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Evolutionary footprint of epistasis.

ABSTRACT: Variation of an inherited trait across a population cannot be explained by additive contributions of relevant genes, due to epigenetic effects and biochemical interactions (epistasis). Detecting epistasis in genomic data still represents a significant challenge that requires a better understanding of epistasis from the mechanistic point of view. Using a standard Wright-Fisher model of bi-allelic asexual population, we study how compensatory epistasis affects the process of adaptation. The main result is a universal relationship between four haplotype frequencies of a single site pair in a genome, which depends only on the epistasis strength of the pair defined regarding Darwinian fitness. We demonstrate the existence, at any time point, of a quasi-equilibrium between epistasis and disorder (entropy) caused by random genetic drift and mutation. We verify the accuracy of these analytic results by Monte-Carlo simulation over a broad range of parameters, including the topology of the interacting network. Thus, epistasis assists the evolutionary transit through evolutionary hurdles leaving marks at the level of haplotype disequilibrium. The method allows determining selection coefficient for each site and the epistasis strength of each pair from a sequence set. The resulting ability to detect clusters of deleterious mutation close to full compensation is essential for biomedical applications. These findings help to understand the role of epistasis in multiple compensatory mutations in viral resistance to antivirals and immune response.

SUBMITTER: Pedruzzi G

PROVIDER: S-EPMC6177197 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Evolutionary footprint of epistasis.

Pedruzzi Gabriele G Barlukova Ayuna A Rouzine Igor M IM

PLoS computational biology 20180917 9

Variation of an inherited trait across a population cannot be explained by additive contributions of relevant genes, due to epigenetic effects and biochemical interactions (epistasis). Detecting epistasis in genomic data still represents a significant challenge that requires a better understanding of epistasis from the mechanistic point of view. Using a standard Wright-Fisher model of bi-allelic asexual population, we study how compensatory epistasis affects the process of adaptation. The main r ...[more]

PMID: 30222748

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Project description:The spike protein on sarbecovirus virions contains two external, protruding domains: an N-terminal domain (NTD) with unclear function and a C-terminal domain (CTD) that binds the host receptor, allowing for viral entry and infection. While the CTD is well studied for therapeutic interventions, the role of the NTD is far less well understood for many coronaviruses. Here, we demonstrate that the spike NTD from SARS-CoV-2 and other sarbecoviruses binds to unidentified glycans in vitro similarly to other members of the Coronaviridae family. We also show that these spike NTD (S-NTD) proteins adhere to Calu3 cells, a human lung cell line, although the biological relevance of this is unclear. In contrast to what has been shown for Middle East respiratory syndrome coronavirus (MERS-CoV), which attaches sialic acids during cell entry, sialic acids present on Calu3 cells inhibited sarbecovirus infection. Therefore, while sarbecoviruses can interact with cell surface glycans similarly to other coronaviruses, their reliance on glycans for entry is different from that of other respiratory coronaviruses, suggesting sarbecoviruses and MERS-CoV have adapted to different cell types, tissues, or hosts during their divergent evolution. Our findings provide important clues for further exploring the biological functions of sarbecovirus glycan binding and adds to our growing understanding of the complex forces that shape coronavirus spike evolution. IMPORTANCE Spike N-terminal domains (S-NTD) of sarbecoviruses are highly diverse; however, their function remains largely understudied compared with the receptor-binding domains (RBD). Here, we show that sarbecovirus S-NTD can be phylogenetically clustered into five clades and exhibit various levels of glycan binding in vitro. We also show that, unlike some coronaviruses, including MERS-CoV, sialic acids present on the surface of Calu3, a human lung cell culture, inhibit SARS-CoV-2 and other sarbecoviruses. These results suggest that while glycan binding might be an ancestral trait conserved across different coronavirus families, the functional outcome during infection can vary, reflecting divergent viral evolution. Our results expand our knowledge on the biological functions of the S-NTD across diverse sarbecoviruses and provide insight on the evolutionary history of coronavirus spike.

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Evolutionary footprint of epistasis.

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Evolutionary footprint of epistasis.

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