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Identification of a large set of rare complete human knockouts



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 <2%, 95% confidence interval (CI) = 10–261).

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Figure 1: Transmission probabilities from carrier parents.
Figure 2: A histogram of the number of frameshift and stop-gain variants by percentage position within the affected protein sequence and the fraction of rare variants within each bin (derived allele frequency (DAF) < 0.5%).
Figure 3: Transcriptome effect of stop-gain SNPs by exon rank.

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We thank all the participants in this study. This study was performed in collaboration with Illumina.

Author information

Authors and Affiliations



P.S., H. Helgason, A.O., U.T., G.M., D.F.G. and K.S. designed the experiment. H.S., H. Holm and U.T. collected the samples. Adalbjorg Jonasdottir, Aslaug Jonasdottir, A.S. and O.T.M. performed the sequencing experiments. P.S., H. Helgason, S.A.G., F.Z., E.H., G.T.S., A.K., G.M. and D.F.G. analyzed the data. P.S., H. Helgason, A.H., D.F.G. and K.S. wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

Ethics declarations

Competing interests

The authors affiliated with deCODE Genetics are employed by the company: P.S., H. Helgason A.O., H.S., S.A.G., F.Z., E.H., G.T.S., Adalbjorg Jonasdottir, Aslaug Jonasdottir, A.S., O.T.M., A.K., A.H., H. Holm, U.T., G.M., D.F.G. and K.S.

Integrated supplementary information

Supplementary Figure 1 The probabilities of a variant being seen once and five times as a function of the number of individuals sequenced by minor allele frequency (MAF).

Variants that are seen at least five times, corresponding to an observed allelic frequency of 0.095%, are likely to be imputed with good quality.

Supplementary Figure 2 The fraction of individuals among 104,220 individuals with imputed genotypes that have genes completely knockout out by LoF variants with MAF below the given threshold.

The second panel shows a magnified view of MAF below 3%.

Supplementary Figure 3 The number of genes that are observed to have at least one LoF variant with MAF below 2% as a function of the number of sequenced individuals and the number of genes that are completely knocked out in at least one individual by LoF variants with MAF below 2% as a function of the number of chip-genotyped individuals.

The curves are derived from the allele frequency distributions and the number of imputed complete knockouts.

Supplementary Figure 4 The cumulative number of genes by the number of completely knocked out individuals.

The total number of genes is 1,171.

Supplementary Figure 5 The frequency distribution of the 6,795 LoF variants among sequenced and imputed individuals.

The leftmost count includes all variants with a frequency less than one and half divided by twice the number of sequenced individuals, which corresponds to the number of variants seen only once in the sequenced set. 

Supplementary Figure 6 A histogram of the number of meiosis between the parents of the 104,220 Icelanders in our study and the fraction of individuals that have at least one gene completely knocked out by rare LoF variants.

Supplementary Figure 7 Transcriptome effect of synonymous SNPs by exon rank.

The allele-specific expression of the non-reference allele was calculated for each variant for a set of 262 individuals with blood RNA sequence data. The top, middle and bottom of the boxes are the top quartile, median and bottom quartile values calculated over the set of variants. The whiskers show the lowest and highest datum within 1.5 times the interquartile range (IQR) from the median. The dots indicate datum more than 1.5 times the IQR from the median. The n values given are the number of variants in each class.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Note and Supplementary Tables 1–3 and 5–11. (PDF 3027 kb)

Supplementary Table 4

The observed list of 6,795 LoF mutations in 4,924 genes. (XLSX 959 kb)

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Sulem, P., Helgason, H., Oddson, A. et al. Identification of a large set of rare complete human knockouts. Nat Genet 47, 448–452 (2015).

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