TY - JOUR T1 - Choosing subsamples for sequencing studies by minimizing the average distance to the closest leaf JF - bioRxiv DO - 10.1101/017822 SP - 017822 AU - Jonathan T. L. Kang AU - Peng Zhang AU - Sebastian Zöllner AU - Noah A. Rosenberg Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/04/09/017822.abstract N2 - Imputation of genotypes in a study sample can make use of sequenced or densely genotyped external reference panels consisting of individuals that are not from the study sample. It can also employ internal reference panels, incorporating a subset of individuals from the study sample itself. Internal panels offer an advantage over external panels, as they can reduce imputation errors arising from genetic dissimilarity between a population of interest and a second, distinct population from which the external reference panel has been constructed. As the cost of next-generation sequencing decreases, internal reference panel selection is becoming increasingly feasible. However, it is not clear how best to select individuals to include in such panels. We introduce a new method for selecting an internal reference panel—minimizing the average distance to the closest leaf (ADCL)—and compare its performance relative to an earlier algorithm: maximizing phylogenetic diversity (PD). Employing both simulated data and sequences from the 1000 Genomes Project, we show that ADCL provides a significant improvement in imputation accuracy, especially for imputation of sites with low-frequency alleles. This improvement in imputation accuracy is robust to changes in reference panel size, marker density, and length of the imputation target region. ER -