Reducing pervasive false-positive identical-by-descent segments detected by large-scale pedigree analysis

Molecular Biology and Evolution
Eric Y DurandCory Y McLean

Abstract

Analysis of genomic segments shared identical-by-descent (IBD) between individuals is fundamental to many genetic applications, from demographic inference to estimating the heritability of diseases, but IBD detection accuracy in nonsimulated data is largely unknown. In principle, it can be evaluated using known pedigrees, as IBD segments are by definition inherited without recombination down a family tree. We extracted 25,432 genotyped European individuals containing 2,952 father-mother-child trios from the 23andMe, Inc. data set. We then used GERMLINE, a widely used IBD detection method, to detect IBD segments within this cohort. Exploiting known familial relationships, we identified a false-positive rate over 67% for 2-4 centiMorgan (cM) segments, in sharp contrast with accuracies reported in simulated data at these sizes. Nearly all false positives arose from the allowance of haplotype switch errors when detecting IBD, a necessity for retrieving long (>6 cM) segments in the presence of imperfect phasing. We introduce HaploScore, a novel, computationally efficient metric that scores IBD segments proportional to the number of switch errors they contain. Applying HaploScore filtering to the IBD data at a precision of 0.8 produc...Continue Reading

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Citations

Jan 23, 2016·Science Translational Medicine·Eric Vallabh MinikelDaniel G MacArthur
Feb 26, 2016·Genome Biology and Evolution·Larisa FedorovaAlexei Fedorov
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Apr 5, 2017·PLoS Genetics·James XueShai Carmi
Feb 9, 2017·Nature Communications·Eunjung HanCatherine A Ball
Jul 18, 2017·Nature Genetics·Nathan NakatsukaKumarasamy Thangaraj
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Apr 18, 2018·BMC Genomics·Rajib DuttaAlexei Fedorov
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Jun 12, 2021·Nature Communications·Ruhollah ShemiraniJosé Luis Ambite

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Methods Mentioned

BETA
genotyping
chip

Software Mentioned

BLAST
fastIBD
GenCall
HaploScore
UCSC Genome Browser
GERMLINE
BEAGLE
RefinedIBD

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