A missense mutation in growth differentiation factor 9 (GDF9) is strongly associated with litter size in sheep

Dag I Våge,Gunnar Klemetsdal,Inger A Boman,Matthew P Kent,Maren Husdal

doi:10.1186/1471-2156-14-1

Abstract

BackgroundA genome wide association study for litter size in Norwegian White Sheep (NWS) was conducted using the recently developed ovine 50K SNP chip from Illumina. After genotyping 378 progeny tested artificial insemination (AI) rams, a GWAS analysis was performed on estimated breeding values (EBVs) for litter size.ResultsA QTL-region was identified on sheep chromosome 5, close to the growth differentiation factor 9 (GDF9), which is known to be a strong candidate gene for increased ovulation rate/litter size. Sequencing of the GDF9 coding region in the most extreme sires (high and low BLUP values) revealed a single nucleotide polymorphism (c.1111G>A), responsible for a Val→Met substitution at position 371 (V371M). This polymorphism has previously been identified in Belclare and Cambridge sheep, but was not found to be associated with fertility. In our NWS-population the c.1111G>A SNP showed stronger association with litter size than any other single SNP on the Illumina 50K ovine SNP chip. Based on the estimated breeding values, daughters of AI rams homozygous for c.1111A will produce minimum 0.46 - 0.57 additional lambs compared to daughters of wild-type rams.ConclusionWe have identified a missense mutation in the bioactive part of the GDF9 protein that shows strong association with litter size in NWS. Based on the NWS breeding history and the marked increase in the c.1111A allele frequency in the AI ram population since 1983, we hypothesize that c.1111A allele originate from Finnish landrace imported to Norway around 1970. Because of the widespread use of Finnish landrace and the fact that the ewes homozygous for the c.1111A allele are reported to be fertile, we expect the commercial impact of this mutation to be high.

Highlights

A genome wide association study for litter size in Norwegian White Sheep (NWS) was conducted using the recently developed ovine 50K SNP chip from Illumina
Association testing was performed by a linear mixed model (GEMMA) [12], using estimated breeding values (EBVs) for daughter litter size as phenotypes
We cannot conclude that the c.1111G>A is the causal mutation for the differences in EBVs for litter size observed in the NWS population, our evidence is suggestive of a functional association for two reasons

Summary

Introduction

A genome wide association study for litter size in Norwegian White Sheep (NWS) was conducted using the recently developed ovine 50K SNP chip from Illumina. Polymorphisms in three different genes have been associated with increased ovulation rate/litter size in sheep. These are the growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and bone morphogenetic protein receptor, type IB (BMPR1B). In the Merino Booroola sheep (FecBB), a glutamine to arginine mutation in position 249 (Q249R) of the BMPR1B gene was found to increase ovulation rate and litter size [2,3,4]. In Cambridge and Belclare sheep two additional mutations affecting ovulation rate were identified in BMP15, a substitution of glutamine with a premature stop codon in position 239 (Q239X) (FecXG) and a change of serine to isoleucine at position 367 (S367I) (FecXB) [5]. A substitution of serine with phenylalanine in position 395 (S395F) (FecGH) of the GDF9 gene was found to be associated with increased ovulation rate

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Discussion

Conclusion