Dataset Information

Reverse Genetic Screen for Deleterious Recessive Variants in the Local Simmental Cattle Population of Switzerland.

ABSTRACT: 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.

SUBMITTER: Hafliger IM

PROVIDER: S-EPMC8698008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMyoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in SGCE, a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of SGCE-linked M-D is unknown, the pathogenicity of SGCE variants identified in patients with M-D may be indeterminant, and SGCE variants predicted to be deleterious by in silico analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies.MethodsSGCE variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms' functional predictions (dbNSFP). We determined the frequency of annotated SGCE variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated SGCE pathogenic variants.ResultsWithin gnomAD v2, there were 56, 408, and 1250 alleles harboring SGCE variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an SGCE variant with a CADD score ≥ 25.DiscussionSGCE M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious SGCE variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees.HighlightsIn silico analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious SGCE variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.

Project description:In Montbéliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbéliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbéliarde bulls through artificial insemination, inbreeding on Montbéliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbéliarde as well as Vorderwald x Montbéliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbéliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible for the present case of abortion and, in addition, we observed this mutation in a homozygous state in a living animal. In conclusion, we could demonstrate the first case of an aborted fetus carrying the deleterious SLC37A2:g.28879810C>T mutation homozygous and show that this deleterious mutation had been introduced through Montbéliarde bulls into Vorderwald cattle.

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Reverse Genetic Screen for Deleterious Recessive Variants in the Local Simmental Cattle Population of Switzerland.

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