A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families

Bingshan Li, Wei Chen, Xiaowei Zhan, Fabio Busonero, Serena Sanna, Carlo Sidore, Francesco Cucca, Hyun M. Kang, Gonçalo R. Abecasis

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Family samples, which can be enriched for rare causal variants by focusing on families with multiple extreme individuals and which facilitate detection of de novo mutation events, provide an attractive resource for next-generation sequencing studies. Here, we describe, implement, and evaluate a likelihood-based framework for analysis of next generation sequence data in family samples. Our framework is able to identify variant sites accurately and to assign individual genotypes, and can handle de novo mutation events, increasing the sensitivity and specificity of variant calling and de novo mutation detection. Through simulations we show explicit modeling of family relationships is especially useful for analyses of low-frequency variants and that genotype accuracy increases with the number of individuals sequenced per family. Compared with the standard approach of ignoring relatedness, our methods identify and accurately genotype more variants, and have high specificity for detecting de novo mutation events. The improvement in accuracy using our methods over the standard approach is particularly pronounced for low-frequency variants. Furthermore the family-aware calling framework dramatically reduces Mendelian inconsistencies and is beneficial for family-based analysis. We hope our framework and software will facilitate continuing efforts to identify genetic factors underlying human diseases.

Original languageEnglish (US)
Article numbere1002944
JournalPLoS Genetics
Volume8
Issue number10
DOIs
StatePublished - Oct 2012

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mutation
Mutation
Genotype
genotype
family relations
human diseases
Software
Sensitivity and Specificity
sampling
detection
family
relatedness
methodology
software
resource
modeling
simulation

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Li, B., Chen, W., Zhan, X., Busonero, F., Sanna, S., Sidore, C., ... Abecasis, G. R. (2012). A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families. PLoS Genetics, 8(10), [e1002944]. https://doi.org/10.1371/journal.pgen.1002944

A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families. / Li, Bingshan; Chen, Wei; Zhan, Xiaowei; Busonero, Fabio; Sanna, Serena; Sidore, Carlo; Cucca, Francesco; Kang, Hyun M.; Abecasis, Gonçalo R.

In: PLoS Genetics, Vol. 8, No. 10, e1002944, 10.2012.

Research output: Contribution to journalArticle

Li, B, Chen, W, Zhan, X, Busonero, F, Sanna, S, Sidore, C, Cucca, F, Kang, HM & Abecasis, GR 2012, 'A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families', PLoS Genetics, vol. 8, no. 10, e1002944. https://doi.org/10.1371/journal.pgen.1002944
Li, Bingshan ; Chen, Wei ; Zhan, Xiaowei ; Busonero, Fabio ; Sanna, Serena ; Sidore, Carlo ; Cucca, Francesco ; Kang, Hyun M. ; Abecasis, Gonçalo R. / A Likelihood-Based Framework for Variant Calling and De Novo Mutation Detection in Families. In: PLoS Genetics. 2012 ; Vol. 8, No. 10.
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