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Dissertation Angus Cattle at High Altitude DISSERTATION ANGUS CATTLE AT HIGH ALTITUDE: PULMONARY ARTERIAL PRESSURE, ESTIMATED BREEDING VALUE AND GENOME-WIDE ASSOCIATION STUDY Submitted by Xi Zeng Department of Animal Sciences In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Fall 2016 Doctoral Committee: Advisor: Milton G. Thomas Co-Advisor: R. Mark Enns Scott E. Speidel Timothy N. Holt Copyright by Xi Zeng 2016 All Rights Reserved ABSTRACT ANGUS CATTLE AT HIGH ALTITUDE: PULMONARY ARTERIAL PRESSURE, ESTIMATED BREEDING VALUE AND GENOME-WIDE ASSOCIATION STUDY In high altitude states such as Colorado, New Mexico, Utah and Wyoming, hypoxia-induced bovine pulmonary hypertension (PH) commonly referred to as “brisket disease” or “high altitude disease (HAD)”, has been observed within the cattle industry. This disease is a major cause of morbidity for beef cattle ranches and feedyards above 1500 m and contributed to an estimated $60 million (based on cattle price of $800/head) loss each year in beef herds at high altitude of the United States. This disease in humans and animals is a response to hypoxia, which results in pulmonary vasoconstriction, vascular remodeling, elevated pulmonary arterial pressure (PAP), pulmonary hypertension, right heart ventricular hypertrophy, and finally death from congestive heart failure. Due to the close physiological relationship between HAD and PAP, this measurement has been used as an indicator trait for studying HAD. The objectives of this study were to explore the phenotypic and genetic characteristics of various yearling PAP phenotypes, develop multivariate models for genetic evaluation of yearling PAP phenotypes, conduct genome-wide association studies (GWAS) on yearling PAP phenotypes and performance traits and evaluate the genomic relationships among traits. Yearling PAP measurements (42.45 ± 0.56 mmHg) and performance phenotypes were collected from Angus cattle born from 1993 to 2015 at John E. Rouse Colorado State University Beef Improvement Center (CSU-BIC, 2,170 m in elevation). Beside the non-transformed yearling PAP measurements (RAW), power-transformed PAP measurements (PT), an ordinal ii three-category phenotype (CAT3), an ordinal two-category phenotype (CAT2) were investigated in this study. The PT (10000×PAP-2) was determined via Box-Cox analysis, the CAT3 observations were defined as low risk (PAP < 41mmHg), moderate risk (41mmHg ≤ PAP ≤ 49mmHg) and high risk (PAP > 49mmHg) for HAD. The CAT2 observations were constructed by combining low and moderate risk categories of CAT3. Performance traits included birth weight (BWT; 36.21 ± 0.50 kg), weaning weight (WW; 213.88 ± 0.34 kg), post-weaning gain (PWG; 127.29 ± 0.88 kg) and yearling weight (YW; 344.85 ± 1.10 kg). Genotype data on 2,765 Angus cattle born from 1997 to 2015 in the CSU-BIC were merged and used in this study. Most individuals were genotyped using various formats of Illumina Bovine SNP50 Beadchip version 2 assays (54,609) over three year-groups (i.e. 2013, 2014 and 2015) and in two labs (i.e. Zoetis and GeneSeek), and with a subset (n=65) steers genotyped in 2013 using Illumina BovineHD BeadChip (777,962 SNP) through GeneSeek (Lincoln, NE). The fixed effects in the models for yearling PAP phenotypes included sex, age of dam, PAP measurement date and age at PAP measurement as a covariate. For performance traits, fixed effects included sex, age of dam, age of measurements (covariate) and contemporary groups. Significance of fixed effects was tested using log-likelihood ratio test from generalized linear models and maximum likelihood method. Univariate linear and threshold models were applied to estimate heritability for yearling PAP phenotypes (i.e. RAW, PT, CAT3 and CAT2), and bivariate and multivariate linear and threshold models were used to obtain genetic correlations between yearling PAP phenotypes and performance traits, and between yearling PAP in different sex categories. Deregressed EBV (DEBV) and associated reliability of various yearling PAP phenotypes and performance traits were developed from their EBV and accuracy from multivariate animal iii models and used as dependent variables in GWAS. The linear models for GWAS were executed using Bayes B and Bayes C methods. The percentage of genetic variance of specific trait explained by a genomic window (~ 1 Mb) was applied to identify significant QTL regions. The SNP effects on each trait from GWAS were obtained to construct associated weight matrix (AWM) and calculate SNP effect based genetic correlation between yearling PAP phenotypes and performance traits. The estimated heritabilities were 0.24, 0.24, 0.25, and 0.32 for RAW, PT, CAT3 and CAT2, respectively. Sire EBV accuracies from univariate models of RAW, PT, CAT3 and CAT2 ranged from 0.03 to 0.67, 0.03 to 0.68, 0.01 to 0.65 and 0.01 to 0.58 with means of 0.31, 0.31, 0.27 and 0.21, respectively (pooled sd = 0.13). The absolute genetic correlations between them were above 0.91, and the rank correlations between EBV from RAW and PT, CAT3 or CAT2 were 0.92, 0.84 and 0.77, respectively. The RAW, CAT3 and CAT2 had a downward sloping genetic trend, and the PT (the inverse transformation of PAP) has an upward sloping genetic trend that consistent with the other PAP phenotypes’ genetic trend. The estimated heritability of yearling PAP phenotypes of bulls were significantly different (P < 0.05) from that of heifers. Genetic correlations between yearling PAP phenotypes in bulls and heifers were 0.82, 0.79, 0.96 and 0.87, and EBV rank correlations were 0.94, 0.93, 0.99 and 0.96 for RAW, PT, CAT3 and CAT2, respectively. Results suggested violation of assumptions in linear modeling had limited influence on genetic evaluation results, and losses in EBV accuracy and some re-ranking of sires was observed in ordinal categorical phenotypes compared to continuous PAP scores. The non- transformed yearling PAP measurements were preferred in genetic evaluation of PAP measurements because of its similar genetic heritability with PT, higher accuracy than categorical phenotypes and easier interpretation. Ordinal categorical phenotypes can be iv alternative dependent variables in studying PAP, however, they would cause some re-ranking of sires related to non-transformed PAP measruments. The PAP phenotypes in different sexes were identified genetically un-identical (P < 0.05). However, it is not necessary to treat yearling PAP as separate traits by sex in genetic evaluation because the EBV from all PAP and PAP of different sexes were highly correlated and would yield similar rank of animals. The estimated genetic correlations between various yearling PAP phenotypes and BWT, WW, PWG, YW and MILK ranged from 0.22 to 0.27, 0.16 to 0.22, 0.03 to 0.16, 0.11 to 0.20, and 0.07 to 0.16 respectively. The average EBV accuracy of yearling PAP phenotypes was improved by 0.011 (sd = 0.0026; 7.20%) and 0.0018 (sd=0.0021, 1.15%) in multivariate (including PAP, BWT, WW, PWG) and bivariate models (including PAP and YW), respectively. This multivariate model was preferred in estimating EBV for yearling PAP phenotypes, since it would increase the accuracy of the EBV and the number of animals used in GWAS. We identified 4, 12 and 9 windows (1-Mb) associated with RAW, CAT3 and CAT2, respectively. The majority of these lead-SNP (with the highest model frequency in identified window) resulted in significant (P < 0.05) additive effects, and only one lead-SNP had significant dominant effect. This demonstrated the polygenetic characteristics of yearling PAP phenotypes, additive effects of most of yearling PAP phenotypes associated SNP and dominant effects of limited number of yearling PAP phenotypes associated SNP. Five concordant windows located on chromosome 7, 11, 12, 15 and 20 were identified across the PAP phenotypes when considering top 2% windows of each phenotype. Gene enrichment and ontology analysis suggested these windows were related to ion binding and transportation, inflammation, innate immunity and cell proliferation mechanisms. This gave evidences of the identified QTL’s association with hypoxia-induced elevated PAP in cattle. v Twenty-two windows were identified to be associated with performance traits (i.e. BWT, WW, PWG, YW, MILK), which illustrated the polygenetic characteristics of these traits. Seven of them located on chromosome 7, 14, 20 and X were pleiotropic across these performance traits. Gene enrichment and ontology of these windows clustered gene functions in categories such as adipose tissue development and innate immunity. Only two windows, located on chromosome 7 at 93 Mb and Chromosome 20 at 4 Mb, were recognized as pleiotropic between yearling PAP phenotypes and performance traits. Low to moderate SNP-based genetic correlation were identified between yearling PAP phenotypes and performance traits, and the SNP-based genetic correlation explained 61 % variation of pedigree- based genetic correlation. Results suggested SNP effects could be used to estimate genetic correlation between traits. Genes in two pleiotropic windows and AWM have roles in intracellular transportation, cellular metabolism, inflammatory, hypoxia response and cell proliferation, which demonstrated the effects of SNP in AWM on PAP phenotypes. Our findings will improve the understandings of biological process involving health and growth in Angus cattle managed at high altitude, and also help genetic improvement in these cattle against PH and HAD. vi ACKNOWLEDGMENTS I would like to express my sincere and grateful appreciations to my advisor Dr. Milton G. Thomas for his guidance, understanding, encourage, patience, and most importantly, continuous support for my PhD studies. His mentorship helped me through the research and writing of this dissertation, and provided well direction in developing my long-term career goals. Without his guidance and persistent help, this dissertation would not be possible. A special thank to my co-advisor Dr. Mark Enns for his input and guidance on my studies, with whose help I explore the idea and development of this dissertation.
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