Population Genetics of IFIH1: Ancient Population Structure, Local Selection

[I2a1a]

Abstract
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.