Homozygous haplotype deficiency reveals deleterious mutations compromising reproductive and rearing success in cattle.
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.
Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. hubert.pausch@tierzucht.tum.de.
Hubert
H
Pausch
ZuchtData EDV-Dienstleistungen GmbH, 1200, Vienna, Austria. schwarzenbacher@zuchtdata.at.
Hermann
H
Schwarzenbacher
Clinic for Ruminants, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. johann.burgstaller@vetmeduni.ac.at.
Johann
J
Burgstaller
Lehrstuhl fuer Biotechnologie der Nutztiere, Technische Universitaet Muenchen, 85354, Freising, Germany. flisikowski@wzw.tum.de.
Krzysztof
K
Flisikowski
Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. christine.wurmser@tierzucht.tum.de.
Christine
C
Wurmser
Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. sandra.jansen@tierzucht.tum.de.
Sandra
S
Jansen
Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. simone.jung@tierzucht.tum.de.
Simone
S
Jung
Lehrstuhl fuer Biotechnologie der Nutztiere, Technische Universitaet Muenchen, 85354, Freising, Germany. angelika.schnieke@wzw.tum.de.
Angelika
A
Schnieke
Clinic for Ruminants, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. thomas.wittek@vetmeduni.ac.at.
Thomas
T
Wittek
Lehrstuhl fuer Tierzucht, Technische Universitaet Muenchen, 85354, Freising, Germany. ruedi.fries@tum.de.
Ruedi
R
Fries
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005198:Fanconi Syndrome / Q000235:genetics* / Q000473:pathology / Q000662:veterinary; D016368:Frameshift Mutation; D016678:Genome; D005838:Genotype; D051273:Glucose Transporter Type 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007315:Insemination, Artificial; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D022821:RNA Splice Sites; D016415:Sequence Alignment
D018797:Cell Cycle Proteins; D051273:Glucose Transporter Type 2; D022821:RNA Splice Sites