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Decreased Fgf8 gene dosage on gene expression

ABSTRACT: Robustness to perturbation, or canalization, is a fundamental and required feature of complex organisms.1 Mutations are the raw material for evolution, but robustness to their effects is required for organisms to tolerate mutational loads.1 Similarly, robustness to environmental perturbations, or limiting environmental responses to an adaptive range, is necessary for organisms to tolerate environmental variation. Robustness is heritable2-4, but the mechanisms that produce it are poorly understood. Explanations range from the role of specific processes such as heat shock proteins to more general embedded features of developmental systems. Nonlinearities are an embedded, ubiquitous feature of development that may modulate how variation in development relates to phenotypic robustness.5,6 Here, we show that variation in Fibroblast Growth Factor 8 (Fgf8) expression across an allelic series has a nonlinear relationship to phenotypic variation, predicting the magnitude of variation within genotypes. These differences in phenotypic variance are independent of genetic variance and so reflect differential robustness to minor environmental variation. Differences in robustness are not related to differences in the variance of gene expression within genotypes. However, mean gene expression levels do vary across genotypes, particularly in genes downstream to FGF8 signaling. Gene expression changes thus explain the genotype-phenotype curve but not the changes in robustness along the curve. This suggests that mechanisms above the gene-regulatory network are important determinants of robustness. Our results show that nonlinearities in developmental mechanisms can persist from genotype to phenotype to produce variation in robustness between genotypes. This suggests that embedded features of development rather than specific canalizing mechanisms explain robustness. How such features vary among individuals in natural populations and relate to genetic variation more generally are key questions for unravelling the origin and evolvability of this fundamental feature of organismal development.

ORGANISM(S): Mus musculus

PROVIDER: GSE87366 | GEO | 2017/09/23

SECONDARY ACCESSION(S): PRJNA344497

REPOSITORIES: GEO

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Project description:BACKGROUND: The transcript levels of many genes exhibit significant variation in tissue samples from inbred laboratory mice. A microarray experiment was designed to separate transcript abundance variation across samples from adipose, heart, kidney, and liver tissues of C57BL/6J mice into within-mouse and between-mouse components. Within-mouse variance captures variation due to heterogeneity of gene expression within tissues, RNA-extraction, and array processing. Between-mouse variance reflects differences in transcript levels between these genetically identical mice. Many biological sources can contribute to heterogeneous transcript levels within a tissue sample including inherent stochasticity of biochemical processes such as intrinsic and extrinsic noise within cells and differences in cell-type composition which can result from heterogeneity of stem and progenitor cell populations. Differences in global signaling patterns between individuals and micro-environmental influences such as interactions with pathogens and cage mates can also contribute to variation, but are likely to contribute more to the between-mouse variance component. RESULTS: The nature and extent of transcript abundance variation differs across tissues. Adipose has the largest total variance and the largest within-mouse variance. Liver has the smallest total variance, but it has the most between-mouse variation. Genes with high variability can be classified into groups with correlated patterns of expression that are enriched for specific biological functions. Variation between mice is associated with circadian rhythm, growth hormone signaling, immune response, androgen regulation, lipid metabolism, and the extracellular matrix. Genes showing correlated patterns of within mouse variation were also associated with biological functions, spatial connectivity of stochastic variation and heterogeneity of cell types within tissues. CONCLUSIONS: Genetically identical mice are individuals and they can experience different outcomes for medically important traits. This is reflected in the stochastic variation in gene expression observed between genetically identical mice. Much of the stochasticity has organismal, tissue, or spatial connectivity. Prior knowledge of the genes and functional classes of genes that are likely to vary in the absence of experimental perturbations, whether these are genetic or environmental, can inform experimental design decisions and the interpretation of gene expression data. Variation in gene expression in genetically identical mice sheds light on the impact of stochastic and micro-environmental factors and their phenotypic consequences.

Project description:Different individuals of the same species are generally thought to have very similar genomes. However, there is growing evidence that structural variation in the form of copy number variation (CNV) and presence-absence variation (PAV) can lead to variation in the genome content of individuals within a species. In order to investigate the potential contribution of CNV and PAV to genomic diversity in maize we used array comparative genomic hybridization (CGH) to compare gene content and copy number variation among 25 diverse maize inbreds 14 genotypes of the wild ancestor of maize, teosinte. The microarray included multiple probes for each of the ~32,500 stringently filtered genes identified in the B73 reference genome. We identified 479 genes exhibiting higher copy number in some genotypes (UpCNV) and 3,410 genes that have either fewer copies or are missing in the genome of at least one genotype relative to B73 (DownCNV/PAV). Many of these DownCNV/PAV are examples of genes that are present in B73 but missing from the genome of several other genotypes. Over 70% of the CNV/PAV examples are identified in multiple genotypes and the majority of events are observed in both maize and teosinte suggesting that these reflect relatively old variants that are not associated with domestication or maize improvement. Many of the genes affected by CNV/PAV are either maize-specific or members of genes families suggesting that the gene loss can be tolerated through buffering by redundant functions encoded elsewhere in the genome. Many plant genomes are relatively large and contain the remnant of whole genome duplications which may provide the ability to tolerate high levels of structural variation. While this structural variation may not result in major qualitative variation due to genetic buffering, it may significantly contribute to quantitative variation. 1-2 replications of 25 maize inbred and 14 teosinte genotypes were hybridized to an array designed from the ~32,400 genes in the maize B73 reference genome.

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Decreased Fgf8 gene dosage on gene expression

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