title: An integrative variant analysis pipeline for accurate genotype/haplotype inference in population NGS data.
abstract: Next-generation sequencing is a powerful approach for discovering genetic variation. Sensitive variant calling and haplotype inference from population sequencing data remain challenging. We describe methods for high-quality discovery, genotyping, and phasing of SNPs for low-coverage (approximately 5×) sequencing of populations, implemented in a pipeline called SNPTools. Our pipeline contains several innovations that specifically address challenges caused by low-coverage population sequencing: (1) effective base depth (EBD), a nonparametric statistic that enables more accurate statistical modeling of sequencing data; (2) variance ratio scoring, a variance-based statistic that discovers polymorphic loci with high sensitivity and specificity; and (3) BAM-specific binomial mixture modeling (BBMM), a clustering algorithm that generates robust genotype likelihoods from heterogeneous sequencing data. Last, we develop an imputation engine that refines raw genotype likelihoods to produce high-quality phased genotypes/haplotypes. Designed for large population studies, SNPTools' input/output (I/O) and storage aware design leads to improved computing performance on large sequencing data sets. We apply SNPTools to the International 1000 Genomes Project (1000G) Phase 1 low-coverage data set and obtain genotyping accuracy comparable to that of SNP microarray.
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Lu
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Fuli
authors.initials: F
authors.lastname: Yu
mesh_terms: D000465:Algorithms; D001483:Base Sequence; D005838:Genotype; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D016045:Human Genome Project; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*