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Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight.
Monday,2019-07-29 13:47 America/Los_Angeles — ecterry
| Title | Systematic analysis of dark and camouflaged genes reveals disease-relevant genes hiding in plain sight. |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | Ebbert, MTW, Jensen, TD, Jansen-West, K, Sens, JP, Reddy, JS, Ridge, PG, Kauwe, JSK, Belzil, V, Pregent, L, Carrasquillo, MM, Keene, D, Larson, E, Crane, P, Asmann, YW, Ertekin-Taner, N, Younkin, SG, Ross, OA, Rademakers, R, Petrucelli, L, Fryer, JD |
| Journal | Genome Biol |
| Volume | 20 |
| Issue | 1 |
| Pagination | 97 |
| Date Published | 2019 05 20 |
| ISSN | 1474-760X |
| Keywords | Genetic Predisposition to Disease, Genome, Human, Humans, Mutation |
| Abstract | <p><b>BACKGROUND: </b>The human genome contains "dark" gene regions that cannot be adequately assembled or aligned using standard short-read sequencing technologies, preventing researchers from identifying mutations within these gene regions that may be relevant to human disease. Here, we identify regions with few mappable reads that we call dark by depth, and others that have ambiguous alignment, called camouflaged. We assess how well long-read or linked-read technologies resolve these regions.</p><p><b>RESULTS: </b>Based on standard whole-genome Illumina sequencing data, we identify 36,794 dark regions in 6054 gene bodies from pathways important to human health, development, and reproduction. Of these gene bodies, 8.7% are completely dark and 35.2% are ≥ 5% dark. We identify dark regions that are present in protein-coding exons across 748 genes. Linked-read or long-read sequencing technologies from 10x Genomics, PacBio, and Oxford Nanopore Technologies reduce dark protein-coding regions to approximately 50.5%, 35.6%, and 9.6%, respectively. We present an algorithm to resolve most camouflaged regions and apply it to the Alzheimer's Disease Sequencing Project. We rescue a rare ten-nucleotide frameshift deletion in CR1, a top Alzheimer's disease gene, found in disease cases but not in controls.</p><p><b>CONCLUSIONS: </b>While we could not formally assess the association of the CR1 frameshift mutation with Alzheimer's disease due to insufficient sample-size, we believe it merits investigating in a larger cohort. There remain thousands of potentially important genomic regions overlooked by short-read sequencing that are largely resolved by long-read technologies.</p> |
| DOI | 10.1186/s13059-019-1707-2 |
| Alternate Journal | Genome Biol. |
| PubMed ID | 31104630 |
| PubMed Central ID | PMC6526621 |
| Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States RC2 HL102419 / HL / NHLBI NIH HHS / United States R35 NS097273 / NS / NINDS NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States U01 HL096812 / HL / NHLBI NIH HHS / United States U54 AG052427 / AG / NIA NIH HHS / United States R01 NS017950 / NS / NINDS NIH HHS / United States NS084974 / NS / NINDS NIH HHS / United States R21 AG047327 / AG / NIA NIH HHS / United States R01 AG054076 / AG / NIA NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States NS099114 / NS / NINDS NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201500001C / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States U01 AG049507 / AG / NIA NIH HHS / United States U01 HL096917 / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States R35 NS097261 / NS / NINDS NIH HHS / United States NS084528 / NS / NINDS NIH HHS / United States AG049992 / AG / NIA NIH HHS / United States AL130125 / / U.S. Department of Defense / International NS094137 / NS / NINDS NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States U01 AG016976 / AG / NIA NIH HHS / United States U01 HL096902 / HL / NHLBI NIH HHS / United States R01 NS093865 / NS / NINDS NIH HHS / United States UF1 AG047133 / AG / NIA NIH HHS / United States U01 AG057659 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01 AG049607 / AG / NIA NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States NS097261 / NS / NINDS NIH HHS / United States R03 AG049992 / AG / NIA NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States R01 NS088689 / NS / NINDS NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States U01 AG049508 / AG / NIA NIH HHS / United States U01 AG052410 / AG / NIA NIH HHS / United States U01 HL096814 / HL / NHLBI NIH HHS / United States R01 AG033040 / AG / NIA NIH HHS / United States U54 HG003079 / HG / NHGRI NIH HHS / United States P01 NS084974 / NS / NINDS NIH HHS / United States U01 AG052409 / AG / NIA NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States R21 NS084528 / NS / NINDS NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States NS088689 / NS / NINDS NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States R01 HL070825 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States NS093865 / NS / NINDS NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States U01 HL096899 / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States P01 NS099114 / NS / NINDS NIH HHS / United States U01 AG049506 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 NS094137 / NS / NINDS NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States AG047327 / AG / NIA NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States NS097273 / NS / NINDS NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States U01 AG049505 / AG / NIA NIH HHS / United States |
ePub date:
19/05