Role of pathogen-driven selection in shaping the predisposition to IBD: identification of disease susceptibility alleles Mario (Mago) Clerici, M.D. Chair of Immunology Head, PhD School in Molecular Medicine, Universita' di Milano Scientific Director, IRCCS SM Nascente, Fondazione Don C Gnocchi, Milano Bardolino, January 16th, 2013
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Role of pathogen-driven selection in shaping the predisposition to IBD: identification of disease susceptibility alleles Mario (Mago) Clerici, M.D. Chair.
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Role of pathogen-driven selection in shaping the predisposition to IBD:
identification of disease susceptibility alleles
Mario (Mago) Clerici, M.D.Chair of Immunology
Head, PhD School in Molecular Medicine, Universita' di Milano
Scientific Director, IRCCS SM Nascente,
Fondazione Don C Gnocchi, Milano
Bardolino, January 16th, 2013
The evolutionary perspective for Inflammatory Diseases
Inflammatory/autoimmune diseases can have early onset (i.e. before reproductive age)
Inflammatory/autoimmune diseases have a strong genetic component
Inflammatory/autoimmune diseases have a relatively high prevalence in human populations
Why has evolution failed to eliminate the risk alleles?
1) Susceptibility alleles increased in frequency by genetic drift
2) Susceptibility alleles increased in frequency as a result of natural selection (they confer a selective advantage to the carriers; e.g. protection from infection) [hygiene hypothesis]
3) Risk alleles were neutral under different environmental conditions (e.g. high prevalence of infections/worms) [hygiene hypothesis]
Aims
Application of population genetic approaches to study the evolutionary history of inflammatory disease risk alleles in human populations
Study the role of past infections in shaping the present-day distribution of inflammatory disease risk alleles
Use evolutionary information to identify novel risk variants for Crohn’s disease
An innovative approach
We developed a strategy to detect pathogen-driven selection
Pathogen-driven selection implies that allele frequencies at a locus are shaped by selective pressure imposed by one or more infectious agents
Strengths: 1) We test a specific hypothesis on the underlying selective pressure (can distinguish among different pathogen groups)
2) High power to detect selection on standing variation
Weaknesses: 1) Use of a relatively low-density SNP panel
2) Use of a population panel with uneven geographic representation
Pathogen-driven selection Identifies correlations between genetic variability and pathogen-driven selective pressure.
We need a measure of selective-pressure that reflects historical pressures (evolution acts over long time periods).