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, 83 (3), 359-72

Runs of Homozygosity in European Populations

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Runs of Homozygosity in European Populations

Ruth McQuillan et al. Am J Hum Genet.

Erratum in

  • Am J Hum Genet. 2008 Nov;83(5):658

Abstract

Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F(roh), this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F(roh) distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F(roh) was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.

Figures

Figure 1
Figure 1
Pedigree of the Offspring of First Cousins An example chromosome is illustrated. The female common ancestor is red. The chromosome inherited from one of her parents is colored red, and the chromosome inherited from her other parent is colored pink. The male common ancestor is blue. The chromosome inherited from one of his parents is colored dark blue, and the chromosome inherited from his other parent is colored light blue. The second generation are sisters. They share around 50% of their chromosomes IBD. The segments colored red and pink are segments inherited from their mother, and the segments colored dark and light blue are segments inherited from their father. The third generation are first cousins. In each case, the second (white) chromosome derives from their fathers (not shown), the red and pink segments are inherited from their maternal grandmother, and the dark and light blue segments are inherited from their maternal grandfather. The offspring of these first cousins has segments inherited from both founders on both copies of the chromosome. Where the same segments have been passed down both sides of the pedigree, the offspring of first cousins has extended identical-by-descent tracts or runs of homozygosity.
Figure 2
Figure 2
Proportion of Subpopulations with One or More ROHs of a Given Length The proportion of individuals with one or more ROHs of up to 0.5–1.49, 1.5–2.49, 2.5–4.99, and 5–9.99 Mb in length, or over 10 Mb in length, is plotted for each of the eight population groups defined in the Statistical Analysis section of Subjects and Methods.
Figure 3
Figure 3
Number of ROHs Compared to Total Length of ROHs (A) Half Orcadian, (B) CEU, (C) Scottish, (D) Croatian, (E) Mixed Orcadian, (F) Mixed Dalmatian, (G) Endogamous Orcadian, and (H) Endogamous Dalmatian.
Figure 4
Figure 4
Effect of Endogamy on Sum and Number of ROHs Offspring of 1st or 2nd cousins are shown in blue, endogamous Orcadians who are not the offspring of 1st or 2nd cousins are shown in red, mixed Orcadians are shown in green, and half Orcadians are shown in black.
Figure 5
Figure 5
Correlation between Fped and Froh in Orkney Sample Correlations, with regression lines, are shown for three different minimum-ROH-length thresholds. (A) shows the correlation between Fped and Froh 0.5, (B) shows the correlation between Fped and Froh 1.5, and (C) shows the correlation between Fped and Froh 5. For colors and details of subgroups, see Figure 4 legend. N = 249.
Figure 6
Figure 6
Mean Total Length of ROHs over a Range of Minimum Tract Lengths The average total length of ROHs per individual, calculated from ROHs above 0.5, 1.5 and 5 Mb, is plotted for each of the eight population groups defined in the Statistical Analysis section of Subjects and Methods. For colors, see Figure 2 legend.
Figure 7
Figure 7
Size and Location of ROHs on Chromosome 1, Comparing Half Orcadians and Offspring of Cousins ROHs measuring ≥ 1.5 Mb in ten half Orcadians are shown in blue, and those of seven offspring of 1st–3rd cousins are shown in red. The numbers shown below each colored segment are the numbers of overlapping ROHs in the Scottish control sample.

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