Characterization of pulmonary hypertension status and utilization of multi-omics analyses to discover variants that may inform selection against high mean pulmonary arterial pressure in Angus cattle
Date
2020
Authors
Jennings, Kaysie Jean, author
Thomas, Milton G., advisor
Coleman, Stephen J., advisor
Enns, R. Mark, committee member
Speidel, Scott E., committee member
Holt, Timothy N., committee member
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Abstract
This multi-part research characterizes pulmonary hypertension (PH) from a physiologic and genetic point of view using the indicator trait mean pulmonary arterial pressure (PAP). Three aims were designed to address the research objective of investigating the genetics underlying PAP for the purposes of variant discovery. The first aim sought to identify different PAP phenotypes based on altitude and diet during the stocker and finishing phases of production. This longitudinal study evaluated steers with a moderate PAP (41-48 mmHg) from yearling age until harvest, collecting PAP and blood gas parameters throughout the study and carcass data at the conclusion. Through this experimental approach, the role of different finishing systems was able to be evaluated and cattle with increased sensitivity to hypoxic conditions were identified. Results from this study indicated that regardless of finishing system, animals exhibited signs of respiratory alkalosis with renal compensation because of hypoxic conditions. The PAP data from this population corroborated that all steers were hypoxic. However, the only carcass quality differences observed were those between cattle that were grain finished compared to those that were grass finished, regardless of altitude. Aim two was to perform next-generation whole genome sequencing for 30 Angus bulls and steers to compare those with high PAP (HPAP) to those with low PAP (LPAP) measures. All cattle sequenced originated from elevations ≥1,500m and were selected based on their pedigree information, as well as PAP observations. The sequence data from these 30 animals were then compared such that sequence from HPAP cattle was compared to that of LPAP cattle. There were 5,543 variants unique to HPAP cattle and 1,690 variants unique to LPAP cattle. Loci across all 30 chromosomes exhibited variation for PAP phenotype. Evaluation of these variants and validation will be necessary to sift through variants that are in linkage or may be less informative. A multi-omics approach was used to perform variant discovery based on the PAP phenotype in aim three. Through combination of RNA sequence with DNA sequence, the list of variants relevant to PAP phenotype was filtered from millions of variants to hundreds of variants. Transcriptome data was compared for each of six tissues between HPAP and LPAP cattle. These variants were then compared to one another to determine which variants were detected in each PAP category across all six tissue types. Those variants were then compared to the DNA sequence from aim two to elucidate concordant variants for HPAP and LPAP cattle respectively. There were three variants that were unique to LPAP cattle and were concordant between DNA and RNA sequence. However, none of these variants were within 1,000bp of a gene recognized in the ARS-UCD1.2 bovine genome assembly and were therefore considered less informative. There were 523 variants unique to HPAP cattle. Within that population there was a subset that was either near or within a gene. There were six genes that were considered informative for further investigation. Three of those genes were uncharacterized genes on chromosome 16. The other three (U6, SIMC1, CDH23), while not well documented in cattle, had functions in humans that would indicate their function could affect PAP phenotype expression. These genes and the variants within them could be useful for selection if validated in a larger population.
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Subject
High Mountain Disease
Pulmonary hypertension
Whole genome sequencing
Mean pulmonary arterial pressure
Cattle
Variant discovery