title: A Bayesian framework for de novo mutation calling in parents-offspring trios.
abstract: BACKGROUND
  Spontaneous (de novo) mutations play an important role in the disease etiology of a range of complex diseases. Identifying de novo mutations (DNMs) in sporadic cases provides an effective strategy to find genes or genomic regions implicated in the genetics of disease. High-throughput next-generation sequencing enables genome- or exome-wide detection of DNMs by sequencing parents-proband trios. It is challenging to sift true mutations through massive amount of noise due to sequencing error and alignment artifacts. One of the critical limitations of existing methods is that for all genomic regions the same pre-specified mutation rate is assumed, which has a significant impact on the DNM calling accuracy.
  
  
  RESULTS
  In this study, we developed and implemented a novel Bayesian framework for DNM calling in trios (TrioDeNovo), which overcomes these limitations by disentangling prior mutation rates from evaluation of the likelihood of the data so that flexible priors can be adjusted post-hoc at different genomic sites. Through extensively simulations and application to real data we showed that this new method has improved sensitivity and specificity over existing methods, and provides a flexible framework to further improve the efficiency by incorporating proper priors. The accuracy is further improved using effective filtering based on sequence alignment characteristics.
  
  
  METHODS
  The C++ source code implementing TrioDeNovo is freely available at https://medschool.vanderbilt.edu/cgg.
  
  
  BACKGROUND
  bingshan.li@vanderbilt.edu
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yongzhuang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA, Center for Quantitative Sciences, Vanderbilt University, Nashville, TN, USA,Center for Human Genetic Variation, Duke University, Durham, NC, USA, School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Bingshan
authors.initials: B
authors.lastname: Li
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D004252:DNA Mutational Analysis / Q000379:methods*; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D016415:Sequence Alignment