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Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene

Stuart Cantsilieris1, Bradley J Nelson1, John Huddleston1,2

  • 1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.

Proceedings of the National Academy of Sciences of the United States of America
|April 25, 2018
PubMed

Insights

The complement factor H (CFH) gene family

Area of Science:

  • Genetics
  • Evolutionary Biology
  • Human Disease Genetics

Background:

  • The complement factor H (CFH) gene family is implicated in complex genetic diseases like age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS).
  • Understanding the structural variation and evolution of the CFH gene family is crucial for deciphering its role in disease pathogenesis.

Purpose of the Study:

  • To investigate the evolutionary history and structural diversity of the CFH gene family across primate lineages.
  • To identify genetic variations within the CFH gene family associated with AMD and AHUS.

Main Methods:

  • High-quality sequencing of the CFH locus (approximately 360 kbp) in six primate lineages and multiple human haplotypes.
  • Comparative sequence analysis to identify gene duplication events and evolutionary breakpoints.
  • Analysis of over 5,000 AMD cases and controls, and over 2,400 individuals for structural variation, to identify disease-associated mutations and rearrangements.

Main Results:

  • Two distinct gene duplication periods (approximately 25-35 Mya and 7-13 Mya) led to the formation of four CFH-related (CFHR) paralogs.
  • A conserved 4.8-kbp ancestral CFHR gene promoter segment was recurrently involved in creating four CFHR fusion genes.
  • A rare missense mutation in CFH was significantly associated with AMD (P = 5.81 × 10^-8, OR = 9.8).
  • Rare nonsynonymous mutations in CFH/CFHR genes showed bipolar clustering in AMD and AHUS patients, mapping to domains under positive selection during primate evolution.
  • Five recurrent structural variation breakpoints were identified with variable frequencies in AMD cases and controls.

Conclusions:

  • The CFH gene family exhibits a dynamic evolutionary history characterized by recurrent duplication and rearrangement events.
  • These evolutionary processes have generated novel CFHR genes and contributed to the predisposition to complex human genetic diseases, including AMD and AHUS.
  • Specific structural variations and mutations within the CFH locus are critical determinants of disease risk.

Keywords:
AMDCFH gene familyage-related macular degenerationnatural selectionstructural variation

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