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Related Experiment Videos

Positive selection on a human-specific transcription factor binding site regulating IL4 expression.

Matthew V Rockman1, Matthew W Hahn, Nicole Soranzo

  • 1Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA. matthew.rockman@duke.edu

Current Biology : CB
|December 5, 2003
PubMed
Summary

A unique human genetic variation in the Interleukin 4 (IL4) promoter influences immune responses. This Interleukin 4 (IL4) promoter polymorphism shows local adaptation, with disease side effects stemming from positive selection for immune defense.

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Area of Science:

  • Immunology
  • Human Genetics
  • Evolutionary Biology

Background:

  • A single nucleotide polymorphism (SNP) in the promoter of the cytokine Interleukin 4 (IL4) impacts NFAT binding.
  • This regulatory polymorphism affects IL4 transcriptional activation in T cells and influences immune system cytokine signaling.
  • Consequences of this polymorphism can be both beneficial and detrimental to human health.

Purpose of the Study:

  • To investigate the evolutionary origin and population genetics of the human-specific NFAT binding site in the IL4 promoter.
  • To determine the selective forces shaping the frequency distribution of this polymorphism across human subpopulations.
  • To understand the relationship between IL4 promoter polymorphism, local adaptation, and disease states.

Main Methods:

Related Experiment Videos

  • Comparative genomics to identify the human-specific origin of the NFAT binding site.
  • Statistical analyses comparing allele frequencies of the IL4 promoter polymorphism with neutral variants.
  • Parametric and nonparametric statistical approaches to assess deviations from neutral drift.

    • Main Results:

    • The NFAT binding site in the IL4 promoter is a human-specific mutation that arose after divergence from other great apes.
    • Allele frequency differentiation among human subpopulations at this locus is significantly higher than expected under neutral drift.
    • Evidence suggests positive selection acting on this binding site, indicating local adaptation to pathogen challenges.

    Conclusions:

    • The IL4 promoter polymorphism is a result of local adaptation driven by diverse pathogenic challenges.
    • Observed disease states associated with the common derived allele are likely pleiotropic side-effects of positive selection for enhanced IL4 function in immunity.
    • This finding highlights the complex interplay between evolutionary adaptation, immune function, and human health.