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Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins.

Sarah L Fong1, John A Capra2,3

  • 1Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee.

Genome Biology and Evolution
|October 31, 2022
PubMed
Summary
This summary is machine-generated.

Human gene enhancers have complex evolutionary origins. Both core and derived sequences show regulatory function, but younger derived sequences have distinct constraints and TF-binding preferences, allowing for functional variation.

Keywords:
evolutionfunctional genomicsgene regulationgenetic variationhuman enhancerssequence age

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Area of Science:

  • Genomics
  • Evolutionary Biology
  • Molecular Biology

Background:

  • Thousands of human gene regulatory enhancers possess sequences from multiple evolutionary origins.
  • These complex enhancers comprise older "core" sequences and younger "derived" sequences.
  • The functional interplay between core and derived sequences within complex enhancers remains poorly understood.

Purpose of the Study:

  • To evaluate the function, selective pressures, and sequence variation of core and derived components in human complex enhancers.
  • To understand the relationship between evolutionary age and functional constraints in enhancer sequences.
  • To investigate how distinct sequence origins contribute to gene regulation and population-level variation.

Main Methods:

  • Massively parallel reporter assays (MPRAs) to assess biochemical activity.
  • Comparative genomics to analyze evolutionary ages and selective pressures (purifying selection).
  • Analysis of transcription factor (TF)-binding preferences and population genetic variation (eQTLs).

Main Results:

  • Both core and derived sequences are evolutionarily older than the genomic background and exhibit significant biochemical activity.
  • Core and derived sequences display distinct TF-binding preferences.
  • Derived sequences show weaker purifying selection, tolerate more genetic variation, and are enriched for expression quantitative trait loci (eQTLs) compared to core sequences.

Conclusions:

  • Both core and derived sequences are functionally active in gene regulation.
  • Derived sequences exhibit unique constraint profiles and TF-binding preferences, contributing to functional variation.
  • The integration of derived sequences with core sequences generates regulatory elements with robust activity and potential for evolutionary innovation.