10.1007/s00335-001-2133-8. Cite this article. D0and r2 If the two loci both have very rare alleles and the rare alleles do not occur together on a haplotype, for example, it is possible for D0to be 1 (since 1 of the haplotypes does not occur in the populations) and for r2 to be small (when the PLoS One. BMC Genet. 2009, 10: 18-10.1186/1471-2156-10-18. 10.1101/gr.10.2.220. A simple algorithm based on syntenic LD was developed to identify misplaced SNPs and to approximate their physical locations. For instance, population bottlenecks predictably result in increased LD, LD between SNP’s in loci under natural selection affect each others rates of adaptive evolution, selfing/inbreeding populations accumulate LD, etc (for an excellent review, see Slatkin 2008). Further, SNPs were divided into groups based on the average MAF (the average of MAF of the two SNPs). This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. where πA, πa, πB, πb denote the allele frequencies and πAB, πAb, πaB, πab are the haplotypes frequencies. r2 between SNP pairs with alleles A and a at the first locus and B and b at the second locus was defined as , where. Residual r2 was on the other hand independent of the average MAF. These commands produce a pruned subset of variants that are in approximate linkage equilibrium with each other, writing the IDs to plink2.prune.in (and the IDs of all excluded variants to plink2.prune.out). Decay of r2 as function of physical distance. It can be explained by not only a lower recombination rate but also by a lower mutation rate and a faster genetic drift due to a smaller effective population size [19]. 10.1046/j.1469-1809.2002.00108.x. BMC Genomics 11, 421 (2010). Google Scholar. Linkage disequilibrium (LD) is the non-random association of marker alleles and can arise from marker proximity or from selection bias. Chromosomes contain local hot spots and cold spots that undergo quite different rates of meiotic recombination and these spikes in r2 could indicate cold spots. 2003, 81: 617-623. SNP pruning - Linkage disequilibrium measure, r2 (0.2), and minor allele frequency (0.05), why these values? Additional file 4, Figure S4 shows the decay of LD with a distance of using their original location and the corrected position of the misplaced SNPs. The effect of MAF on |D'| and r2 was investigated as suggested by Du et al. The physical map of SNPs was built using the UMD 3.1. bovine genome sequence assembly [23]. Tenesa A, Knott SA, Ward D, Smith D, Williams JL, Visscher PM: Estimation of linkage disequilibrium in a sample of the United Kingdom dairy cattle population using unphased genotypes. PubMed  Kim ES, Kirkpatrick BW: Linkage disequilibrium in the North American Holstein population. When moving from 60 to 500 kb, average r2 declined from 0.16 to 0.11. The reasoning is that pedigree structure leads to overrepresentation of the paternal haplotypes in the sample, because sires have multiple progeny in the data set, which inflates frequencies of certain haplotypes and consequently leads to overestimation of LD. 2006, 173: 1777-1786. Figure 4 compares the decay of linkage disequilibrium with distance on BTA 1 when r2 was computed from maternal, paternal or both haplotypes. However, a high degree of heterogeneity of LD was observed across the genome. Within each window, average values of r2 and |D'| were calculated for SNPs separated by between 200 to 600 kb. Residual LD was calculated for each pair by subtracting average LD of the bin the pair belonged to from the LD of the pair. All of the following calculations only consider founders. Since two-variant r2 only makes sense for biallelic variants, these collapse multiallelic variants down to most common allele vs. the rest. Part of LD is a function of distance, therefore in order to evaluate the effect of MAF on the measures of LD independently of distance, r2 and |D'| between all pairs of SNPs were adjusted for inter-marker distance. Therefore SNPs positioned in the PAR region can have up to three different genotypes. Int J Biol Sci. Sargolzaei M, Schenkel FS, Jansen GB, Schaeffer LR: Extent of linkage disequilibrium in Holstein cattle in North America. On the other hand, SNPs were not evenly spaced on Chr X (Additional file 3, Figure S3). There were certain regions of Chr X where adjacent SNPs were separated by more than 1 Mb (Figure 1). Therefore |D'| is rather an indicator of missing haplotypes than a reliable measure of LD [1]. The range of both measures is between 0 and 1. If this distance was larger than 10 MB, the particular SNP was flagged as a possibly misplaced SNP and it was further investigated. r2 represents the correlations between the two loci and r2 = 1 when only two haplotypes are present, which is usually a consequence of population bottlenecks or genetic drift [3]. fl�w��,�C��O���ћ�LWK>�2 €$�#�9L1R���#�%n��*���)�P��3�݉��*�H���y�Jz��B��WEX�1z�p _DTj�|�*���.����V�O�A�i�g��e���uք⭖4�T^diE�����Ot�Ű������ �fH��Y����;�����Ey�S��5"�W�����$��F㬳��'�EP@�X�pO�*xλL�2h�h��)������Ta0� e'�L�Ϣ�x��~+j���R�{V J�RF�g�T(hQF�{. Vallejo RL, Li YL, Rogers GW, Ashwell MS: Genetic diversity and background linkage disequilibrium in the North American Holstein cattle population. Cookies policy. PLINK 2 cannot estimate LD effectively when very few founders are present, so it normally errors out when there are less than 50. The extent of LD was higher on the X chromosome compared to the autosomes. This is not a surprising finding, because the denominator in the formula of |D'| is equal to a minimal product of SNP allele frequencies. [8]. Two hundred replicates were generated for each sample size. 2003, 4: 587-597. Google Scholar. 2003, 86: 4137-4147. Only windows consisting of at least 20 SNP pairs were considered. High degree of heterogeneity of LD was observed on both autosomes and Chr X. 1967, 21: 137-143. The X chromosome (Chr X) is the second largest chromosome of the bovine karyotype [6] and is composed of two distinct regions: the pseudo-autosomal region (PAR), which is homologous to the Y chromosome and the X-specific region. Centre for Genetic Improvement of Livestock, Animal and Poultry Science, Department, University of Guelph, Guelph, Ontario, Canada, L'Alliance Boviteq, Saint-Hyacinthe, Québec, Canada, You can also search for this author in If the two loci are independent, then the expected frequency of haplotypes AB is πA πB. The two most commonly used measures of LD for bi-allelic markers are r2 and |D'|. Hassold T, Sherman S, Hunt P: Counting cross-overs: characterizing meiotic recombination in mammals. All autosomes are acrocentric, however, both gonosomes (X and Y) are submetacentric [5]. [20] reported a higher LD and a higher variation in intragenic regions than in intergenic regions. PubMed  If you can't solve the problem with PLINK 1.9 --make-founders, you can use --bad-ld as a last resort to force PLINK 2 to proceed. On Chr X, LD was calculated separately for SNPs located on the X-specific and the PAR regions of Chr X (Table 3). It is very likely that there could be other SNP with incorrect location, especially on BTA 14 and Chr X, where the pattern of LD was slightly erratic in certain regions even after the corrections. --ld ['dosage'] ['hwe-midp']. Additional file 1: Frequency distribution of minor allele frequency of all SNPs before editing. Haplotypes phases were inferred from pedigree by a method by Sargolzaei et al. In SNP pairs with low allele frequency, D will be in the formula divided by a small number, resulting in a large |D'|. Because of the widespread use of a few elite sires in dairy cattle, paternally inherited haplotypes are recommended to be discarded, because if they are included in the analyses it could lead to overestimation of the extent of LD. No differences in the extent of LD and the decline of LD with distance were found between intragenic and intergenic regions. The average MAF per chromosome ranged from 0.28 to 0.30. Residual |D'| was negative at a high MAF, indicating that |D'| is underestimated at high MAF. Martin WB, Flanagan M: Karyotype analysis of leucocytes from normal and lymphosarcomatous cattle (Bos taurus).