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The existing molecular variance levels in haplotypes of the interferon-alpha-beta receptor gene in Orthopoxviruses

In a recent study posted to bioRxiv*, researchers performed an analysis of molecular variance (AMOVA) in 59 haplotypes of the interferon (IFN)-alpha (α) /beta (β) receptor (IFNAR) gene, departing from monkeypox (MPX) virus (MPXV), camelpox virus, buffalopox virus, ectromelia virus, cowpox virus, rabbitpox virus, variola virus (VARV), and vaccinia virus.

Study: Population Genetics and Analysis of Molecular Variance (AMOVA) of the Monkeypox virus interferon-alpha-beta receptor gene and its evolutionary relationship with the Orthopoxvirus genus. Image Credit: Dotted Yeti/Shutterstock


Over time, Orthopoxviruses have gained evolutionary characteristics to adapt and limit host immunological responses. Immune-evasive strategies used by viruses could impact smallpox vaccinations through mechanisms that weaken effector actions for antiviral inhibition and confer immunoregulatory features.

About the study

In the present study, researchers performed a molecular variance analysis using 59 haplotypes of the IFNAR gene obtained from the NCBI (national biotechnology information center) database to improve understanding of the evolutionary aspects of the IFN gene and its probable behavior in MPX.

Haplotypes of the IFNAR genes of MPXV, camelpox virus, buffalopox virus, cowpox virus, rabbitpox virus, ectromelia virus, VARV, and vaccinia virus were retrieved from the NCBI database on 6 August 2022. Viral sequences were analyzed using genetic structural analyses to evaluate molecular variance, haplotypic diversity, genetic mismatch, incompatibility, genetic distance, demographic and spatial expansion, molecular diversity, and evolutionary divergence time.

Spectrum analytical tests (SFS) were conducted to estimate the demographical parameters of the frequency spectrum, and simulation analyses were performed. Molecular diversity indices were calculated based on sequence differences, and Theta estimators were used for homozygosity estimation based on the balance between mutations and genetic drift.

The Jukes and Singer method was used for estimating haplotype differences, and the Kimura and Tamura methods were used for estimating haplotype frequencies. The Tajima and Nei method was used to assess nucleotide differences in haplotypes and the rates of transitions, transversions, and insertion-deletion mutations. A minimum spanning network (MSN) tree was used for calculating distances between the operational taxonomic units (OTUs) of paired haplotype distance matrices.

Maximum probability modeling was used for reconstructing the gametic phase of multilocal genotypes, and locus-per-locus molecular variance analyses were performed. Neutrality tests such as the Ewens-Watterson homozygosis test, Ewens-Watterson-Slatkin test, Tajima selective neutrality test, and FS FU selective neutrality test were conducted.


Eight distinctive groups of orthopoxviruses were detected with variations and varying extent of structuring, being generally greater (with more insertion-deletion mutations) for the Cowpox virus. The Tajima and FS FU tests showed disagreements between the π and φ estimates, indicative of no population expansion of all viruses except for the cowpox virus.

High genomic divergence due to mutations and extensive structuring was observed among five groups (cowpox, camelpox, MPX, variola, and vaccinia) which could be due to intermediate haplotype loss among generations, probably associated with gene flow absence. The structuring levels indicated a discontinuous genetic divergence pattern between the studied groups, considering the potential existence of several stages of mutations, particularly in cowpox.

IFNAR gene mutations in the five groups were highly fixed (FST value 76%) based on genetic drift and the founding effect accompanying the behavior of intermediate haplotype loss and/or dispersion among viral generations. The genetic distance values were indicative of a continuous high divergence pattern for the study groups.

In addition, the differences among 59 haplotypes were reflected by the high numbers of inter-haplotype variations and hierarchies in all components of covariance: by the inter- and intra- differences at the group and individual levels. The AMOVA and genetic distance analyses showed significant findings for the tested virus groups with inter-group and intra-group variation components of 25% and eight percent, respectively, indicative of high evolutionary divergence among the groups. No significant similarities were found for genetic evolutionary divergence time among all populations.

Theta estimators didn’t show uniformity in results across all methods, indicating no IFNAR conservation among the studied viruses. Haplotype polymorphisms denoted large variations (silent and rapid mutations) and genetic diversity in the products of proteins of the studied orthopoxviruses, increasing the difficulty of developing molecular targets for drug and vaccine development. The findings indicated that the IFNAR gene may not effectively suppress viral infections.

Fewer molecular diversities were observed for the ectromelia virus, rabbitpox virus, and buffalopox virus. Tau variations and incompatibility analyses showed significant divergence, especially between the MPXV, cowpox virus, and camelpox virus groups based on the ancestral population sizes and the non-constant mutational rates.


Overall, the study findings showed high haplotype diversity, with increased insertion-deletion mutations, transversions, and transitions, for five viral groups with marginal expansions of viral populations. The estimators indicated a lack of IFNAR gene (and its protein product) conservation among viruses, underpinning the usage of neutralizing antibody-based therapies and developing novel drugs that could function as effective adjuvants for the IFNAR gene.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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