Variation in genome-wide mutation rates within and between human families
Open accessAbstract
J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.
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The genome-wide rate of nucleotide substitutions is estimated at 30-100 per generation, with about one per exome.
“The rate of nucleotide substitutions genome-wide is estimated at 30–100 per generation (Conrad et al., 2011) and ~1 per exome.”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Conrad et al., 2011
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- Authors
- the 1000 Genomes Project
- Affiliations
- Wellcome Sanger Institute (GB)
- Corresponding author
- the 1000 Genomes Project
- Venue
- Nature Genetics
- Published
- 2011-06-12
- Volume
- 43
- Issue
- 7
- Pages
- 712-714
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3322360
- OpenAlex
- W2004209173
- Cited by
- 581
- References
- 20
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 21 · 2023: 19 · 2022: 31 · 2021: 21 · 2020: 20 · 2019: 36 · 2018: 63 · 2017: 42 · 2016: 46 · 2015: 54 · 2014: 51 · 2013: 55 · 2012: 67
- FWCI
- 38.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (085532, 077014, 090532, 077014/Z/05/Z)
- National Institute of General Medical Sciences (R01GM070806)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- germline mutation rate, de novo mutations, Haldane's rule, parent-offspring trios, somatic mutations, 1000 Genomes Project
- MeSH terms
- Chromosome Mapping, DNA Mutational Analysis, Family, Female, Humans, Male, Genetic Variation, Genome, Human, Polymerase Chain Reaction, Germ-Line Mutation
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