Estimating the human mutation rate using autozygosity in a founder population.
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Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10(-8) (95% confidence interval 0.89-1.43 × 10(-8)) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10(-8)) was 9.5-fold that of non-CpG bases, and there was strong evidence (P = 2.67 × 10(-4)) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the autozygous segments (P = 0.001), which is suggestive of mutational hotspots or sites of long-range gene conversion.
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Based on R=0.29, a mutation rate of 1.2×10−8/bp per generation, and a diploid effective population size of 20,000, the target size for autosomal recessive lethal mutations is estimated to be 6.8×10^4 bp.
“Based on our estimate of R = 0.29, a mutation rate of 1.2 3 10 2 8 /bp per generation (Campbell et al. 2012), and a diploid effective population size of 20,000, the target size is then estimated to be 6.8 3 10 4 bp.”
From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Campbell et al. 2012
Plugging in s=1, h=0.01, and a mutation rate of 1.2×10−8/bp per generation, the target size of nearly recessive mutations is estimated to be 2.4×10^5 bp.
“Plugging in s = 1, h = 0.01 and taking a mutation rate of 1.2 3 10 2 8 /bp per generation (Campbell et al. 2012), we estimate that the target size of such nearly recessive mutations is 2.4 3 10 5 bp.”
From An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans (2015) · cites this paper as Campbell et al. 2012
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- Authors
- Campbell, C. D., Chong, J. X., Malig, M., Ko, A., Dumont, B. L., Han, L., Vives, L., O'Roak, B. J., Sudmant, P. H., Shendure, J., Abney, M., Ober, C., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- University of Chicago (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eichler, Evan E
- ORCID
- Venue
- Nature Genetics
- Published
- 2012-09-23
- Volume
- 44
- Issue
- 11
- Pages
- 1277-1281
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3483378
- OpenAlex
- W2020784233
- Cited by
- 215
- References
- 32
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 2 · 2023: 4 · 2022: 15 · 2021: 10 · 2020: 10 · 2019: 13 · 2018: 14 · 2017: 17 · 2016: 22 · 2015: 35 · 2014: 28 · 2013: 24 · 2012: 7
- FWCI
- 18.06
- 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R01HL085197)
- National Human Genome Research Institute (F32HG006070, R01HG002899)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD21244, R01HD021244)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- autozygosity, Hutterites, founder populations, parent-offspring trios, single nucleotide variants, mutational hotspots, whole genome sequencing
- MeSH terms
- Alleles, Chromosome Mapping, Genetics, Population, Heterozygote, Homozygote, Humans, Mutation, Pedigree, Genome, Human, Evolution, Molecular, Polymorphism, Single Nucleotide, High-Throughput Nucleotide Sequencing, Mutation Rate
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