A de novo germline mutation of KIT in a white-spotted Brown Swiss cow.

White-spotting coat colour phenotypes in cattle are either fixed characteristics of specific cattle breeds or occur sporadically owing to germline genetic variation of solid-coloured parents. A Brown Swiss cow showing a piebald pattern resembling colour-sidedness was referred for genetic evaluation. Both parents were normal solid-brown-coloured cattle. The cow was tested negative for the three known DNA variants in KIT, MITF and TWIST2 associated with different depigmentation phenotypes in Brown Swiss cattle. Whole-genome sequencing of the cow was performed and a heterozygous variant affecting the coding sequence of the bovine KIT gene was identified on chromosome 6. The variant is a 40 bp deletion in exon 9, NM_001166484.1:c.1390_1429del, and leads to a frameshift that is predicted to produce a novel 50 amino acid-long C-terminus replacing almost 50% of the wt KIT protein, including the functionally important intracellular tyrosine kinase domain (NP_001159956.1:p.(Asn464AlafsTer50)). Interestingly, among three available offspring, two solid-coloured daughters were genotyped as homozygous wt whereas a single son showing a slightly milder but still obvious depigmentation phenotype inherited a copy of the novel variant allele. The genetic findings provide strong evidence that the identified loss-of-function KIT variant most likely represents a de novo germline mutation that is causative owing to haploinsufficiency.

Accuracy of direct genomic values for functional traits in Brown Swiss cattle.

In this study, direct genomic values for the functional traits general temperament, milking temperament, aggressiveness, rank order in herd, milking speed, udder depth, position of labia, and days to first heat in Brown Swiss dairy cattle were estimated based on ~777,000 (777 K) single nucleotide polymorphism (SNP) information from 1,126 animals. Accuracy of direct genomic values was assessed by a 5-fold cross-validation with 10 replicates. Correlations between deregressed proofs and direct genomic values were 0.63 for general temperament, 0.73 for milking temperament, 0.69 for aggressiveness, 0.65 for rank order in herd, 0.69 for milking speed, 0.71 for udder depth, 0.66 for position of labia, and 0.74 for days to first heat. Using the information of ~54,000 (54K) SNP led to only marginal deviations in the observed accuracy. Trying to predict the 20% youngest bulls led to correlations of 0.55, 0.77, 0.73, 0.55, 0.64, 0.59, 0.67, and 0.77, respectively, for the traits listed above. Using a novel method to estimate the accuracy of a direct genomic value (defined as correlation between direct genomic value and true breeding value and accounting for the correlation between direct genomic values and conventional breeding values) revealed accuracies of 0.37, 0.20, 0.19, 0.27, 0.48, 0.45, 0.36, and 0.12, respectively, for the traits listed above. These values are much smaller but probably also more realistic than accuracies based on correlations, given the heritabilities and samples sizes in this study. Annotation of the largest estimated SNP effects revealed 2 candidate genes affecting the traits general temperament and days to first heat.

[BLIRD - a new genetic disease in Holstein cattle in Switzerland]. / BLIRD ­ eine neue genetische Erkrankung beim Holsteinrind in der Schweiz.

INTRODUCTION: Recently, a new hereditary disease, bovine lymphocyte intestinal retention defect (BLIRD), was discovered in Holstein cattle in France and is caused by a variant in the Integrin subunit beta 7 (ITGB7) gene. The altered cell adhesion molecule resulting from this point mutation is responsible for an impaired tissue of CD4 T lymphocytes from the blood to intestinal tissue. The aim of this study was to assess the allelic frequency of this deleterious variant in the local Holstein population and to clinically examine ten BLIRD-affected Holstein cattle from Switzerland in order to characterise the phenotype of this new hereditary disease, which is still unknown to the veterinary community. BLIRD was associated with severely impaired animal health in the rearing phase and significantly reduced animal welfare due to weakened immune defences, below-average development and recurrent diarrhoea. Further examinations revealed increased leucocyte values and a slightly increased average age at first calving. Affected homozygous animals are labelled internationally as BLIRD-carrier homozygous (LRS), BLIRD-carrier heterozygous (LRC) and BLIRD-free (LRF). An obvious inbreeding practice was clearly demonstrated by the pedigree analysis of the ten animals, which all trace back to the potential founder bull. Herein, BLIRD has been detected and described in Switzerland for the first time. The ITGB7 variant allele has a frequency of 2,1 % in the current Swiss Holstein population, which is below the level of the cholesterol deficiency (CD)-associated apolipoprotein B (APOB) variant allele with a frequency of 3,9 %. Although relatively rare, attention should be paid to the BLIRD genotype when mating in order to exclude further affected animals. In cattle with clinically suspected BLIRD, the diagnosis should be confirmed by genetic testing.

INTRODUCTION: Récemment, une nouvelle maladie héréditaire récessive, le défaut de rétention intestinale des lymphocytes bovins (bovine lymphocyte intestinal retention defect BLIRD), a été découverte chez les bovins Holstein en France. Elle est causée par une variante du gène Integrin subunit beta 7 (ITGB7). L'altération de la molécule d'adhésion cellulaire résultant de cette mutation ponctuelle est responsable de l'altération du transfert des lymphocytes T CD4 du sang vers le tissu intestinal. L'objectif de cette étude était d'évaluer la fréquence allélique de cette variante délétère dans la population Holstein locale et d'examiner cliniquement dix bovins Holstein suisses atteints de BLIRD afin de caractériser le phénotype de cette nouvelle maladie héréditaire, qui est encore inconnue de la communauté vétérinaire. La BLIRD a été associée à une grave détérioration de la santé des animaux pendant la phase d'élevage et à une réduction significative de leur bien-être en raison de l'affaiblissement des défenses immunitaires, d'un développement inférieur à la moyenne et de diarrhées récurrentes. Des examens complémentaires ont révélé une augmentation des valeurs leucocytaires et une légère augmentation de l'âge moyen au premier vêlage. Les animaux homozygotes affectés sont étiquetés au niveau international comme homozygotes porteurs de BLIRD (LRS), hétérozygotes porteurs de BLIRD (LRC) et exempts de BLIRD (LRF). Une pratique de consanguinité évidente a été clairement démontrée par l'analyse généalogique des dix animaux, qui remontent tous au taureau fondateur potentiel. La BLIRD a été ainsi détectée et décrite pour la première fois en Suisse. La allèle délétère ITGB7 a une fréquence de 2,1 % dans la population Holstein suisse actuelle, ce qui est inférieur au niveau de la allèle délétère de l'apolipoprotéine B (APOB) associée à la déficience en cholestérol (CD), dont la fréquence est de 3,9 %. Bien que relativement rare, il convient de prêter attention au génotype BLIRD lors de l'accouplement afin d'exclure de la reproduction d'autres animaux affectés.