Estimating error models for whole genome sequencing using mixtures of Dirichlet-multinomial distributions.
BACKGROUND
Accurate identification of genotypes is an essential part of the analysis of genomic data, including in identification of sequence polymorphisms, linking mutations with disease and determining mutation rates. Biological and technical processes that adversely affect genotyping include copy-number-variation, paralogous sequences, library preparation, sequencing error and reference-mapping biases, among others.


RESULTS
We modeled the read depth for all data as a mixture of Dirichlet-multinomial distributions, resulting in significant improvements over previously used models. In most cases the best model was comprised of two distributions. The major-component distribution is similar to a binomial distribution with low error and low reference bias. The minor-component distribution is overdispersed with higher error and reference bias. We also found that sites fitting the minor component are enriched for copy number variants and low complexity regions, which can produce erroneous genotype calls. By removing sites that do not fit the major component, we can improve the accuracy of genotype calls.


METHODS
Methods and data files are available at https://github.com/CartwrightLab/WuEtAl2017/ (doi:10.5281/zenodo.256858).


BACKGROUND
cartwright@asu.edu.


BACKGROUND
Supplementary data is available at Bioinformatics online.
The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA.
Steven H
SH
Wu
The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA.|Department of Biological Sciences, The University of Rhode Island, Kingston, RI 02881, USA.
Rachel S
RS
Schwartz
The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA.
David J
DJ
Winter
Department of Genetics, Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Donald F
DF
Conrad
The Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA.|School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA.
Reed A
RA
Cartwright
D056915:DNA Copy Number Variations; D015894:Genome, Human; D023281:Genomics / Q000379:methods / Q000592:standards; D060005:Genotyping Techniques / Q000379:methods / Q000592:standards; D006801:Humans; D015233:Models, Statistical; D012680:Sensitivity and Specificity; D016008:Statistical Distributions; D000073336:Whole Genome Sequencing / Q000379:methods* / Q000592:standards