Background In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. Results Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. Conclusions In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.
Researching depletions in homozygous genotypes for specific haplotypes among the large cohorts of animals genotyped for genomic selection is a very efficient strategy to map recessive lethal mutations. In this study, by analyzing real or imputed Illumina BovineSNP50 (Illumina Inc., San Diego, CA) genotypes from more than 250,000 Holstein animals, we identified a new locus called HH6 showing significant negative effects on conception rate and nonreturn rate at 56 d in at-risk versus control mating. We fine-mapped this locus in a 1.1-Mb interval and analyzed genome sequence data from 12 carrier and 284 noncarrier Holstein bulls. We report the identification of a strong candidate mutation in the gene encoding SDE2 telomere maintenance homolog (SDE2), a protein essential for genomic stability in eukaryotes. This A-to-G transition changes the initiator ATG (methionine) codon to ACG because the gene is transcribed on the reverse strand. Using RNA sequencing and quantitative reverse-transcription PCR, we demonstrated that this mutation does not significantly affect SDE2 splicing and expression level in heterozygous carriers compared with control animals. Initiation of translation at the closest in-frame methionine codon would truncate the SDE2 precursor by 83 amino acids, including the cleavage site necessary for its activation. Finally, no homozygote for the G allele was observed in a large population of nearly 29,000 individuals genotyped for the mutation. The low frequency (1.3%) of the derived allele in the French population and the availability of a diagnostic test on the Illumina EuroG10K SNP chip routinely used for genomic evaluation will enable rapid and efficient selection against this deleterious mutation.
Summary In this article, we analyzed pedigree information on males from 12 bovine breeds born in France between 2015 and 2019. We report an overall small number of paternal lineages with, for example, a minimal number of ancestors accounting for 95% of the Y‐chromosome pool of their breed ranging from only 2 to 15 individuals. Then, we mined whole‐genome sequence data from 811 sires (2 ≤ n ≤ 510 per breed) and built a median‐joining network using 1411 SNPs. Most branches were breed‐specific and in agreement with the geographic and genetic relatedness of these populations. The within‐breed haplotype diversity was lower than expected based on genealogical information, which supports the existence of major male founder effects predating pedigree recording. In addition, we observed de novo mutation events among the descendants of the same ancestors, which are of interest to define paternal sub‐lineages. Our results pave the way to future studies on the estimation of the effects of Y‐chromosome haplotypes on male reproductive performances and on the conservation of Y‐chromosome diversity.
A data mining method applied to large-scale genotyping data is proposed to detect recessive loci responsible for increased mortality in cattle and that have remained undetected by previous approaches. It is based on a screen for homozygous haplotype enrichment/depletion in groups of females with different life trajectories. After validation of the results in at risk and control mating, 34 deleterious haplotypes (13 in Holstein, 11 in Montbéliarde, and 10 in Normande) were identified, with frequencies ranging from 1.5 to 7.6%. Profiles of survival curves and causes of mortality differed greatly between loci, with early juvenile, late juvenile and evenly distributed death events. Candidate causal variants were found for fifteen haplotypes. A frameshift mutation of NOA1 and a disruptive inframe deletion of RFC5, affecting two genes with no previous record of live homozygous mutants in mammals, were subject to phenotypical characterization.
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