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Novel insights into the genetics of schistosoma reflexum in Holstein cattle
Jacinto, J., Häfliger, I., Freick...
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Objectives
Schistosoma reflexum (SR) is a lethal congenital syndrome in cattle characterized by U-shaped dorsal retroflexion of the spine and eventration of the viscera. A recessive mode of inheritance has been hypothesized but not yet proven. The aim of this study was to identify genetic causes of SR in a series of affected Holstein cattle by whole-genome sequencing (WGS).
Materials and Methods
Genomic DNA was extracted from ear cartilage of 10 SR affected Holstein calves, from EDTA blood of their dams and from semen of their sires (10 trios; 30 samples). Genomic DNA extracted from ear cartilage was available from additionally 9 SR affected Holstein calves. Short-read WGS was performed in all 39 animals, including the applied trio-approach for the 10 SR cases. The sequenced reads were mapped to the ARS‐UCD1.2 reference genome and single-nucleotide and small indel variants were called. In order to identify private variants, the genotypes of the 19 SR cases were compared with a global cohort of 5347 cattle genomes of various breeds, including 1209 purebred Holstein. In silico tools were used to predict the biological consequences of the detected variants. Candidate variants were visually inspected. The term candidate was used to describe variants considering the affected gene function/associated phenotype, rarity and the predicted impact of the variant in the protein. In order to evaluate possible structural variants and chromosomal abnormalities the read depth along all chromosomes was calculated using a sliding window approach with a size of 10 kb and 200 kb. These coverage plots were obtained for all cases and available dams and sires.
Results
Assuming a recessive mode of inheritance, analysis of the WGS data reveled no single-nucleotide or small indel variants common to all cases. Assuming a dominant de novo event and therefore considering individually each case, it was possible to identify candidate causal protein-changing variants for 10 out of 19 SR-cases involving 10 genes. Particularly, by applying the trio-approach it was possible to identify de novo candidate variants for 3 SR-cases that were absent in both parents and in a global cohort of 5345 cattle control genomes. The identified variants affected MLLT1 (p. Arg20Cys), ACTL6A (p.Met92fs), and MAST3 (p.Pro1202fs) genes. Furthermore, in 7 SR-cases without sequenced parents it was possible to identify heterozygous, possible de novo, candidate variants that were absent in a global cohort of 5347 cattle control genomes. The identified variants affected the ANO4 (p.Trp639Cys), MYH1 (p.Thr663Ala), DYNC1LI1 (p.Arg505Trp), UBP1 (p.Arg388Gly), SUGP1 (p. Arg326Cys), SCAF8 (p.Val378fs) and SYT12 (p.Ser238Leu) genes. All these 10 coding variants were predicted to be deleterious. It could be speculated that the identified variants occurred either as a parental germline mutation or post-zygotically in the developing embryo. Furthermore, no evidence for larger structural variants or chromosomal abnormalities were detected by analyzing the obtained read depth and coverage along all chromosomes.
Conclusions
The previously hypothesized simple recessive inheritance for SR in Holstein cattle could not be confirmed. This study describes, for the first time, WGS findings for SR and provides evidence of unexpected heterogenic causality for SR by spontaneous de novo mutations affecting different genes. Herein, 10 protein-changing heterozygous variants are proposed as potential cause for SR located in candidate genes involved in embryonic and pre-weaning lethality thus giving a genetic diagnosis for 53% of the cases. So far, in cattle the efficiency of WGS for genetic diagnosis has not been investigated; however, the obtained results are considerable positive when compared with the efficiency of WGS-based genetic diagnostics in humans. Moreover, the unsolved genetic diagnosis for 9 cases might be explained 1) by limitations of the cattle genome annotation and/or 2) by limitations of the short-read WGS-approach. Sporadic lethal disorders such as SR affecting negatively dam's fertility and health, welfare and consequently economy in livestock are usually not diagnosed to the molecular level, mainly because of the lack of resources and diagnostic tools. Therefore, this study highlights that WGS-based precision diagnostics allows to better understand sporadic disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders.
Keywords: Bovine, Dystocia, Congenital malformations, Precision medicine, Whole-genome sequencing.
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