When this rate was applied to estimate the TMRCA between two Y chromosomes that encompass the oldest known patrilineal bifurcation between any humans (representing haplogroups A00 and A0, with 75 derived mutational differences in 180 kb of XDG sequence)19, we obtained a maximum-likelihood estimate21 of 239,000 years ago and a 95% CI of 188,000–296,000 years ago (174,000–321,000 years ago when incorporating the 95% CI of our mutation rate).This seems similar to the 254kya estimated by Karmin et al.
Nature Genetics (2015) doi:10.1038/ng.3247
Large-scale whole-genome sequencing of the Icelandic population
Daniel F Gudbjartsson et al.
Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
Nature Genetics (2015) doi:10.1038/ng.3171
The Y-chromosome point mutation rate in humans
Agnar Helgason et al.
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.
Nature Genetics (2015) doi:10.1038/ng.3246
Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease
Stacy Steinberg et al.
We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).
Nature Genetics (2015) doi:10.1038/ng.3243
Identification of a large set of rare complete human knockouts
Patrick Sulem et al.
Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF less than 2%, 95% confidence interval (CI) = 10–261).