A Multi-Breed Reference Panel and Additional Rare Variation Maximizes Imputation Accuracy in Cattle

Abstract

Background The use of array-based SNP genotyping in the beef and dairy industries has produced an astounding amount of medium-to-low density genomic data in the last decade. While low-density assays work exceptionally well in the context of genomic prediction, they are less useful in mapping and causal variant discovery. This project focuses on maximizing imputation accuracies to the marker set of two high-density research assays, the Illumina Bovine HD, and the GGP-F250 which contains a large proportion of rare and potentially functional variants (~850,000 total SNPs). This 850K SNP set is well-suited for both imputation to sequence-level genotypes and direct downstream analysis. Results We find that a large multi-breed composite imputation reference comprised of 36,131 samples with either HD and/or F250 genotypes significantly increases imputation accuracy compared to a standard within-breed reference panel, particularly at low minor allele frequencies. Imputation accuracies were maximized when an individual’s ancestry was adequately represented in the composite reference, particularly with complete 850K genotypes. The addition of rare content from the F250 to our composite reference panel significantly increased the imputation accuracy of rare variants found exclusively on the HD. Additionally, we identify 50,000 variants as an ideal starting density for 850K imputation. Conclusion Using high-density genotypes on all available individuals in a multi-breed reference panel maximizes imputation accuracy for all cattle populations. Admixed breeds or those sparsely represented in the composite reference are still imputed at high accuracy which will increase further as the reference panel grows. We expect that the addition of rare variation from the F250 will increase the accuracy of imputation at the sequence level.