Abstract
Simple SummaryToday’s Swiss Simmental represents a local dual-purpose breed of cattle. Within closed populations, deleterious variants can reach problematic frequencies, explaining substantial proportions of inbreeding depression. Depletions in homozygous genotypes for certain haplotypes among large cohorts of animals genotyped for the purpose of genomic selection is a widely used approach to pinpoint undesired recessive alleles. In the course of a reverse genetic screen, we aimed to identify single recessive Mendelian variants that potentially affect fertility and rearing success without any phenotypic information available. We detected eleven genome regions showing obvious depletion of homozygosity based on genome-wide SNP data. Furthermore, after performing whole-genome sequencing of selected animals, we propose three candidate causative variants affecting different genes with possibly detrimental effects for embryonic development. The established haplotypes, as well as the identified protein-changing variants, can be directly implemented into breeding practice to avoid the risk of mating carriers and thereby increase breeding success.We herein report the result of a large-scale reverse genetic screen in the Swiss Simmental population, a local dual-purpose cattle breed. We aimed to detect possible recessively inherited variants affecting protein-coding genes, as such deleterious variants can impair fertility and rearing success significantly. We used 115,000 phased SNP data of almost 10 thousand cattle with pedigree data. This revealed evidence for 11 genomic regions of 1.17 Mb on average, with haplotypes (SH1 to SH11) showing a significant depletion in homozygosity and an allele frequency between 3.2 and 10.6%. For the proposed haplotypes, it was unfortunately not possible to evaluate associations with fertility traits as no corresponding data were available. For each haplotype region, possible candidate genes were listed based on their known function in development and disease. Subsequent mining of single-nucleotide variants and short indels in the genomes of 23 sequenced haplotype carriers allowed us to identify three perfectly linked candidate causative protein-changing variants: a SH5-related DIS3:p.Ile678fs loss-of-function variant, a SH8-related CYP2B6:p.Ile313Asn missense variant, and a SH9-related NUBPL:p.Ser143Tyr missense variant. None of these variants occurred in homozygous state in any of more than 5200 sequenced cattle of various breeds. Selection against these alleles in order to reduce reproductive failure and animal loss is recommended.
Highlights
Simmental is a globally recognized cattle breed, originating in the Simmental valley in the canton Bern in Switzerland
The effects of protein-changing variant were estimated using PROVEAN [54] and PredictSNP [55]. In this reverse genetic study, we used SNP data to identify haplotypes showing a depletion in homozygosity and applied whole-genome sequencing (WGS) data to pinpoint candidate causal variants in purebred Swiss Simmental animals
We focused on variants having a moderate impact, such as missense variants, conservative inframe insertions and deletions up to a size of 50 bp, as well as on all other protein-changing with high impact including loss-of-function variants, such as stop-gains, splice site-disrupting SNVs, frameshift indels in a coding sequence, or deletions that remove coding exons
Summary
Simmental is a globally recognized cattle breed, originating in the Simmental valley in the canton Bern in Switzerland. Autochthonous of Switzerland, today up to 40 million cattle worldwide are designated as members of the Simmental breed. Simmental are characterized by very different local breeding objectives (http://wsff.info; accessed on 24 October 2021). In the 19th century, crossbreeding of local cattle with Simmental cattle exported from Switzerland led to Fleckvieh populations in neighboring countries, including Austrian and German Fleckvieh, French Montbeliarde, and Italian. In the 20th century, introduction of animals of the Holstein breed into the Swiss Simmental population led to today’s Fleckvieh population in Switzerland (Swiss Fleckvieh). A recent analysis of the population structure of Swiss cattle showed a clear differentiation between today’s Swiss Simmental cattle and all other Swiss cattle populations, including the modern Swiss Fleckvieh [1,2].
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