title: Estimating the human mutation rate using autozygosity in a founder population.
abstract: 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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, USA.
authors.forename: Catarina D
authors.initials: CD
authors.lastname: Campbell
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.forename: Maika
authors.initials: M
authors.lastname: Malig
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.forename: Beth L
authors.initials: BL
authors.lastname: Dumont
authors.forename: Lide
authors.initials: L
authors.lastname: Han
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sudmant
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Mark
authors.initials: M
authors.lastname: Abney
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D019143:Evolution, Molecular; D005828:Genetics, Population; D015894:Genome, Human; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide