While we believe that reference-based phasing using large reference panels such as the HRC is a valuable phasing paradigm, we note a few limitations. First, reference-based phasing accuracy is limited not only by reference panel size but also by genotyping and phasing accuracy in the reference panel. In particular, the HRC reference haplotypes are largely derived from low-coverage sequencing data (which is generally prone to higher errors in genotype calling), and efforts to improve the accuracy of the reference panel are ongoing. Second, for reference-based phasing to be effective, the reference panel needs to contain a sizable subset of samples with genetic ancestry well-matched to the target samples. Consequently, phasing using the HRC is currently only advantageous for European-ancestry target samples, although plans are underway to grow the HRC to better represent worldwide populations. Third, for very large cohorts (substantially larger than the reference size), we expect that reference-based phasing will achieve only marginal gains in accuracy over cohort-based phasing. For such cohorts, we expect that cohort-based phasing may remain the preferred option due to ease of execution—although reference sizes
