Abstract

Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS. Using simulated phenotypes, we showed that EG-GWAS has a higher power than cHD to detect associations within target regions and less power outside target regions, with power being influenced further by sample size and SNP density. We analyzed two real phenotypes (hair length and furnishing), that are fixed in certain breeds to characterize mapping precision of the known causal mutations. EG-GWAS identified the associated exonic and 3′UTR variants within the FGF5 and RSPO2 genes, respectively, with only a few samples per breed. In conclusion, we demonstrated that EG-GWAS can identify loci associated with Mendelian phenotypes both within and across breeds.

Highlights

  • Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits

  • Definition wise, any variant that is in linkage disequilibrium (LD) with other variants in the neighborhood and that as such can be used to tag the mutational variability in that region, can be seen as a tag Single Nucleotide Polymorphisms (tagSNPs)

  • A direct comparison of the physical distance of canine high-density (cHD) tagSNPs and whole exome sequencing (WES) informative SNPs that passed the filters for LD calculation, shows that whereas the mean distance between WES SNPs (1 SNP every 40 kb) is larger relative to cHD SNPs (1 SNP every 17 kb), the median distance is smaller (WES: 1 SNP every 1 kb, cHD: 1 SNP every 13 kb), indicating a highly skewed distance distribution (Fig. 1)

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Summary

Introduction

Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. In genome-wide association studies (GWAS), it is generally not the causal mutation that is directly genotyped. When GWAS is used that way, it is an indirect method and requires further steps downstream (e.g. fine mapping, candidate gene sequencing) to detect the causal mutation. This is in contrast to whole exome sequencing (WES) and whole genome sequencing (WGS) where one tries to identify the disease-causing mutation directly, often by the sequential use of a set of heuristic filters[4]. WES focuses on pre-specified target regions, generally the exonic part of protein-coding regions (even though non-coding RNAs are included in some WES designs)[5]

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