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Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle.

Pausch H, Schwarzenbacher H, Burgstaller J, Flisikowski K, Wurmser C, Jansen S, Jung S, Schnieke A, Wittek T, Fries R - BMC Genomics (2015)

Bottom Line: A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success.The mutation was not found in homozygous state in 10,363 animals (P=1.79×10(-5)) and is thus likely to cause lethality of homozygous embryos.Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

View Article: PubMed Central - PubMed

Affiliation: Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. hubert.pausch@tierzucht.tum.de.

ABSTRACT

Background: Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes.

Results: A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P=1.79×10(-5)) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2.

Conclusions: Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

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Phenotypic manifestation of the FH2-associated mutation(s). Photograph of a 15-months old Fleckvieh bull being homozygous for the rs379675307 mutation in SLC2A2(A). Histological sections of the liver (B). Micrographs of PAS-stained liver specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Histological sections of the kidney (C). Micrograph of PAS stained kidney specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Two nineteen weeks old Fleckvieh calves (E). The calf on the left side is homozygous for the SLC2A2 mutation and the calf on the right side is a healthy animal. Photograph of a nine weeks old Fleckvieh calf homozygous for the SLC2A2-mutation (F). Please note the lean body of the FH2-homozygous calf. The affected animal (right side) is compared with a seven weeks (left side) old coeval (G). Figures were kindly supplied by Martina Wassertheurer (NOE Genetik, Austria). The weight of two FH2-homozygous twin calves (orange and red diamonds) is compared to the weight of 74,422 Fleckvieh calves with unknown genotypes (grey boxes) (D). The solid blue line represents the weaning period of the two homozygous calves.
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Fig2: Phenotypic manifestation of the FH2-associated mutation(s). Photograph of a 15-months old Fleckvieh bull being homozygous for the rs379675307 mutation in SLC2A2(A). Histological sections of the liver (B). Micrographs of PAS-stained liver specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Histological sections of the kidney (C). Micrograph of PAS stained kidney specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Two nineteen weeks old Fleckvieh calves (E). The calf on the left side is homozygous for the SLC2A2 mutation and the calf on the right side is a healthy animal. Photograph of a nine weeks old Fleckvieh calf homozygous for the SLC2A2-mutation (F). Please note the lean body of the FH2-homozygous calf. The affected animal (right side) is compared with a seven weeks (left side) old coeval (G). Figures were kindly supplied by Martina Wassertheurer (NOE Genetik, Austria). The weight of two FH2-homozygous twin calves (orange and red diamonds) is compared to the weight of 74,422 Fleckvieh calves with unknown genotypes (grey boxes) (D). The solid blue line represents the weaning period of the two homozygous calves.

Mentions: Two male animals were detected to be homozygous for FH2 in the initial scan for HHD. One 15-month old bull was still alive. Sanger sequencing of the bull’s DNA confirmed homozygosity for the rs384285149 variant in EIF5A2 and for the rs379675307 variant in SLC2A2. The growth of the bull was severely retarded although feed intake was reported to be normal (Figure 2A). At the time of admission to the clinic, the bull’s weight was 268.5 kg, which is half of the weight expected at this age for the Fleckvieh breed. Clinical examination did not reveal infectious and chronic diseases. Body temperature, pulse and respiratory rates were within normal ranges. During the hospitalization period of 50 days, the average weight gain was 330 g/day only, although feed intake and rumination were normal. There were no obvious abnormalities of the digestive system (i.e., oral cavity, pharynx, oesophagus, forestomachs).Figure 2


Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle.

Pausch H, Schwarzenbacher H, Burgstaller J, Flisikowski K, Wurmser C, Jansen S, Jung S, Schnieke A, Wittek T, Fries R - BMC Genomics (2015)

Phenotypic manifestation of the FH2-associated mutation(s). Photograph of a 15-months old Fleckvieh bull being homozygous for the rs379675307 mutation in SLC2A2(A). Histological sections of the liver (B). Micrographs of PAS-stained liver specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Histological sections of the kidney (C). Micrograph of PAS stained kidney specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Two nineteen weeks old Fleckvieh calves (E). The calf on the left side is homozygous for the SLC2A2 mutation and the calf on the right side is a healthy animal. Photograph of a nine weeks old Fleckvieh calf homozygous for the SLC2A2-mutation (F). Please note the lean body of the FH2-homozygous calf. The affected animal (right side) is compared with a seven weeks (left side) old coeval (G). Figures were kindly supplied by Martina Wassertheurer (NOE Genetik, Austria). The weight of two FH2-homozygous twin calves (orange and red diamonds) is compared to the weight of 74,422 Fleckvieh calves with unknown genotypes (grey boxes) (D). The solid blue line represents the weaning period of the two homozygous calves.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4403906&req=5

Fig2: Phenotypic manifestation of the FH2-associated mutation(s). Photograph of a 15-months old Fleckvieh bull being homozygous for the rs379675307 mutation in SLC2A2(A). Histological sections of the liver (B). Micrographs of PAS-stained liver specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Histological sections of the kidney (C). Micrograph of PAS stained kidney specimens from the homozygous animal (upper panel) and from an unaffected control animal (lower panel). PAS-D shows the positive diastase test. Two nineteen weeks old Fleckvieh calves (E). The calf on the left side is homozygous for the SLC2A2 mutation and the calf on the right side is a healthy animal. Photograph of a nine weeks old Fleckvieh calf homozygous for the SLC2A2-mutation (F). Please note the lean body of the FH2-homozygous calf. The affected animal (right side) is compared with a seven weeks (left side) old coeval (G). Figures were kindly supplied by Martina Wassertheurer (NOE Genetik, Austria). The weight of two FH2-homozygous twin calves (orange and red diamonds) is compared to the weight of 74,422 Fleckvieh calves with unknown genotypes (grey boxes) (D). The solid blue line represents the weaning period of the two homozygous calves.
Mentions: Two male animals were detected to be homozygous for FH2 in the initial scan for HHD. One 15-month old bull was still alive. Sanger sequencing of the bull’s DNA confirmed homozygosity for the rs384285149 variant in EIF5A2 and for the rs379675307 variant in SLC2A2. The growth of the bull was severely retarded although feed intake was reported to be normal (Figure 2A). At the time of admission to the clinic, the bull’s weight was 268.5 kg, which is half of the weight expected at this age for the Fleckvieh breed. Clinical examination did not reveal infectious and chronic diseases. Body temperature, pulse and respiratory rates were within normal ranges. During the hospitalization period of 50 days, the average weight gain was 330 g/day only, although feed intake and rumination were normal. There were no obvious abnormalities of the digestive system (i.e., oral cavity, pharynx, oesophagus, forestomachs).Figure 2

Bottom Line: A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success.The mutation was not found in homozygous state in 10,363 animals (P=1.79×10(-5)) and is thus likely to cause lethality of homozygous embryos.Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

View Article: PubMed Central - PubMed

Affiliation: Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. hubert.pausch@tierzucht.tum.de.

ABSTRACT

Background: Cattle breeding populations are susceptible to the propagation of recessive diseases. Individual sires generate tens of thousands of progeny via artificial insemination. The frequency of deleterious alleles carried by such sires may increase considerably within few generations. Deleterious alleles manifest themselves often by missing homozygosity resulting from embryonic/fetal, perinatal or juvenile lethality of homozygotes.

Results: A scan for homozygous haplotype deficiency in 25,544 Fleckvieh cattle uncovered four haplotypes affecting reproductive and rearing success. Exploiting whole-genome resequencing data from 263 animals facilitated to pinpoint putatively causal mutations in two of these haplotypes. A mutation causing an evolutionarily unlikely substitution in SUGT1 was perfectly associated with a haplotype compromising insemination success. The mutation was not found in homozygous state in 10,363 animals (P=1.79×10(-5)) and is thus likely to cause lethality of homozygous embryos. A frameshift mutation in SLC2A2 encoding glucose transporter 2 (GLUT2) compromises calf survival. The mutation leads to premature termination of translation and activates cryptic splice sites resulting in multiple exon variants also with premature translation termination. The affected calves exhibit stunted growth, resembling the phenotypic appearance of Fanconi-Bickel syndrome in humans (OMIM 227810), which is also caused by mutations in SLC2A2.

Conclusions: Exploiting comprehensive genotype and sequence data enabled us to reveal two deleterious alleles in SLC2A2 and SUGT1 that compromise pre- and postnatal survival in homozygous state. Our results provide the basis for genome-assisted approaches to avoiding inadvertent carrier matings and to improving reproductive and rearing success in Fleckvieh cattle.

Show MeSH
Related in: MedlinePlus