodevelopmental disorders. Interestingly, deletions in both affected and control individuals were clustered in the 5' portion of NRXN1 and its immediate upstream region. To explore the mechanism of deletion, we mapped and analyzed the breakpoints of 32 deletions. At the deletion breakpoints, frequent microhomology (68.8%, 2-19 bp) suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end-joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error. Our observations highlight the potential importance of inverted repeats of variable sizes in generating a rearrangement hotspot in which individual breakpoints are not recurrent. Mechanisms that involve short inverted repeats in initiating deletion may also apply to other deletion hotspots in the human genome.
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