Allelic decomposition and exact genotyping of highly polymorphic and structurally variant genes

Nature Communications
Ibrahim NumanagićS Cenk Sahinalp

Abstract

High-throughput sequencing provides the means to determine the allelic decomposition for any gene of interest-the number of copies and the exact sequence content of each copy of a gene. Although many clinically and functionally important genes are highly polymorphic and have undergone structural alterations, no high-throughput sequencing data analysis tool has yet been designed to effectively solve the full allelic decomposition problem. Here we introduce a combinatorial optimization framework that successfully resolves this challenging problem, including for genes with structural alterations. We provide an associated computational tool Aldy that performs allelic decomposition of highly polymorphic, multi-copy genes through using whole or targeted genome sequencing data. For a large diverse sequencing data set, Aldy identifies multiple rare and novel alleles for several important pharmacogenes, significantly improving upon the accuracy and utility of current genotyping assays. As more data sets become available, we expect Aldy to become an essential component of genotyping toolkits.

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Citations

Jul 19, 2018·Pharmacogenomics·Charity Nofziger, Markus Paulmichl
Jun 18, 2019·Clinical Pharmacology and Therapeutics·Seung-Been LeeDeborah A Nickerson
Sep 24, 2019·Clinical Pharmacology and Therapeutics·Charity NofzigerAndrea Gaedigk
Apr 1, 2020·International Journal of Molecular Sciences·Sylvan M CasparGabor Matyas
Jul 1, 2020·Clinical Pharmacology and Therapeutics·Mariana R BottonAndrea Gaedigk
Nov 6, 2018·Nature Communications·Kristoffer SahlinPaul Medvedev
Jan 20, 2021·The Pharmacogenomics Journal·Xiao ChenMichael A Eberle
Feb 2, 2021·Pharmacogenomics·Sylvan Manuel CasparGabor Matyas
Dec 10, 2020·Genes·Maaike van der LeeJesse J Swen
Jan 21, 2021·Pharmacogenomics and Personalized Medicine·Hang TongLy Le
Jan 26, 2021·Clinical Pharmacology and Therapeutics·David TwesigomweScott Hazelhurst
Jan 16, 2021·Clinical Pharmacology and Therapeutics·Zeruesenay DestaAndrea Gaedigk
Apr 4, 2021·Journal of Personalized Medicine·Sumi Elsa JohnFahd Al-Mulla
Apr 1, 2021·British Journal of Pharmacology·Malgorzata BorczykMichal Korostynski
May 1, 2021·Clinical Pharmacology and Therapeutics·Shishi LuoNicole L Washington
Aug 27, 2021·CPT: Pharmacometrics & Systems Pharmacology·Blessed W AruldhasSenthilkumar Sadhasivam
Nov 7, 2021·The Pharmacogenomics Journal·Maaike van der LeeSeyed Yahya Anvar

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Methods Mentioned

BETA
RNA-Seq
genotyping

Software Mentioned

GASVPro
Pindel
Delly
SCIP
GeT
VariationHunter
RM
novoBreak
Gurobi
Dissect

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