A comparative study of structural variant calling in WGS from Alzheimer's disease families.

TitleA comparative study of structural variant calling in WGS from Alzheimer's disease families.
Publication TypeJournal Article
Year of Publication2024
AuthorsMalamon, JS, Farrell, JJ, Xia, LCharlie, Dombroski, BA, Das, RG, Way, J, Kuzma, AB, Valladares, O, Leung, YYee, Scanlon, AJ, Lopez, IAntonio Ba, Brehony, J, Worley, KC, Zhang, NR, San Wang, L-, Farrer, LA, Schellenberg, GD, Lee, W-P, Vardarajan, BN
JournalLife Sci Alliance
Volume7
Issue5
Date Published2024 May
ISSN2575-1077
KeywordsAlzheimer Disease, Humans, Whole Genome Sequencing
Abstract

Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.

DOI10.26508/lsa.202302181
Alternate JournalLife Sci Alliance
PubMed ID38418088
PubMed Central IDPMC10902710
Grant ListHHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
RF1 AG058066 / AG / NIA NIH HHS / United States
U01 AG058635 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
U01 AG058654 / AG / NIA 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
U54 HG003067 / HG / NHGRI 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
UF1 AG068028 / 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
HHSN268201100011C / HL / NHLBI NIH HHS / United States
RF1 AG054074 / AG / NIA NIH HHS / United States
U01 AG016976 / 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
UF1 AG047133 / AG / NIA NIH HHS / United States
U01 AG057659 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01 AG062943 / 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
U01 AG058589 / AG / NIA 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
R01 AG048927 / AG / NIA NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI 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
N01HC25195 / HL / NHLBI NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
U01 HL096899 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
U01 AG049506 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States

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