A likelihood ratio-based method to predict exact pedigrees for complex families from next-generation sequencing data

Abstract

MotivationNext generation sequencing technology considerably changed the way we screen for pathogenic mutations in rare Mendelian disorders. However, the identification of the disease-causing mutation amongst thousands of variants of partly unknown relevance is still challenging and efficient techniques that reduce the genomic search space play a decisive role. Often segregation- or linkage analysis are used to prioritize candidates, however, these approaches require correct information about the degree of relationship among the sequenced samples. For quality assurance an automated control of pedigree structures and sample assignment is therefore highly desirable in order to detect label mix-ups that might otherwise corrupt downstream analysis.ResultsWe developed an algorithm based on likelihood ratios that discriminates between different classes of relationship for an arbitrary number of genotyped samples. By identifying the most likely class we are able to reconstruct entire pedigrees iteratively, even for highly consanguineous families. We tested our approach on exome data of different sequencing studies and achieved high precision for all pedigree predictions. By analyzing the precision for varying degrees of relatedness or inbreeding we could show that a prediction is robust down to magnitudes of a few hundred loci.Availability and ImplementationA java standalone application that computes the relationships between multiple samples as well as a Rscript that visualizes the pedigree information is available for download as well as a web service at www.gene-talk.de.Supplementary information Supplementary data are available at Bioinformatics online.

Quantitative analysis of connectivity in populations of a semi‐aquatic mammal using kinship categories and network assortativity

“…The reconstructions of pedigrees were essential to evaluate the consistency of the methods used here to estimate kinship categories (Heinrich et al, ; Staples et al, ). The pedigrees were also helpful to extract fundamental information of the reproductive biology of a species that is only rarely observed in the wild.…”

“…We also used the VCF2LR software, which takes inbreeding into account (Heinrich et al, ). As input for the program, we provided the SNP file in VCF format generated with Stacks.…”

“…However, high levels of inbreeding may affect relatedness and therefore pedigree inference (Wang, ). More recently, methods that use a likelihood‐ratio test to discriminate various degrees of relatives, even for highly consanguineous families, have been developed to deal with the issue of inbreeding (Heinrich, Kamphans, Mundlos, Robinson, & Krawitz, ; Huisman, ). Despite the huge potential of these modern methods, they have been mostly applied to genetic data from human populations, usually derived from complete genome sequences (Heinrich et al, ; Ko & Nielsen, ; Staples et al, ); how they perform using SNPs of wild populations obtained from reduced‐representation libraries remains to be seen.…”

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction

“…Parenthood was confirmed by SNP analysis of the next-generation sequencing data of families 1 and 5, as well as by single-tandem-repeat analysis in families 2-4. 20 The missense variants c.650G>A and c.649C>T were not found in the ExAC Browser, gnomAD, or 1000 Genomes. 14,15 The variants were classified as disease causing by Muta-tionTaster, 21 damaging by SIFT, 22 and probably damaging by PolyPhen-2 23 as a result of the evolutionary conservation of the arginine residue at position 217 ( Figure 2A).…”

Who’s who? Detecting and resolving sample anomalies in human DNA sequencing studies with peddy

“…While tools such as Plink [1] and KING [5] can detect sex and pedigree errors, they require conversion from the standard VCF [6] format to PLINK format and solely produce text output that requires further manual inspection of custom scripts to detect sample issues. Other tools [7,8] are able to infer pedigree structure from sample genotype data, but they are cumbersome for identifying and resolving sample swaps. To address the need for robust, rapid, and automated detection of problems with sample DNA fidelity, we have developed peddy , a software package that evaluates correspondence between the stated sexes, relationships, and ancestries in a pedigree file [1] and those inferred from the genotypes in the VCF file resulting from human WES or WGS studies.…”