Academic journal article Genetics

Extensive Long-Range and Nonsyntenic Linkage Disequilibrium in Livestock Populations: Deconstruction of a Conundrum

Academic journal article Genetics

Extensive Long-Range and Nonsyntenic Linkage Disequilibrium in Livestock Populations: Deconstruction of a Conundrum

Article excerpt

ABSTRACT

Great interest was aroused by reports, based on microsatellite markers, of high levels of statistically significant long-range and nonsyntenic linkage disequilibrium (LD) in livestock. Simulation studies showed that this could result from population family structure. In contrast, recent SNP-based studies of livestock populations report much lower levels of LD. In this study we show, on the basis of microsatellite data from four cattle populations, that high levels of long-range LD are indeed obtained when using the multi-allelic D' measure of LD. Long-range and nonsyntenic LD are exceedingly low, however, when evaluated by the standardized chi-square measure of LD, which stands in relation to the predictive ability of LD. Furthermore, specially constructed study populations provided no evidence for appreciable LD resulting from family structure at the grandparent level. We propose that the high statistical significance and family structure effects observed in the earlier studies are due to the use of large sample sizes, which accord high statistical significance to even slight deviations from asymptotic expectations under the null hypothesis. Nevertheless, even after taking sample size into account, our results indicate that microsatellites testify to the presence of usable LD at considerably wider separation distances than SNPs, suggesting that use of SNP haplotypes may considerably increase the usefulness of a given fixed SNP array.

THE effectiveness of whole-genome association studies (WGA) or whole-genome selection (WGS) depends on the level of linkage disequilibrium (LD) in the population. Consequently, great interest was aroused by reports, based on microsatellites, of relatively high statistically significant levels of marker-marker LD in dairy cattle and other farm animals over extended intrachromosomal regions and even between chromosomes (Farnir et al. 2000;McRae et al. 2002; Tenesaet al. 2003;Nsengimanaet al.2004;Heifetz et al.2005).Onthe basisof simulationstudies, Farniret al. (2000) concluded that the observed values of their LD measure could be explained as derived from the family structure of their population. Incontrast, recent studiesusingSNPmarkers report much lower levels of LD, limited to ≤100 kb (McKay et al. 2007; Khatkar et al. 2008; Sargolzaei et al. 2008). Other studies have found significant LD between microsatellite markers over larger separation distances than between SNP markers (Varilo et al. 2003), but the magnitude of difference reported above is unprecedented. Although inmany applications high-density SNP arraysappear tobereplacingmicrosatellites as themarker of choice, it is difficult to believe that microsatellites, which so beautifully embody all the desired qualities of a genetic marker, will be superceded by SNP arrays in all applications. Additionally, there is some evidence that SNP haplotypes combine the advantages of multi-allelic markers and array technology (Pe'er et al. 2006), while extension of array technology to microsatellites is certainly within the realm of possibility. Thus, it is of interest to continue to explore the properties of microsatellites as representative of multi-allelic markers in general and to search for a solution to the above conundrum in particular.

All of the microsatellite-based livestock studies cited above, with the exception of Heifetz et al. (2005), used Hedrick's multi-allelic D' (henceforth denoted D'*; Hedrick 1987) as the measure of LD, while the SNP studies used Hill and Robertson's r^sup 2^ (Hill and Robertson 1968). In contrast to r^sup 2^, D'* does not provide a quantitative estimate of the information provided by one locus for the other (Ardlie et al. 2002; McRae et al. 2002; Flint-Garcia et al. 2003; Zhao et al. 2005). Zhao et al. (2005, 2007) found that standardized x2 (henceforth denoted x2'*; Yamazaki 1977) closely tracked the regression of the allelic state at a QTL on the allelic state at a multi-allelic marker and hence conveys the same information for multi-allelic markers as r^sup 2^ does for diallelic markers. …

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