TY - JOUR
T1 - Population genetics of IFIH1
T2 - Ancient population structure, local selection, and implications for susceptibility to type 1 diabetes
AU - Fumagalli, Matteo
AU - Cagliani, Rachele
AU - Riva, Stefania
AU - Pozzoli, Uberto
AU - Biasin, Mara
AU - Piacentini, Luca
AU - Comi, Giacomo P.
AU - Bresolin, Nereo
AU - Clerici, Mario
AU - Sironi, Manuela
PY - 2010/11
Y1 - 2010/11
N2 - The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations. Results herein suggest that two major IFIH1 haplotype clades originated from ancestral population structure (or balancing selection) in the African continent and that local selective pressures have acted on the gene. Specifically, directional selection in Europe and Asia resulted in the spread of a common IFIH1 haplotype carrying a derived His460 allele. This variant changes a highly conserved arginine residue in the helicase domain, possibly conferring altered specificity in viral recognition. An alternative common haplotype has swept to high frequency in South Americans as a result of recent positive selection. Previous studies suggested that a portion of risk alleles for autoimmune diseases could have been maintained in humans as they conferred a selective advantage against infections. This is not the case for IFIH1, as population genetic differentiation and haplotype analyses indicated that the T1D susceptibility alleles behaved as neutral or nearly neutral polymorphisms. Our findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections and provide insight into the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations.
AB - The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations. Results herein suggest that two major IFIH1 haplotype clades originated from ancestral population structure (or balancing selection) in the African continent and that local selective pressures have acted on the gene. Specifically, directional selection in Europe and Asia resulted in the spread of a common IFIH1 haplotype carrying a derived His460 allele. This variant changes a highly conserved arginine residue in the helicase domain, possibly conferring altered specificity in viral recognition. An alternative common haplotype has swept to high frequency in South Americans as a result of recent positive selection. Previous studies suggested that a portion of risk alleles for autoimmune diseases could have been maintained in humans as they conferred a selective advantage against infections. This is not the case for IFIH1, as population genetic differentiation and haplotype analyses indicated that the T1D susceptibility alleles behaved as neutral or nearly neutral polymorphisms. Our findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections and provide insight into the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations.
KW - antiviral response
KW - IFIH1
KW - local selective pressure
KW - population structure
KW - positive selection
KW - type 1 diabetes
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U2 - 10.1093/molbev/msq141
DO - 10.1093/molbev/msq141
M3 - Article
C2 - 20538742
AN - SCOPUS:77958131532
VL - 27
SP - 2555
EP - 2566
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 11
ER -