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, 44 (11), 1277-81

Estimating the Human Mutation Rate Using Autozygosity in a Founder Population


Estimating the Human Mutation Rate Using Autozygosity in a Founder Population

Catarina D Campbell et al. Nat Genet.


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.

Conflict of interest statement


E.E.E. is on the scientific advisory boards for Pacific Biosciences, Inc., SynapDx Corp., and DNAnexus, Inc.


Figure 1
Figure 1. Relationship of sequenced individuals
A simplified pedigree showing the relationship between the 15 sequenced individuals is shown. Children in the five trios are colored in black and their parents in gray. Founders are connected by shades of blue lines denoting the number of generations separating those individuals. For clarity, only the shortest relationships between each individual and the parents of each individual are shown.
Figure 2
Figure 2. Elevated autozygosity in the Hutterite individuals
Autozygous segments were binned by size for the five Hutterite individuals, three European-American individuals, and two Yoruba individuals. The x-axis represents bins of autozygous segment sizes and the y-axis is the number of segments in each bin. Each individual is represented by a “bubble” for each bin where the size of the bubble represents the total amount of genomic sequence in that bin.
Figure 3
Figure 3. Determination of the MRCA for an autozygous segment
A) A 54 Mbp autozygous segment on chromosome 2 in Individual 3. Genomic coordinates (hg18) are represented horizontally, and each individual is represented vertically: the five Hutterite individuals, followed by the three European-American individuals, and then the two Yoruba. Each SNV is represented by a vertical bar colored blue if the variant is homozygous and green if it is heterozygous. The autozygous segment in Individual 3 is boxed in orange. B) Determination of the MRCA for this autozygous segment. The pedigree containing all the haplotype carriers of the autozygous haplotype is shown. Cyan lines connect the same individuals who are represented twice in the pedigree. Individual 3 is shown in yellow. All samples with SNP microarray data are shown with red arrows, and haplotype carriers are shown in gray. These haplotype carriers have two MRCAs (boxed) as well as additional CAs further up the pedigree. The paths from these individuals to the autozygous subject are shown in red for the maternal ancestors and blue for the paternal ancestors; all ancestors of the individual are marked with a star.
Figure 4
Figure 4. SNV mutation rate estimates
The SNV mutation rate point estimates are shown for each individual and all five individuals combined with the error bars representing the 95% confidence intervals based on a Poisson distribution. μ – SNV mutations per generation per basepair. Filled diamonds are estimates from autozygous segments and open diamonds are estimates from the most recent generation.

Comment in

  • Older Males Beget More Mutations
    M Hurles. Nat Genet 44 (11), 1174-6. PMID 23104062.
    Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role fo …

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