Abstract
There is increasing recognition that the underlying genetic variation contributing to complex traits influences transcriptional regulation and can be detected at a population level as expression quantitative trait loci. At the level of an individual, allelic variation in transcriptional regulation of individual genes can be detected by measuring allele-specific expression in RNAseq data. We reasoned that extreme variants in gene expression could be identified by analysis of inbred progeny with shared grandparents. Commercial chickens have been intensively selected for production traits. Selection is associated with large blocks of linkage disequilibrium with considerable potential for co-selection of closely linked “hitch-hiker alleles” affecting traits unrelated to the feature being selected, such as immune function, with potential impact on the productivity and welfare of the animals. To test this hypothesis that there is extreme allelic variation in immune-associated genes we sequenced a founder population of commercial broiler and layer birds. These birds clearly segregated genetically based upon breed type. Each genome contained numerous candidate null mutations, protein-coding variants predicted to be deleterious and extensive non-coding polymorphism. We mated selected broiler-layer pairs then generated cohorts of F2 birds by sibling mating of the F1 generation. Despite the predicted prevalence of deleterious coding variation in the genomic sequence of the founders, clear detrimental impacts of inbreeding on survival and post-hatch development were detected in only one F2 sibship of 15. There was no effect on circulating leukocyte populations in hatchlings. In selected F2 sibships we performed RNAseq analysis of the spleen and isolated bone marrow-derived macrophages (with and without lipopolysaccharide stimulation). The results confirm the predicted emergence of very large differences in expression of individual genes and sets of genes. Network analysis of the results identified clusters of co-expressed genes that vary between individuals and suggested the existence of trans-acting variation in the expression in macrophages of the interferon response factor family that distinguishes the parental broiler and layer birds and influences the global response to lipopolysaccharide. This study shows that the impact of inbreeding on immune cell gene expression can be substantial at the transcriptional level, and potentially opens a route to accelerate selection using specific alleles known to be associated with desirable expression levels.
Highlights
A large proportion of causal genetic variation implicated in complex traits in humans is associated with regulatory variants that impact on the level of gene expression (Zhu et al, 2016)
For reasons that will become evident in subsequent analysis described below, we generated a principal component analysis (PCA) based solely upon single nucleotide variants (SNVs) detected within loci encoding the members of the interferon-responsive factor (IRF) family, which may produce potential trans-acting transcriptional regulators of inducible gene expression in macrophages
In addition to CSF1R and interleukin 34 (IL34) we focused on IL10 because of our recent data indicating substantial variance
Summary
A large proportion of causal genetic variation implicated in complex traits in humans is associated with regulatory variants that impact on the level of gene expression (Zhu et al, 2016). Modern western broiler and layer chickens have been divergently selected for meat and egg production respectively, increasingly using genomic selection with dense genotyping chips (Kranis et al, 2013; Gheyas et al, 2015). This intense selection has generated selective sweeps around regions associated with production traits, for example genes linked to appetite, growth, metabolic regulation and carcase traits in broilers and eggproduction in layers (Qanbari et al, 2019). In the current study we take a novel approach to identifying the potential immunological consequences of trait selection in commercial chickens
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