A conditional multi-trait sequence GWAS discovers pleiotropic candidate genes and variants for sheep wool, skin wrinkle and breech cover traits

Sunduimijid Bolormaa,Naomi Duijvesteijn,Iona M Macleod,Andrew A Swan,Nasir Moghaddar,Paul Stothard,Majid Khansefid,Hans D Daetwyler,Julius H J Van Der Werf

doi:10.1186/s12711-021-00651-0

Abstract

BackgroundImputation to whole-genome sequence is now possible in large sheep populations. It is therefore of interest to use this data in genome-wide association studies (GWAS) to investigate putative causal variants and genes that underpin economically important traits. Merino wool is globally sought after for luxury fabrics, but some key wool quality attributes are unfavourably correlated with the characteristic skin wrinkle of Merinos. In turn, skin wrinkle is strongly linked to susceptibility to “fly strike” (Cutaneous myiasis), which is a major welfare issue. Here, we use whole-genome sequence data in a multi-trait GWAS to identify pleiotropic putative causal variants and genes associated with changes in key wool traits and skin wrinkle.ResultsA stepwise conditional multi-trait GWAS (CM-GWAS) identified putative causal variants and related genes from 178 independent quantitative trait loci (QTL) of 16 wool and skin wrinkle traits, measured on up to 7218 Merino sheep with 31 million imputed whole-genome sequence (WGS) genotypes. Novel candidate gene findings included the MAT1A gene that encodes an enzyme involved in the sulphur metabolism pathway critical to production of wool proteins, and the ESRP1 gene. We also discovered a significant wrinkle variant upstream of the HAS2 gene, which in dogs is associated with the exaggerated skin folds in the Shar-Pei breed.ConclusionsThe wool and skin wrinkle traits studied here appear to be highly polygenic with many putative candidate variants showing considerable pleiotropy. Our CM-GWAS identified many highly plausible candidate genes for wool traits as well as breech wrinkle and breech area wool cover.

Highlights

Imputation to whole-genome sequence is possible in large sheep populations
This is expected because population structure has been captured in our analysis by fitting both a random Merino strain effect and a genomic relationship matrix
Many of the variants were in strong linkage disequilibrium (LD), to be able to identify independent putative causal variants we extended the published M-genome-wide association studies (GWAS) method to include a conditional multi-trait GWAS (CM-GWAS)

Summary

Introduction

It is of interest to use this data in genome-wide association studies (GWAS) to investigate putative causal variants and genes that underpin economically important traits. Merino wool is globally sought after for luxury fabrics, but some key wool quality attributes are unfavourably correlated with the characteristic skin wrinkle of Merinos. We use wholegenome sequence data in a multi-trait GWAS to identify pleiotropic putative causal variants and genes associated with changes in key wool traits and skin wrinkle. More than half of the 70 million sheep in Australia are pure Merino that are traditionally bred for high value wool which is globally sought after for luxury fabric manufacture. While breech skin wrinkle and breech area wool cover are not of direct economic value, they are positively genetically correlated to susceptibility to “flystrike” (Cutaneous myiasis) [4]. Flystrike imposes a heavy economic and welfare burden in Australian sheep flocks and was recently estimated to cost the Australian industry over $170 million annually [5]

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