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Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4).
Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease.
The real missing link in Ebola control efforts to date may lie in the failure to apply core principles of health promotion: the early, active and sustained engagement of affected communities, their trusted leaders, networks and lay knowledge, to help inform what local control teams do, and how they may better do it, in partnership with communities. The predominant focus on viral transmission has inadvertently stigmatized and created fear-driven responses among affected individuals, families and communities. While rigorous adherence to standard infection prevention and control (IPC) precautions and safety standards for Ebola is critical, we may be more successful if we validate and combine local community knowledge and experiences with that of IPC medical teams. In an environment of trust, community partners can help us learn of modest adjustments that would not compromise safety but could improve community understanding of, and responses to, disease control protocol, so that it better reflects their 'community protocol' (local customs, beliefs, knowledge and practices) and concerns. Drawing on the experience of local experts in several African nations and of community-engaged health promotion leaders in the USA, Canada and WHO, we present an eight step model, from entering communities with cultural humility, though reciprocal learning and trust, multi-method communication, development of the joint protocol, to assessing progress and outcomes and building for sustainability. Using examples of changes that are culturally relevant yet maintain safety, we illustrate how often minor adjustments can help prevent and treat the most serious emerging infectious disease since HIV/AIDS.