The imputation pipeline.

<p>Given a pedigree tree of 3,671 Hutterites (1), 1,415 individuals in the three most recent generations (within the red box) were genotyped with framework markers (2). The first part of the pipeline (steps 2–6) depends only on the framework marker data; the second part (steps 7–9) imputes the whole genome sequence variants. First, estimates of identity coefficients and the transition rate parameter λ [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004139#pcbi.1004139.ref024" target="_blank">24</a>] between each pair of the 1,415 individuals are calculated (3). The framework genotypes are then phased (4), IBD segments between haplotypes are identified using a HMM (5), and indexed into an efficient data structure consisting of IBD cliques (6). Haplotypes are assigned parental origins consistent across the pedigree using the cliques (7). Then, the whole genome sequences of 98 Hutterites (8) are cleaned using several filters, including a novel generalized Mendelian error check (9), and imputed to the remaining 1,317 Hutterites using IBD cliques (10). Call rates are boosted by imputing as many of remaining genotypes as possible using an LD-based imputation method, IMPUTE2 (11). To ensure that accuracy is not compromised, we calculate the concordance of the shared genotypes between the two methods and keep only variants that are highly concordant (12).