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A common inversion under selection in Europeans


A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

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Figure 1: A 900-kb inversion polymorphism was detected on one of the RP11 chromosomes at the 17q21.31 locus.
Figure 2: The sequence divergence of the H1 and H2 lineages.
Figure 3: Networks depicting the haplotype structure of the inversion.
Figure 4: The impact of the inversion on LD patterns.
Figure 5: Worldwide distribution of the H2 lineage based on allele frequencies of two diagnostic SNPs obtained from the ALFRED database19.
Figure 6: The genome-wide impact of the number of H2 copies on the rate of recombination in mothers.

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We thank D. Reich, N. Patterson and D. Donnelly for constructive comments regarding this work.

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Correspondence to Augustine Kong or Kari Stefansson.

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Competing interests

H. Stefansson, A. Helgason, G. Thorleifsson, V. Steinthorsdottir, G. Masson, A. Baker, A. Jonasdottir, A. Ingason, V. G. Gudnadottir, N. Desnica, A. Hicks, A. Gylfason, D. F. Gudbjartsson, G. M. Jonsdottir, J. Sainz, K. Agnarsson, B. Birgisdottir, S. Ghosh, A. Olafsdottir, J.-B. Cazier, K. Kristjansson, M. L. Frigge, T. E. Thorgeirsson, J. R. Gulcher, A. Kong & K. Stefansson own stock or stock options in deCODE Genetics.

Supplementary information

Supplementary Fig. 1

Genotype analysis on homozygous samples sharing (identical-by-descent) over the 17q21.31 locus. (PDF 597 kb)

Supplementary Fig. 2

The relative copy number for H1D1 and H1D3 variants compared to H2 variants estimated by gene dose analysis at three loci. (PDF 97 kb)

Supplementary Fig. 3

Five chromosomal variants with considerable variation in size at the inverted locus on 17q21.31. (PDF 87 kb)

Supplementary Fig. 4

Positive correlation is found between copy numbers of the 5′ end of the NSF gene per sample. (PDF 62 kb)

Supplementary Fig. 5

A sliding window analysis of sequence divergence in 5 kb sequence segments inside the inverted region of a 77 kb fragment that spans much of intron 1 and 2 from the MAPT gene from 44.444005-44.520949 Mb in the H1 orientation in Build 34. (PDF 203 kb)

Supplementary Fig. 6

LD between SNP markers spanning the inversion at 17q21.31. (PDF 241 kb)

Supplementary Fig. 7

The estimate frequency of H2 for females and males who have 0, 1, 2, 3, 4 and 5 or more children. (PDF 261 kb)

Supplementary Table 1

Available sequences and contigs from the RP11 library mapping to 17q21.31. (PDF 160 kb)

Supplementary Table 2

Test for the impact of selection of H2 chromosomes in the Utah sample using the mutational diversity of five microsatellites. (PDF 319 kb)

Supplementary Table 3

The distribution of the number of children for 82,992 Icelandic males and for 79,811 Icelandic females born between 1925 and 1965. (PDF 251 kb)

Supplementary Table 4

Results from multiple regression analyses for a cohort of 16959 females and 12178 males born between 1925 and 1965. (PDF 230 kb)

Supplementary Table 5

Primer sequences for markers shown in Figures 1 and 3. (PDF 305 kb)

Supplementary Table 6

Difference in mutation rate for microsatellites on H1 and H2 backgrounds. (PDF 189 kb)

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Stefansson, H., Helgason, A., Thorleifsson, G. et al. A common inversion under selection in Europeans. Nat Genet 37, 129–137 (2005).

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