A Family-Based Probabilistic Method for Capturing De Novo Mutations from High-Throughput Short-Read Sequencing Data

Abstract

Recent advances in high-throughput DNA sequencing technologies and associated statistical analyses have enabled in-depth analysis of whole-genome sequences. As this technology is applied to a growing number of individual human genomes, entire families are now being sequenced. Information contained within the pedigree of a sequenced family can be leveraged when inferring the donors' genotypes. The presence of a de novo mutation within the pedigree is indicated by a violation of Mendelian inheritance laws. Here, we present a method for probabilistically inferring genotypes across a pedigree using high-throughput sequencing data and producing the posterior probability of de novo mutation at each genomic site examined. This framework can be used to disentangle the effects of germline and somatic mutational processes and to simultaneously estimate the effect of sequencing error and the initial genetic variation in the population from which the founders of the pedigree arise. This approach is examined in detail through simulations and areas for method improvement are noted. By applying this method to data from members of a well-defined nuclear family with accurate pedigree information, the stage is set to make the most direct estimates of the human mutation rate to date.

The Next-Generation Sequencing Revolution and Its Impact on Genomics

“…An entire class of computational tools has arisen that utilize both sequencing data and pedigree information to identify de novo mutations genome wide. Most of these tools currently deal with trios (mother, father, and child) only and can identify de novo variants arising in the children (Cartwright et al, 2012; http://sourceforge.net/p/denovogear/wiki/Home/; Li et al, 2012; Li, 2011). Because sequencing reads have a higher error rate than traditional genotyping, these tools incorporate information about coverage, the sequencing error rate, the expected de novo mutation rate, and family relationships.…”

Rare allelic forms of PRDM9 associated with childhood leukemogenesis

“…In the ALL quartet, SNP calling from exome data was performed as described in Supplemental Methods. De novo mutation discovery was performed using the DND software (Cartwright et al 2012). In the 22 trios, we called SNPs in parents using Samtools and only SNPs within targeted regions with Phred score above 30 were kept.…”

DeNovoGear: de novo indel and point mutation discovery and phasing

“…While we and others have shown that it is feasible to accurately detect de novo point mutations from whole genome sequencing (WGS) data, our ability to reliably detect de novo indels is much less certain 1–4 . In the recently published Phase I analyses of the 1000 genomes project, experimental validation of an initial indel call set yielded an estimated false discovery rate of 35% 5 .…”