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The Y-chromosome point mutation rate in humans


Mutations are the fundamental source of biological variation, and their rate is a crucial parameter for evolutionary and medical studies. Here we used whole-genome sequence data from 753 Icelandic males, grouped into 274 patrilines, to estimate the point mutation rate for 21.3 Mb of male-specific Y chromosome (MSY) sequence, on the basis of 1,365 meioses (47,123 years). The combined mutation rate for 15.2 Mb of X-degenerate (XDG), X-transposed (XTR) and ampliconic excluding palindromes (rAMP) sequence was 8.71 × 10−10 mutations per position per year (PPPY). We observed a lower rate (P = 0.04) of 7.37 × 10−10 PPPY for 6.1 Mb of sequence from palindromes (PAL), which was not statistically different from the rate of 7.2 × 10−10 PPPY for paternally transmitted autosomes1. We postulate that the difference between PAL and the other MSY regions may provide an indication of the rate at which nascent autosomal and PAL de novo mutations are repaired as a result of gene conversion.

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Figure 1: A de novo mutation at MSY position 7,270,276 in the largest patriline used in this study.
Figure 2: The number of mutations by branch length and calendar year.


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We thank E. Haraldsdóttir for help with processing some of the whole-genome sequencing data and K.S.H. Moore for help with calling SNP microarray genotypes. A.W.E. was funded by a grant from Rannís, Icelandic Student Research Fund (1103340061). A.J. was funded by the EUROTAST Marie Curie Framework Programme 7 Initial Training Network (290344).

Author information




A.H., A.W.E. and K.S. planned and directed the research. A.H. and A.W.E. analyzed the data, with A.K., V.B.G., E.D.G., A.J. and S.S.E. providing assistance with particular tasks. Á.S. performed the Sanger sequencing for the validation of de novo mutations. A.H., A.W.E. and K.S. wrote the manuscript.

Corresponding authors

Correspondence to Agnar Helgason or Kári Stefánsson.

Ethics declarations

Competing interests

A.H., V.B.G., A.S., E.D.G., A.K. and K.S. are employees of deCODE Genetics/Amgen.

Integrated supplementary information

Supplementary Figure 1 An example of a de novo mutation at paralogous positions.

We examine a G>A de novo mutation in the largest patriline with 86 meioses (the same patriline shown in Fig. 1), where sequence reads with the mutation map to three paralogous positions that are flanked by identical sequence in the human reference genome (NCBI b36), each shown in a separate depiction of the patriline: (a) 23,235,573 (rAMP7), (b) 24,071,677 (PAL1 arm 1), (c) 26,710,008 (PAL1 arm 2) and (d) with all reads combined (adjusting for the reverse complement orientation of reads at position 24,071,677 relative to positions 23,235,573 and 26,710,008). The allele state of the human reference sequence is indicated after the text "ref." Each square represents a male in the patriline, with vertical position scaled by birth year and the lines between squares representing Y-chromosome transmission events. The filled squares represent males demarcating the branches to which mutations can be assigned. Males with WGS data are indicated underneath a subset of filled squares by counts of alleles mapped to forward and reverse strands at the shown position(s) and inside each such square is the genotype called on the basis of these alleles. When examined separately, the genotypes called for the WGS males at the three positions provide inconsistent results about the branch on which the mutation occurred and the number of mutations required to account for the distribution of genotypes in the patriline. However, when the genotypes at all three positions are combined (d), it becomes clear that a single G>A mutation occurred on the branch labeled with the mutation event. We note, however, that it is not possible to resolve at which of the three positions the mutation occurred. Thus, for the purposes of this mutation rate study, each of the three paralogous positions was assigned one-third of a mutation, i.e., a weight of 1/3.

Supplementary Figure 2 The XDG normalized sequence depth of branches by sequence region and haplogroup.

Results are shown for the 482 branches with an average XDG sequence depth >10×. For each branch, the average depth in each of 27 regions of the 4 sequence classes was normalized through division by its average XDG sequence depth. This was done because the branches have very different baseline expectations of sequence depth, which depend on the number of males who belong to them and the amount of sequencing undertaken for each. Normalization by average XDG sequence depth allows meaningful comparison of sequence depth among branches. Moreover, as the XDG region is mostly present in single copy, the normalized value provides some information about the relative magnitude of change in copy number. For each sequence region and haplogroup, we then calculated and plotted the average XDG normalized sequence depth with 95% confidence intervals. The greatest differences are seen for region PAL_IR2. Here we see that males belonging to haplogroup Q1a3a appear to have just a single copy of each orientation of IR2 (around 70 and 80 kb in length, respectively), as seen in the NCBI Build 36 reference sequence, whereas males from the other haplogroups have an excess of 17–30% of reads that map to these small sequence regions, indicating a greater copy number of at least part of the IR2 sequence. Other regions that exhibit differences between haplogroups are rAMP2, where the XDG normalized sequence depth is greater in E1b1 and Q1a3a than in the other haplogroups, and XTR2, where R1b1a and Q1a3a exhibit greater XDG normalized sequence depth than the rest. For most other sequence regions, there is little evidence for differences in copy number among haplogroups. On the basis of this evidence, we deem it unlikely that our mutation rate estimates are affected by copy number variation of MSY sequence.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1, 5–7, 10 and 11, and Supplementary Note. (PDF 656 kb)

Supplementary Table 2

Summary of 739 branches in 274 patrilines with weighted sums of mutations. (XLSX 98 kb)

Supplementary Table 3

Summary of the 274 patrilines used in the study. (XLSX 13 kb)

Supplementary Table 4

Full list of 1,456 candidate de novo mutations at 2,050 positions with weights. (XLSX 258 kb)

Supplementary Table 8

Comparison of WGS and Illumina SNP chip genotypes. (XLSX 34 kb)

Supplementary Table 9

Mutation rate by haplogroup and sequence region for branches with XDG sequence depth >10×. (XLSX 18 kb)

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Helgason, A., Einarsson, A., Guðmundsdóttir, V. et al. The Y-chromosome point mutation rate in humans. Nat Genet 47, 453–457 (2015).

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