Extent of linkage disequilibrium in the domestic cat, Felis silvestris catus, and its breeds

Abstract

Domestic cats have a unique breeding history and can be used as models for human hereditary and infectious diseases. In the current era of genome-wide association studies, insights regarding linkage disequilibrium (LD) are essential for efficient association studies. The objective of this study is to investigate the extent of LD in the domestic cat, Felis silvestris catus, particularly within its breeds. A custom illumina GoldenGate Assay consisting of 1536 single nucleotide polymorphisms (SNPs) equally divided over ten 1 Mb chromosomal regions was developed, and genotyped across 18 globally recognized cat breeds and two distinct random bred populations. The pair-wise LD descriptive measure (r(2)) was calculated between the SNPs in each region and within each population independently. LD decay was estimated by determining the non-linear least-squares of all pair-wise estimates as a function of distance using established models. The point of 50% decay of r(2) was used to compare the extent of LD between breeds. The longest extent of LD was observed in the Burmese breed, where the distance at which r(2) ≈ 0.25 was ∼380 kb, comparable to several horse and dog breeds. The shortest extent of LD was found in the Siberian breed, with an r(2) ≈ 0.25 at approximately 17 kb, comparable to random bred cats and human populations. A comprehensive haplotype analysis was also conducted. The haplotype structure of each region within each breed mirrored the LD estimates. The LD of cat breeds largely reflects the breeds' population history and breeding strategies. Understanding LD in diverse populations will contribute to an efficient use of the newly developed SNP array for the cat in the design of genome-wide association studies, as well as to the interpretation of results for the fine mapping of disease and phenotypic traits.

Figure 1. Population based SNP analysis of the domestic cat.

Number of monomorphic SNPs (left) and SNPs with a minor allele frequency 0< MAF <0.05 (right). Legend corresponds to the ten chromosomal regions.

Figure 2. Domestic cat population analysis.

F_st based neighbor-joining tree of cat populations. Red color represents eastern derived populations, blue represents western derived populations, and green color represents other populations.

Figure 3. Extent of LD in domestic cats.

a) Decay of r² value of autosomal chromosomes combined as a function of distance (Kb). Colored decay lines represent selected populations that depict upper, middle, and lower estimates of the LD measures. Gray decay lines represent the remaining populations. Filled circles indicate the point of 50% decay of r² maximum value. b) Distance in kilobases at which r² decays to 50% of the maximum value, which is the distance at r² ≈ 0.25. The distances correspond to the filled circles in (a).

Figure 4. Fraction of GWAS-informative SNP pairs at different distance classes in domestic cat breeds.

Colored lines represent selected populations that depict upper, middle, and lower examples whereas the gray lines represent the remaining populations (Table S6).

Figure 5. Domestic cat haplotype structure and diversity of two autosomal regions.

a) Haplotype analysis of chromosome A1 region, which exhibits long extent of LD. b) Haplotype analysis of chromosome C2 region, which exhibits short extent of LD. Breeds/populations are represented on the y-axis and the position of haplotype blocks are shown on the x axis. Haplotype blocks are represented by horizontal rectangles. The frequency of individual haplotypes within a block is proportional to the height of the color. Major haplotype is represented by black color, intermediate haplotypes with frequency >0.1 are represented by blue, light blue, red, green and yellow, respectively. Pink color represents the sum of the frequencies of all haploypes with a frequency <0.1. Empty regions between blocks indicate lack any informative markers (MAF ≥0.05) and can be considered monomorphic across all individuals within a population.