Evolution of dosage-sensitive genes by tissue-restricted expression changes
Authors: Rice Alan M. , Li Yuanshuo , Donnelly Pauric , McLysaght Aoife 
Published: October 2024

Dosage-sensitive genes have characteristic patterns of evolution that include being refractory to small-scale duplication, depleted on human benign copy number variants (CNVs) and enriched on pathogenic CNVs. This intolerance to copy number change is likely due to an expression constraint that exists in one or more tissues. While genomic copy number changes alter the encompassed genes’ expression across all tissues, expression quantitative trait loci (eQTLs) –genomic regions harbouring sequence variants that influence the expression level of one or more genes– can act in a tissue-specific manner. In this work we examine expression variation of presumed dosage-sensitive and non-dosage-sensitive genes to discover how the locus duplicability constraints translate into gene expression constraints. Here we test the hypothesis that expression changes due to the presence of eQTLs acting in unconstrained tissues will not be deleterious and thus allow dosage-sensitive genes to vary expression while obeying constraints in other tissues. Using eQTLs across 48 human tissues from The Genotype-Tissue Expression (GTEx) project, we find that dosage-sensitive genes are enriched for being affected by eQTLs and that the eQTLs affecting dosage-sensitive genes are biased towards having narrow tissue-specificity with these genes having fewer eQTL-affected tissues than non-dosage-sensitive genes. Additionally, we find that dosage-sensitive genes are depleted for being affected by broad tissue breadth eQTLs, likely due to the increased chance of these eQTLs conflicting with expression constraints and being removed by purifying selection. These patterns suggest that dosage-sensitivity shapes the evolution of these genes by precluding copy number evolution and restricting their evolutionary trajectories to changes in expression regulation compatible with their functional constraints. Thus deeper interpretation of the patterns of constraints can be informative of the temporal or spatial location of the gene dosage sensitivity and contribute to our understanding of functional genomics.

Author summary

Gene duplication is an important and powerful evolutionary force that is responsible for the expansion of the coding capacity of genomes ultimately resulting in great genetic novelty. However, the opportunity for this evolutionary change can be limited by dosage constraints on some genes, meaning they are not normally duplicable, except in a balanced, whole genome event. This results in important, biologically relevant, differences between genes that are retained from whole genome duplication events versus those retained from small scale duplications, especially in terms of dosage sensitivity. We explored how the different dosage sensitivity in these sets of genes relates to quantitative expression variation present in populations. We found that while dosage-sensitive genes are more likely to have their expression levels influenced by genetic variation, these changes are often specific a small number of tissues. In contrast, genes that are less sensitive to dosage changes show greater variation in expression levels across multiple tissues. Our findings suggest that dosage-sensitive genes evolve through fine-tuned adjustments in their expression levels in specific tissues, thus bypassing constraints operating on other tissues. This understanding sheds light on how dosage-sensitive genes evolve and could have implications for understanding human diseases caused by these genes.