Interpretive Summary: Genome-wide association study of lung lesions and pleurisy in New Zealand lambs
By: Jackie Walling
Chronic nonprogressive pneumonia is a complex disease and is detrimental to New Zealand sheep production. This disease results in reduced growth rate and predisposition to pleurisy, an inflammation of the membrane surrounding the lungs. A recent article published in the November 2018 Issue of the Journal of Animal Science presents a genome-wide association study of lung lesions and pleurisy in New Zealand lambs to utilize information for alternative treatments to antibiotic use. Genotype data was used to locate parts of the genome associated with pneumonic lesions and pleurisy. This allowed assessment of genetic mechanisms involved in responses to disease providing a foundation for genetic selection to improve resistance to the disease.
There were 3,572 lambs from four flocks slaughtered between ages 4-8 months. Lungs were scored for presence and severity of pneumonic lesions. Phenotypic measurements scored lesions using the Consolidated Pneumonia Score (CPS) of 0 to 2. No lesions were present at 0, any lobe up to 50% affected classified as 1, and any lobe greater than 50% was a 2. Lesions were identified as dark compacted areas of purple-red color firm to the touch. Genotype data was collected from ear tissue and heritability calculated from univariate analysis. Genome-wide association analyses used Efficient Mixed-Model Association eXpedited (EMMAX) and haplotype trend regression (HTR) to evaluate lesion data adjusted for heteroscedasticity in animals with no lesions and those with severe lesions.
Phenotypic analysis revealed 35% of lambs studied had lesions with 9% hosting severe lesions of CPS 2 and 9% having pleurisy. Adjusted estimates of heritability and pleurisy were .16 and .05, slightly higher than previous reports. A genetic and phenotypic correlation for those traits were .58 and .15 respectively.
Single nucleotide polymorphisms (SNPs) associated with pneumonic lesions were found in intergenic regions of sheep. Genome-wide analysis of all animals using EMMAX revealed no suggestively significant SNPs. HTR showed four interest regions on chromosomes 3,6, 8, and 13 as significant with an additional 31 suggestively significant SNPs. EMMAX of extreme animals (CPS 0 vs. 2) revealed several suggestively significant SNPs with the top three interrupting sequences in LSAMP, PPIL6, and KCNMA1 genes. HTR of extreme animals showed suggestively significant SNPs with the EYA4 gene and 2 missense (point mutations) variants in ATAD5. EMMAX and HTR regarding pleurisy indicated a significant peak on chromosome 2.
The SNPs identified surrounded genes involved with responding to DNA damage such as EYA4 (Eyes absent proteins), ATAD5, and RFC4 (Replication factor C). EYA4 specializes in DNA repair and enhances the innate immune response. RFC replicate and repair DNA. PPIL6 is involved with the respiratory system in its variability of immune response while KCNMA1 influences potassium channels and is found in high concentrations in asthmatic rats. Two methods discovered the peak on Chromosome 2 for pleurisy downstream from transcription factor SP3, known to activate or suppress genes involved with immunity. Identifying the genes associated with the respiratory and immune system allows researchers to target SNPs capable of changing the immune response to lung damage caused by pneumonia and pleurisy. Understanding pathways of genetic involvement in disease response could begin selecting for animals more resistant to pneumonic diseases thus reducing the use of antibiotics and loss of animals in production.
For a closer look at the genes involved, visit the Journal of Animal Science.