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Whole genome resequencing identifies the CPQ gene as a determinant of ascites syndrome in broilers.

ABSTRACT: Ascites syndrome is the most severe manifestation of pulmonary hypertension in fast-growing broilers. The disease can be attributed to increased body weights of birds, where the higher metabolic load is not matched by sufficient oxygen supply to the cells and tissues. Although there are environmental components, the disease exhibits moderate to high heritability. The current study uses high throughput whole genome resequencing (WGR) to identify genes and chromosomal regions associated with ascites.The WGR data identified the CPQ gene on chromosome 2. The association was confirmed by genotyping a large collection of DNAs from phenotyped birds from three distinct broiler lines using SNPs in intron 6 and exon 8 of the CPQ gene. By combining the genotype data for these two SNP loci, we identified three different alleles segregating in the three broiler lines. Particular genotypes could be associated with resistance to ascites. We further determined that particular genotypes most associated with resistance overexpress CPQ mRNA in three tissues which might explain the role of these alleles in contributing to resistance.Our findings indicate CPQ is an important determinant of pulmonary hypertension syndrome leading to ascites in broilers. We identified particular SNPs that can be used for marker-assisted selection of broilers for resistance to the disease. Our findings validate WGR as a highly efficient approach to map determinants contributing to complex phenotypic or disease-related traits. The CPQ gene has been associated with pulmonary hypertension in genome-wide association studies in humans. Therefore, ascites investigations in broilers are likely to provide insights into some forms of hypertension in humans.

SUBMITTER: Dey S

PROVIDER: S-EPMC5749702 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Whole genome resequencing identifies the CPQ gene as a determinant of ascites syndrome in broilers.

Dey Shatovisha S Parveen Alia A Tarrant Katy J KJ Licknack Timothy T Kong Byungwhi C BC Anthony Nicholas B NB Rhoads Douglas D DD

PloS one 20180102 1

<h4>Background</h4>Ascites syndrome is the most severe manifestation of pulmonary hypertension in fast-growing broilers. The disease can be attributed to increased body weights of birds, where the higher metabolic load is not matched by sufficient oxygen supply to the cells and tissues. Although there are environmental components, the disease exhibits moderate to high heritability. The current study uses high throughput whole genome resequencing (WGR) to identify genes and chromosomal regions as ...[more]

PMID: 29293530

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Project description:BACKGROUND:Pulmonary arterial hypertension, also known as Ascites syndrome (AS), remains a clinically challenging disease with a large impact on both humans and broiler chickens. Pulmonary arterial remodeling presents a key step in the development of AS. The precise molecular mechanism of pulmonary artery remodeling regulating AS progression remains unclear. METHODOLOGY/PRINCIPAL FINDINGS:We obtained pulmonary arteries from two positive AS and two normal broilers for RNA sequencing (RNA-seq) analysis and pathological observation. RNA-seq analysis revealed a total of 895 significantly differentially expressed genes (DEGs) with 437 up-regulated and 458 down-regulated genes, which were significantly enriched to 12 GO (Gene Ontology) terms and 4 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (Padj<0.05) regulating pulmonary artery remodeling and consequently occurrence of AS. These GO terms and pathways include ribosome, Jak-STAT and NOD-like receptor signaling pathways which regulate pulmonary artery remodeling through vascular smooth cell proliferation, inflammation and vascular smooth cell proliferation together. Some notable DEGs within these pathways included downregulation of genes like RPL 5, 7, 8, 9, 14; upregulation of genes such as IL-6, K60, STAT3, STAT5 Pim1 and SOCS3; IKK?, IkB, P38, five cytokines IL-6, IL8, IL-1?, IL-18, and MIP-1?. Six important regulators of pulmonary artery vascular remodeling and construction like CYP1B1, ALDH7A1, MYLK, CAMK4, BMP7 and INOS were upregulated in the pulmonary artery of AS broilers. The pathology results showed that the pulmonary artery had remodeled and become thicker in the disease group. CONCLUSIONS/SIGNIFICANCE:Our present data suggested some specific components of the complex molecular circuitry regulating pulmonary arterial remodeling underlying AS progression in broilers. We revealed some valuable candidate genes and pathways that involved in pulmonary artery remodeling further contributing to the AS progression.

Project description:The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF???1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal?=?53,236) and fracture (ntotal?=?508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n?=?2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n?=?3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n?=?26,534), and de novo replication genotyping (n?=?20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF?=?1.6%, replication effect size?=?+0.20 s.d., Pmeta?=?2?×?10(-14)), which was also associated with a decreased risk of fracture (odds ratio?=?0.85; P?=?2?×?10(-11); ncases?=?98,742 and ncontrols?=?409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF?=?1.2%, replication effect size?=?+0.41 s.d., Pmeta?=?1?×?10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Dataset Information

Whole genome resequencing identifies the CPQ gene as a determinant of ascites syndrome in broilers.

Publications

Whole genome resequencing identifies the CPQ gene as a determinant of ascites syndrome in broilers.

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