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Distinct sequence features underlie microdeletions and gross deletions in the human genome
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  • Mengling Qi,
  • Peter Stentson,
  • Edward Ball,
  • John Tainer,
  • Bacolla Albino,
  • Hildegard Kehrer-Sawatzki,
  • David Cooper,
  • huiying zhao
Mengling Qi
Sun Yat-Sen University

Corresponding Author:[email protected]

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Peter Stentson
Cardiff University
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Edward Ball
Cardiff University
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John Tainer
The University of Texas MD Anderson Cancer Center
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Bacolla Albino
The University of Texas MD Anderson Cancer Center
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Hildegard Kehrer-Sawatzki
University of Ulm
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David Cooper
Cardiff University
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huiying zhao
Sun Yat-Sen University
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Abstract

Microdeletions and gross deletions are important causes (~20%) of human inherited disease. Their genomic locations are strongly influenced by the local DNA sequence environment. Yet no systematic study has examined the generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database (HGMD) that together form a continuum of germline deletions ranging in size from 1 bp to 28,394,429 bp. We analyzed the sequence within 1-kb of the breakpoint junctions and found the frequencies of non-B DNA-forming repeats, GC content, and the presence of seven of 78 specific sequence motifs in the vicinity of pathogenic deletions correlated with deletion length for deletions of length ≤30 bp. Furthermore, we found the repeats of DR, GQ, and STR appear to be important for the formation of longer deletions (>30 bp) but not for the formation of shorter deletions (≤30 bp) and significantly (Chi-square test P-value < 2E-16) more microhomologies were identified in flanking short deletions than long deletions (length >30 bp). We provide evidence to support a functional distinction between microdeletions and gross deletions. A deletion length cut-off of 25-30 bp may serve as an objective means to functionally distinguish microdeletions from gross deletions.
09 Sep 2021Submitted to Human Mutation
11 Sep 2021Submission Checks Completed
11 Sep 2021Assigned to Editor
12 Sep 2021Reviewer(s) Assigned
29 Sep 2021Review(s) Completed, Editorial Evaluation Pending
10 Oct 2021Editorial Decision: Revise Minor
27 Oct 20211st Revision Received
05 Nov 2021Submission Checks Completed
05 Nov 2021Assigned to Editor
01 Dec 2021Reviewer(s) Assigned
13 Dec 2021Review(s) Completed, Editorial Evaluation Pending
14 Dec 2021Editorial Decision: Accept
Mar 2022Published in Human Mutation volume 43 issue 3 on pages 328-346. 10.1002/humu.24314