Bovine Exome Sequence Analysis and Targeted SNP Genotyping of Recessive Fertility Defects BH1, HH2, and HH3 Reveal a Putative Causative Mutation in SMC2 for HH3

Matthew C Mcclure,George Wiggans,Paul Vanraden,Steve Schroeder,Derek Bickhart,Tad S Sonstegard,George Liu,John B Cole,Jarret Glasscock,Dan Null,Jon Armstrong,Curtis P Van Tassell,Lingyang Xu,Stephen Moore

doi:10.1371/journal.pone.0092769

Matthew C Mcclure, George Wiggans + Show 12 more

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https://doi.org/10.1371/journal.pone.0092769

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Abstract

The recent discovery of bovine haplotypes with negative effects on fertility in the Brown Swiss, Holstein, and Jersey breeds has allowed producers to identify carrier animals using commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the causative mutations underlying defective bovine embryo development contained within three of these haplotypes (Brown Swiss haplotype 1 and Holstein haplotypes 2 and 3) by combining exome capture with next generation sequencing. Of the 68,476,640 sequence variations (SV) identified, only 1,311 genome-wide SNP were concordant with the haplotype status of 21 sequenced carriers. Validation genotyping of 36 candidate SNP identified only 1 variant that was concordant to Holstein haplotype 3 (HH3), while no variants located within the refined intervals for HH2 or BH1 were concordant. The variant strictly associated with HH3 is a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. Because only exome capture sequencing was used, we could not rule out the possibility that the true causative mutation for HH3 might lie in a non-exonic genomic location. Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation. The absence of concordant variations for HH2 or BH1 suggests either the underlying causative mutations lie within a non-exomic region or in exome regions not covered by the capture array.

Highlights

While a number of recessive disease loci and a few causative disease mutations have been discovered in cattle [1,2], few individual loci that reduce embryo viability or early fetus development in cattle were known until recently
Had identified the haplotype boundaries based on UMD 3.1 genome coordinates as follows: 1) Brown Swiss haplotype 1 (BH1) on Chromosome (Chr) 7 from 42,545,709 to 47,002,161 spanning 74 BovineSNP50 markers, 2) Holstein haplotype 2 (HH2) on bovine Chr 1 from 93,172,083 to
No homozygous animals were observed, but based on the haplotype frequencies and the mating pattern 24 homozygotes were expected for BH1, while 11 and 29 were expected for HH2 and Holstein haplotype 3 (HH3), respectively [1]

Summary

Introduction

While a number of recessive disease loci and a few causative disease mutations have been discovered in cattle [1,2], few individual loci that reduce embryo viability or early fetus development in cattle were known until recently. Breed associations and artificial insemination companies have officially reported the inheritance of these a live animal received the original HH2 from one parent and the left-most 20 markers of HH2 from the other parent, the region containing those 20 homozygous markers was removed to reduce the haplotype length. A fertility haplotype associated with Brachyspina, a defect causing early abortion or births of calves with congenital defects, was found to be a 3,329 bp deletion in the FANCI gene [5].

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