Characteristics of linkage disequilibrium in North American Holsteins

Abstract

Background: Effectiveness of genomic selection and fine mapping is determined by the level of linkage disequilibrium (LD) across the genome. Knowledge of the range of genome-wide LD, defined as a non-random association of alleles at different loci, can provide an insight into the optimal density and location of single-nucleotide polymorphisms (SNPs) for genome-wide association studies and can be a keystone for interpretation of results from QTL mapping.

Results: Linkage disequilibrium was measured by /D'/ and r2 between 38,590 SNPs (spaced across 29 bovine autosomes and the X chromosome) using genotypes of 887 Holstein bulls. The average level of /D'/ and r2 for markers 40-60 kb apart was 0.72 and 0.20, respectively in Holstein cattle. However, a high degree of heterogeneity of LD was observed across the genome. The sample size and minor allele frequency had an effect on /D'/ estimates, however, r2 was not noticeably affected by these two factors. Syntenic LD was shown to be useful for verifying the physical location of SNPs. No differences in the extent of LD and decline of LD with distance were found between the intragenic and intergenic regions.

Conclusions: A minimal sample size of 444 and 55 animals is required for an accurate estimation of LD by /D'/ and r2, respectively. The use of only maternally inherited haplotypes is recommended for analyses of LD in populations consisting of large paternal half-sib families. Large heterogeneity in the pattern and the extent of LD in Holstein cattle was observed on both autosomes and the X chromosome. The extent of LD was higher on the X chromosome compared to the autosomes.

Figure 1

Distribution of SNPs across Chr X. The dashed line depicts the boundary between the X-specific and the pseudo-autosomal regions.

Figure 2

Decay of |D'| as function of physical distance on BTA 1. The white line represents the median decline of |D'|.

Figure 3

Decay of r² as function of physical distance. The plots represent pairwaise LD on chromosomes 1, 6, 26 and X before and after (corr) positions of the misplaced SNPs were corrected.

Figure 4

Comparison of decay of linkage disequilibrium with distance (r²) on BTA1 using only maternal, paternal or both haplotypes. The white line represents the average decline of linkage disequilibrium.

Figure 5

Distribution of average pairwise r² and |D'| by sample size and distance. The number in parenthesis in the legend indicates the sample size of each subset.

Figure 6

Average residual |D'| as a function of average MAF of a SNP pair.

Figure 7

Average r² per sliding window (scatter plot), number of SNPs per window (bottom bar plot) and frequency of SNPs with MAF < 0.1 per window (top bar plot).