Choosing subsamples for sequencing studies by 1 minimizing the average distance to the closest leaf

19 Imputation of genotypes in a study sample can make use of sequenced or densely genotyped 20 external reference panels consisting of individuals that are not from the study sample. It can 21 also employ internal reference panels, incorporating a subset of individuals from the study 22 sample itself. Internal panels offer an advantage over external panels, as they can reduce 23 imputation errors arising from genetic dissimilarity between a population of interest and a 24 second, distinct population from which the external reference panel has been constructed. 25 As the cost of next-generation sequencing decreases, internal reference panel selection is 26 becoming increasingly feasible. However, it is not clear how best to select individuals to 27 include in such panels. We introduce a new method for selecting an internal reference panel— 28 minimizing the average distance to the closest leaf (ADCL)—and compare its performance 29 relative to an earlier algorithm: maximizing phylogenetic diversity (PD). Employing both 30 simulated data and sequences from the 1000 Genomes Project, we show that ADCL provides 31 a significant improvement in imputation accuracy, especially for imputation of sites with low32 frequency alleles. This improvement in imputation accuracy is robust to changes in reference 33 panel size, marker density, and length of the imputation target region. 34