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Title: Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects HH2, HH3, and BH1 reveals causative mutation in SMC2 for HH3

item MC CLURE, MATTHEW - Collaborator
item Bickhart, Derek
item Null, Daniel
item Vanraden, Paul
item XU, LINGYANG - University Of Maryland
item Wiggans, George
item Liu, Ge - George
item Schroeder, Steven - Steve
item GLASSCOCK, JARED - Cofactor Genomics
item ARMSTRONG, JON - Cofactor Genomics
item Cole, John
item Sonstegard, Tad
item Van Tassell, Curtis - Curt

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2014
Publication Date: 3/25/2014
Publication URL:
Citation: Mc Clure, M., Bickhart, D.M., Null, D.J., Van Raden, P.M., Xu, L., Wiggans, G.R., Liu, G., Schroeder, S.G., Glasscock, J., Armstrong, J., Cole, J.B., Sonstegard, T.S., Van Tassell, C.P. 2014. Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects HH2, HH3, and BH1 reveals causative mutation in SMC2 for HH3. PLoS One. 9(3):e92769.

Interpretive Summary: Many regions of the bovine genome contain newly discovered mutations that have negative effects on fetal viability. Current genetic markers for these conditions are not 100% accurate because the exact genetic mutations causing the defects are not known. A study was undertaken to identify the causative mutations for three known conditions that cause embryonic death, including Holstein haplotype 2 (HH2), Holstein haplotype 3 (HH3), and Brown Swiss haplotype 1 (BH1). By sequencing specific regions of DNA from 20 carrier animals, we identified and validated the mutation for the HH3 condition, which was found within a protein that is critical for maintaining chromosome structure during cell divisions. This information allows for the development of a genetic test that is 100% accurate for predicting carrier animals for the HH3 mutation. Through the use of such a test, animal breeders could eliminate the HH3 condition in Holstein herds and improve their overall reproductive success.

Technical Abstract: The recent discovery of bovine haplotypes with negative effects on fertility in the Holstein, Jersey, and Brown Swiss breeds has allowed producers to identify carrier animals using current commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the causative mutations underlying defective embryo development contained within three of these haplotypes (Holstein haplotypes 2 and 3 and Brown Swiss haplotype 1) by combining bovine exome capture array with next generation sequencing. Of the 68,476,640 sequence variations 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 were concordant to HH2 or BH1. The variant strictly associated with HH3 is a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) gene located on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1,135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the ATPase domain of the encoded protein. Given the essential functional role of this domain for DNA repairs, our findings support the SMC2 coding SNP as the HH3 causative mutation. The lack 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.