Identification of candidate lethal haplotypes and genomic association with post-natal mortality and reproductive traits in Nellore cattle

Authors: SCHMIDT, PATRICIA - Sao Paulo State University (UNESP); MOTA, LUCIO - Sao Paulo State University (UNESP); FONSECA, LARISSA - Sao Paulo State University (UNESP); DOS SANTOS SILVA, DANIELLY - Sao Paulo State University (UNESP); FREZZARIM, GABRIELA - Sao Paulo State University (UNESP); ARIKAWA, LEONARDO - Sao Paulo State University (UNESP); DE ABREU SANTOS, DANIEL - University Of Maryland; MAGALHAES, ANA - Sao Paulo State University (UNESP); COLE, JOHN - Former ARS Employee; CARVALHEIRO, ROBERTO - Sao Paulo State University (UNESP); DE OLIVEIRA, HENRIQUE - Sao Paulo State University (UNESP); Null, Daniel; Vanraden, Paul; MA, LI - University Of Maryland; DE ALBUQUERQUE, LUCIA - Sao Paulo State University (UNESP)

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/23/2023
Publication Date: 6/27/2023
Citation: Schmidt, P., Mota, L., Fonseca, L., Dos Santos Silva, D., Frezzarim, G., Arikawa, L., De Abreu Santos, D., Magalhaes, A., Cole, J., Carvalheiro, R., De Oliveira, H., Null, D.J., Van Raden, P.M., Ma, L., De Albuquerque, L. 2023. Identification of candidate lethal haplotypes and genomic association with post-natal mortality and reproductive traits in Nellore cattle. Scientific Reports. 13:10399. https://doi.org/10.1038/s41598-023-37586-z.
DOI: https://doi.org/10.1038/s41598-023-37586-z

Interpretive Summary: The wide use of genomic information has enabled the identification of lethal recessive alleles that can cause reduced conception rates, longer calving intervals, or lower survival. This approach requires genotypes only from apparently normal individuals and not from affected embryos. The study in Nellore beef cattle in Brazil examined 62,022 animals with imputed genotypes for a high-density panel (777,962 markers), discovered potentially lethal recessive haplotypes, detected significant effects on fertility and mortality traits, and identified candidate genes involved in their expression. Discovery of lethal haplotypes helps breeders detect carriers, implement selection, and manage matings to reduce mortality and improve fertility of their herds.

Technical Abstract: The wide use of genomic information has enabled the identification of lethal recessive alleles that are the major genetic causes of reduced conception rates, longer calving intervals, or lower survival for live-born animals. This approach requires genotypes only from apparently normal individuals and not from affected embryos. The study was carried out to screen lethal recessive haplotypes based on expected population frequencies; and to detect the significant SNP markers surrounding the lethal haplotypes region for heifer rebreeding (HR), post-natal mortality (PNM) and stayability (STAY) in Nellore cattle using the genome-wide association approach (GWAS) in order to identify candidate genes and biological mechanisms involved in the expression of these traits. A total of 62,022 animals were genotyped and imputed to a high-density panel (777,962 SNP markers). The genomic positions of the markers were based on the ARS-UCD1.2 Bos taurus genome assembly. The conflict.f90 software was used to correct mendelian errors and fill missing SNP using parental genotypes and the findhap.f90 to construct the haplotypes by sliding window method. By default, the program first examined haplotypes constructed using 2,000 markers, then 632 markers, and finally identified haplotypes with <=200 markers for further analysis. Expected numbers of homozygous individuals were calculated through two methods: Simple - assuming random mating and using the number of individuals genotyped divided by 4 and multiplied by the square of the carrier frequency; and Mating - using the actual mating pattern for calculating the number of carrier service sire × carrier dams (or maternal grandsire matings) divided by 4. The probabilities of observing 0 homozygotes when n is expected was obtained by two analogous formulas that were used to obtain expectations. Before the GWAS analysis, genomic and breeding values [(G)EBVs] was obtained and then they were deregressed, and only the animals presenting deregressed (G)EBVs (d(G)EBV) at least 0.40 of accuracy (based on prediction error variance) were used on GWAS analysis. The GWAS was performed using the GCTA program for HR (n. 43,250), STAY (n. 42,787) and PNM (n. 25,330) and only significant SNPs that were within or close to regions with haplotypes in deficit of homozygosity were selected. For the functional analyses, the BioMart tool, from the ENSEMBL software, was used to search the genes harboring 100 kb down and upstream of each significant SNP marker and the Cytoscape software was used to visualize the non-redundant biological terms for clusters of genes in a functionally grouped network. Thirty haplotypes had high expected frequency, but no homozygotes observed. Among these, the haplotypes with the largest number of expected homozygotes were on chromosomes 19, located at 54,651,560-55,237,521 (simple method – 927; mating method – 1028), and 8 located at 84,943,889-85,809,360 (simple method – 625; mating method – 588). The probabilities of not observing homozygotes were similar for both single and mating methods. Most of the alleles present in the haplotypes had a negative mean effect for PNM, HR and STAY. The GWAS pointed out a total of significant SNP markers that implies in different physiological mechanisms leading to harmful effect on HR (146), PNM (267) and STAY (482) in Nellore cattle. The functional analysis showed 26 genes enriched for 19 GO terms (biological processes). There were observed that most of the GO terms found for biological processes, molecular functions and pathways were related with tissues development and immune system. More phenotypes underlying these putative regions for this population and could be the subject of future investigation. Tests to find lethal haplotypes carriers could help breeders to implement selection actions in order to eliminate these haplotypes from the population or manag