Genome-Wide Identification of a Regulatory Mutation in BMP15 Controlling Prolificacy in Sheep.

Louise Chantepie,Florence Plisson-Petit,Julien Ruesche,Florent Woloszyn,Loys Bodin,Stéphane Fabre,Julien Sarry,Laurence Drouilhet

doi:10.3389/fgene.2020.00585

Abstract

The search for the genetic determinism of prolificacy variability in sheep has evidenced several major mutations in genes playing a crucial role in the control of ovulation rate. In the Noire du Velay (NV) sheep population, a recent genetic study has evidenced the segregation of such a mutation named FecLL. However, based on litter size (LS) records of FecLL non-carrier ewes, the segregation of a second prolificacy major mutation was suspected in this population. In order to identify this mutation, we have combined a case/control genome-wide association study with ovine 50k SNP chip genotyping, whole genome sequencing, and functional analyses. A new single nucleotide polymorphism (OARX:50977717T > A, NC_019484) located on the X chromosome upstream of the BMP15 gene was evidenced to be highly associated with the prolificacy variability (P = 1.93E-11). The variant allele was called FecXN and shown to segregate also in the Blanche du Massif Central (BMC) sheep population. In both NV and BMC, the FecXN allele frequency was estimated close to 0.10, and its effect on LS was estimated at +0.20 lamb per lambing at the heterozygous state. Homozygous FecXN carrier ewes were fertile with increased prolificacy in contrast to numerous mutations affecting BMP15. At the molecular level, FecXN was shown to decrease BMP15 promoter activity and supposed to impact BMP15 expression in the oocyte. This regulatory action was proposed as the causal mechanism for the FecXN mutation to control ovulation rate and prolificacy in sheep.

Highlights

There is an accumulation of evidence that the oocyte plays a central role in controlling the ovarian folliculogenesis from the early stages up to ovulation
Completed by the whole-genome sequencing of two chosen animals based on their genotypes, we have identified a new regulatory variant called FecXN proposed to affect the oocyte-dependent expression of BMP15 in association with increased prolificacy in sheep
Through a case/control genome-wide association study (GWAS) strategy and genome sequencing, we have identified in the Noire du Velay (NV) breed a second prolific mutation named FecXN affecting the expression of the BMP15 gene, a well-known candidate gene controlling ovulation rate (OR) and litter size (LS) in sheep

Summary

Introduction

There is an accumulation of evidence that the oocyte plays a central role in controlling the ovarian folliculogenesis from the early stages up to ovulation. Among the local factors produced by the oocyte itself, members of the bone morphogenetic protein/growth and differentiation factor (BMP/GDF) family play an integral role in this control (Persani et al, 2014). The most important are surely BMP15 and GDF9. Knockout mice models gave the first evidence of the importance of these two oocyte-derived factors acting individually as homodimers and/or through a synergistic cooperation to control the ovarian function (Elvin et al, 1999; Yan et al, 2001). A focus was done on BMP15 and GDF9 about their implication in various ovarian dysfunctions. Numerous heterozygous missense mutations have been identified in both genes associated with primary or secondary amenorrhea in different cohorts of women

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Conclusion