13: Human de novo mutation rates from a four‑generation pedigree

Nature - A telomere‑to‑telomere, multigenerational study that uses five sequencing technologies to assemble and phase near‑complete diploid genomes from a 28‑member family (CEPH 1463) to measure de novo mutation rates across the genome. Key terms: de novo mutation, long-read sequencing, tandem repeats, centromeres, Y chromosome.

Study Highlights:
The authors generated phased, near‑T2T assemblies for members of a four‑generation pedigree and traced inheritance to estimate 98–206 de novo mutations per transmission, including single‑nucleotide, indel, tandem‑repeat and structural variants. Short tandem repeats and larger VNTRs, centromeres and Yq12 satellite DNA are far more mutable than euchromatin, with 32 recurrently mutated TR loci and 288 assembled centromeres revealing integer HOR changes. There is a strong paternal bias (≈75–81%) for germline DNMs and a paternal age effect for germline SNVs, while 16% of autosomal SNVs are postzygotic and show no paternal bias. A high‑resolution recombination map (~3.4 kb breakpoint resolution) was produced and no correlation was found between meiotic crossovers and de novo structural variants.

Conclusion:
Multiplatform long‑read assemblies across four generations provide a near‑complete pedigree truth set that revises genome‑wide and region‑specific de novo mutation rates, highlights repeat‑driven mutability, and offers a benchmark for future mutation‑rate and assembly studies.

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-04-25.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- De novo mutation rate per transmission is 98–206 with average 152, roughly doubling prior estimates.
- Repeat-rich regions (centromeres, SDs, Yq12 satellites) have elevated mutation rates; Yq12 satellites are ~30x more mutable than euchromatin.
- Paternal bias in germline DNMs is strong (75–81%), and paternal age increases DNMs by ~1.55 per year.
- Postzygotic DNMs constitute about 16% of de novo SNVs and show no paternal bias.
- Centromeres show de novo SVs and SNVs; reported 18 de novo SVs in centromeres and 16 centromeric SNVs with elevated rate.
- Y chromosome DNMs are high due to Yq12 repeats; SNV rate across MSY is 1.99e-7 per bp per generation.

QC result: Pass.