Estimating de novo mutation rates using parent-offspring pairs

Abstract

Existing pedigree approaches to identifying de novo mutations (DNMs) require at least two parents and a single offspring, limiting applicability. Here, we introduce OOPS (Only One Parent Sequencing), a framework for detecting DNMs using only a single parent-offspring pair. OOPS uses short-read data from the parent and both short and long-read data from the offspring to reconstruct haplotypes in the child, one of which can then be assigned to the sequenced parent. We show that candidate de novo mutations from the assigned haplotype can be identified, allowing for estimation of the mutation rate. To demonstrate the accuracy of OOPS, we apply it to a human pedigree in which mutations have also been identified using standard trio-based approaches. OOPS achieves comparable accuracy to trio-based pipelines and recovers consistent mutation rate estimates. By removing the requirement for complete trio sequencing, OOPS expands mutation rate estimation to a wider range of settings.