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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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The genomes of eukaryotes are punctuated by long stretches of sequence which do not code for proteins or RNAs. Although some of these regions do contain crucial regulatory sequences, the vast majority of this DNA serves no known function. Typically, these regions of the genome are the ones in which the fastest change, in evolutionary terms, is observed, because there is typically little to no selection pressure acting on these regions to preserve their sequences.
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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Evolution of Dosage-Sensitive Genes by Tissue-Restricted Expression Changes.

Alan M Rice1,2, Yuanshuo Li1, Pauric Donnelly1

  • 1Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.

Genome Biology and Evolution
|July 7, 2025
PubMed
Summary
This summary is machine-generated.

Dosage-sensitive genes evolve with strict constraints, avoiding duplication and copy number variants. Their expression is fine-tuned by tissue-specific regulatory elements, influencing evolutionary paths in functional genomics.

Keywords:
dosage-sensitivityexpression evolutionexpression quantitative trait locigene duplicationohnologs

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Area of Science:

  • Evolutionary genomics
  • Functional genomics
  • Gene regulation

Background:

  • Dosage-sensitive genes exhibit unique evolutionary patterns, including resistance to duplication and depletion on benign copy number variants (CNVs).
  • This intolerance to copy number changes suggests expression constraints across specific tissues.
  • Expression quantitative trait loci (eQTLs) can modulate gene expression in a tissue-specific manner, distinct from global copy number alterations.

Purpose of the Study:

  • To investigate how locus duplicability constraints on dosage-sensitive genes translate into gene expression constraints.
  • To test if expression changes from eQTLs in unconstrained tissues permit dosage-sensitive genes to vary expression while respecting constraints in other tissues.

Main Methods:

  • Analysis of presumed dosage-sensitive and non-dosage-sensitive genes using eQTL data.
  • Utilized eQTL data across 48 human tissues from The Genotype-Tissue Expression (GTEx) project.
  • Examined the tissue-specificity of eQTLs affecting dosage-sensitive genes.

Main Results:

  • Dosage-sensitive genes are enriched for being influenced by eQTLs.
  • eQTLs affecting dosage-sensitive genes show a bias towards narrow tissue-specificity.
  • Dosage-sensitive genes are depleted for association with broad tissue breadth eQTLs, suggesting selection against conflicts with expression constraints.

Conclusions:

  • Dosage-sensitivity shapes gene evolution by limiting copy number changes and restricting expression regulation to compatible trajectories.
  • Tissue-specific eQTLs play a crucial role in maintaining dosage-sensitive gene function within evolutionary constraints.
  • Understanding these constraint patterns can reveal the spatial and temporal aspects of gene dosage sensitivity, advancing functional genomics.