Gene function & annotation

Application of trio-based whole-genome sequencing for investigating genetic conditions in Holstein cattle

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Abstract

As inbreeding rates continue to increase within dairy cattle populations, the risk of recessively inherited genetic conditions increases, underscoring the need for effective detection and management strategies. In addition, spontaneous dominant de novo mutations originating from germline mosaicism in the sire should also be considered a potential cause. Currently, there is no centralized reporting system to identify genetic conditions in Canada; however, early and accurate detection is essential to mitigate emerging genetic risks before they become widespread. A trio-based whole-genome sequence (WGS) approach can be used to compare offspring genotypes with those of its parents, offering a powerful method for identifying candidate variants associated with genetic conditions. The objective of this study was to apply a trio-based WGS approach to identify private causal variants associated with a suspected case of Ehlers-Danlos syndrome (EDS) in a 15-week-old Holstein calf in Switzerland. EDS is a heritable skin fragility disorder characterised by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility. WGS was performed using Illumina short-read sequencing on DNA extracted from blood samples of the calf and its dam, and semen from the sire, resulting in ~14.5x read depth. Reads were aligned to the ARS-UCD1.2 reference genome, and variant calling was conducted using the GCF_002263795.3-RS_2024_12 annotation. In the absence of a homozygous candidate for a causal recessive allele, a dominant mode of inheritance was assumed. Variants were filtered retaining only those heterozygous in the calf and absent in the dam, allowing heterozygosity if the sire is a germinal mosaic. The filtered variants were then compared against public bovine control genomes (n = 6,282) to identify private variants unique to the affected calf. Further analysis focused on investigating candidate genes associated with genodermatoses. Twelve heterozygous protein-changing variants private to the calf were identified. The variants identified were then classified according to the latest animal variant classification guidelines. Following the functional analysis and classification, a single missense variant in TNXB (chr23:27319383C >T) was classified as pathogenic and as a potential candidate causal variant. TNXB encodes tenascin-X, a glycoprotein important for maintaining connective tissue structure and elastic fibers. Deficiencies in this protein have been associated with inherited forms of EDS in humans and dogs. This study highlights TNXB as a candidate gene for bovine EDS and demonstrates the effectiveness of trio-based WGS for investigating genetic conditions in cattle. Although spontaneous de novo mutations are rare, their identification is critical for genetic management, as they can introduce new deleterious alleles into the population independently of inbreeding in particular in the progeny of frequently used sires. The methods used in this study can be integrated into a centralized reporting system to enhance the detection and monitoring of genetic conditions in Canadian dairy cattle.

Keywords: 2026

How to Cite:

Baes, C., Cole, J., Condello, G., Drögemà¼ller, C., Gearing, J., Jacinto, J., Letko, A., Maltecca, C., Miglior, F. & Schenkel, F., (2026) “Application of trio-based whole-genome sequencing for investigating genetic conditions in Holstein cattle”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2286360. doi: https://doi.org/10.31274/wcgalp.23955

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