Widespread modulation of gene expression by copy number variation in skeletal muscle

Abstract

Copy number variation (CNV) is a frequently observed deviation from the diploid state due to duplication or deletion of genomic regions. Although intensively analyzed for association with diseases and production traits, the specific mechanisms and extent by which such variations affect the phenotype are incompletely understood. We present an integrative study on CNV and genome-wide gene expression in Brazilian Bos indicus cattle. We analyzed CNVs inferred from SNP-chip data for effects on gene expression measured with RNA-seq in skeletal muscle samples of 183 steers. Local effects, where expression changes coincided with CNVs in the respective genes, were restricted to immune genes. Distal effects were attributable to several high-impact CNVs that modulated remote expression in an orchestrated and intertwined fashion. These CNVs were located in the vicinity of major skeletal muscle pathway regulators and associated genes were enriched for proteolysis, autophagy, and muscle structure development. From association analysis between CNVs and several meat quality and production traits, we found CNV-associated expression effects to also manifest at the phenotype level. Based on genome sequences of the population founders, we further demonstrate that CNVs with impact on expression and phenotype are passed on from one generation to another.

Genome-wide scan for selection signatures reveals novel insights into the adaptive capacity in local North African cattle

“…We suggest that the aforementioned genes have been under evolutionary pressure in North African cattle and that some of them may have experienced enhanced fixation of duplicates resulting from selection for increased dosage to effectively regulate the innate and acquired immune response to parasitic diseases. A previous study 34 conducted on Brazilian Bos indicus cattle, similarly reported that CNVs are important modulators of immune gene expression. Our results have also revealed a series of other genes involved in the regulation of blood pressure and heart contraction ( ACE , ACE3 , COX4I1 , NOS3, CXADR ), blood vessel development and morphogenesis ( CCM2 , FOXC2 , FOXF1 , MAP3K3 ).…”

The Genomic Complexity of a Large Inversion in Great Tits

“…2018). In general, an increase in the number of gene copies can alter trans - and cis - gene expression, which might generate novel phenotypic variation (Geistlinger et al. 2018).…”

CNVRanger: association analysis of CNVs with gene expression and quantitative phenotypes

“…The CNVRanger package implements association testing between CNV regions and RNA-seq read counts based on edgeR (Robinson et al, 2010). For CNV regions with only one CN state deviating from the 2n reference group, this reduces to the classical 2-group comparison as previously described (Geistlinger et al, 2018). For multi-allelic CNVs (e.g.…”

“…Such regions are denoted as CNV calls and are the starting point for subsequent downstream analysis. In previous work, we developed, described, and applied functionality for analyzing CNVs across a population, including association analysis with gene expression and quantitative phenotypes (da Silva et al, 2016(da Silva et al, , 2018Geistlinger et al, 2018). To allow straightforward application to similar datasets, we generalize these concepts and provide refined implementations in the CNVRanger R/Bioconductor package.…”