A Nonsense Variant in CCDC65 Gene Causes Respiratory Failure Associated with Increased Lamb Mortality in French Lacaune Dairy Sheep.

Maxime Ben Braiek,Florence Plisson-Petit,Philippe Bardou,Carole Moreno-Romieux,Julien Sarry,Florent Woloszyn,Némuel Tadi,Cord Drögemüller,Frédéric Debat,David Portes,Charlotte Allain,Arnaud Bordes,Stéphane Fabre

doi:10.3390/genes13010045

Abstract

We recently demonstrated that the Lacaune deficient homozygous haplotype 6 (LDHH6) potentially hosts a recessive perinatal lethal mutation in Lacaune dairy sheep mapped on OAR3. In the present study, we have analyzed the whole-genome sequences of two Lacaune ram heterozygous carriers of LDHH6. After variant calling and filtering against the variants of 86 non-carrier rams, we have identified a single nucleotide variant (SNV) in the two LDHH6 carriers whose variant allele induced a premature stop codon (p.Glu111*) in the Coiled-Coil Domain Containing 65 (CCDC65) gene. CCDC65 is involved in the assembly of the nexin-dynein regulatory complex for the formation of microtubules in ciliated cells. In order to identify the phenotype in homozygous sheep, we generated at-risk matings (n = 17) between rams and ewes heterozygous for the candidate variant in CCDC65. A total of 16 lambs were born alive with five genotyped as homozygous carriers. The homozygous lambs suffered from respiratory problems, and four of them died within the first month of life. At necropsy, we observed a broad hepatization of lung lobes possibly induced by infectious pneumonia. The management of this lethal recessive allele (frequency of 0.06) through reasoned mating in the Lacaune sheep selection schemes could reduce lamb mortality by 2%.

Highlights

Health and animal welfare are major concerns in livestock populations with important economic repercussions
To identify the putative causal variant hosted by the Lacaune deficient homozygous haplotype 6 (LDHH6) haplotype, we considered biallelic polymorphisms (SNPs and InDels) proven from 88 ovine whole genome sequences (WGS) containing 24 Lacaune sequences and, among them, two LDHH6 heterozygous carriers
Using sheep whole-genome sequences, the present study identified a causal variant as the g.147,207,999C > A substitution on ovine chromosome 3 linked to the LDHH6 haplotype, and this single nucleotide variant (SNV) corresponds to the c.521G > T nonsense variation in the Coiled-Coil Domain Containing 65 (CCDC65) gene introducing a premature stop codon (p.Glu111*)

Summary

Introduction

Health and animal welfare are major concerns in livestock populations with important economic repercussions. The risk factors for lamb mortality are mainly due to parameters depending on the mother (nutrition, mothering ability, health status, parturition conditions), the lamb itself (low birth weight, vigor, colostrum intake, congenital malformations) and/or their environment (extreme weather, predation, infectious diseases) [1,3]. The QTL approach for mapping genetic variants/loci affecting this trait is difficult due to low heritability (h2 < 0.1) and multifactorial nature of lamb survival or lamb birthweight (i.e., best proxy for lamb survival) [1,4,5,6]. Thanks to the use of high throughput genomic tools (single nucleotide polymorphism arrays, whole-genome sequences), the study of genetic disorders and analysis of associated data have successfully led the identification of many causal variants affecting the viability of young animals [7]

Methods

Results

Discussion

Conclusion