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A Rapid In Vivo Bioassay for Developmentally Active Enhancers
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Evolutionary Innovations in Conserved Regulatory Elements Associate With Developmental Genes in Mammals.

Severin Uebbing1,2, Acadia A Kocher1, Marybeth Baumgartner1

  • 1Department of Genetics, Yale School of Medicine, New Haven, CT, USA.

Molecular Biology and Evolution
|September 20, 2024
PubMed
Summary

Accelerated evolution in transcriptional enhancers frequently impacts pleiotropic genes controlling development and gene regulation. This enhancer evolution drives regulatory innovation, as seen in HES1 during hoofed mammal digit reduction.

Keywords:
Conserved non-coding sequencesenhancer evolutionmammal evolutionnotch signalingsequence acceleration

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Area of Science:

  • Evolutionary biology
  • Genomics
  • Developmental biology

Background:

  • Transcriptional enhancers control cell-specific gene expression.
  • Genetic variations in enhancers contribute to phenotypic diversity, adaptation, and disease.
  • The scale and patterns of regulatory evolution across mammalian phylogeny remain largely unexplored.

Purpose of the Study:

  • To investigate patterns of accelerated sequence evolution in conserved mammalian enhancers.
  • To identify genes and pathways enriched for regulatory evolution.
  • To understand the functional consequences of enhancer evolution.

Main Methods:

  • Large-scale comparative genomics analysis of conserved enhancer elements across mammalian species.
  • Identification of signatures of accelerated sequence evolution.
  • Functional analysis of specific enhancer evolution events, including HES1.

Main Results:

  • A significant pattern of accelerated enhancer evolution was observed across the mammalian phylogeny.
  • Pleiotropic genes involved in gene regulation and development were disproportionately enriched for accelerated enhancer evolution.
  • Sequence acceleration in enhancers was linked to regulatory function turnover, exemplified by HES1 enhancer evolution associated with digit reduction.

Conclusions:

  • Enhancer evolution is a common mechanism for regulatory innovation in conserved developmental genes in mammals.
  • Pleiotropic genes with multiple enhancer connections are hotspots for regulatory evolution.
  • Specific enhancer evolutionary events can coincide with major phenotypic adaptations.