Direct estimate of the rate of germline mutation in a bird

TLDR

DNA replication fidelity and repair normally preserve genetic integrity, but rare unrepaired damages generate germline mutations, making mutation‑rate estimation difficult, especially in large‑genome, nonmodel organisms. We sequenced 11 collared flycatcher genomes across three generations, applied stringent bioinformatic filtering, and validated mutations by tracking their stable inheritance. We detected 55 de novo mutations (10‑fold CpG enrichment, modest male bias) at a per‑site per‑generation rate of 4.6 × 10⁻⁹ (2.3 × 10⁻⁹ yr⁻¹), comparable to mice, half that of humans, and showed mutation rate scales with genome size and inversely with effective population size, proving direct estimates are feasible in any organism with family material.

Abstract

The fidelity of DNA replication together with repair mechanisms ensure that the genetic material is properly copied from one generation to another. However, on extremely rare occasions when damages to DNA or replication errors are not repaired, germline mutations can be transmitted to the next generation. Because of the rarity of these events, studying the rate at which new mutations arise across organisms has been a great challenge, especially in multicellular nonmodel organisms with large genomes. We sequenced the genomes of 11 birds from a three-generation pedigree of the collared flycatcher (Ficedula albicollis) and used highly stringent bioinformatic criteria for mutation detection and used several procedures to validate mutations, including following the stable inheritance of new mutations to subsequent generations. We identified 55 de novo mutations with a 10-fold enrichment of mutations at CpG sites and with only a modest male mutation bias. The estimated rate of mutation per site per generation was 4.6 × 10(-9), which corresponds to 2.3 × 10(-9) mutations per site per year. Compared to mammals, this is similar to mouse but about half of that reported for humans, which may be due to the higher frequency of male mutations in humans. We confirm that mutation rate scales positively with genome size and that there is a strong negative relationship between mutation rate and effective population size, in line with the drift-barrier hypothesis. Our study illustrates that it should be feasible to obtain direct estimates of the rate of mutation in essentially any organism from which family material can be obtained.