Dataset Information

Extreme evolutionary conservation of functionally important regions in H1N1 influenza proteome.

ABSTRACT: The H1N1 subtype of influenza A virus has caused two of the four documented pandemics and is responsible for seasonal epidemic outbreaks, presenting a continuous threat to public health. Co-circulating antigenically divergent influenza strains significantly complicates vaccine development and use. Here, by combining evolutionary, structural, functional, and population information about the H1N1 proteome, we seek to answer two questions: (1) do residues on the protein surfaces evolve faster than the protein core residues consistently across all proteins that constitute the influenza proteome? and (2) in spite of the rapid evolution of surface residues in influenza proteins, are there any protein regions on the protein surface that do not evolve? To answer these questions, we first built phylogenetically-aware models of the patterns of surface and interior substitutions. Employing these models, we found a single coherent pattern of faster evolution on the protein surfaces that characterizes all influenza proteins. The pattern is consistent with the events of inter-species reassortment, the worldwide introduction of the flu vaccine in the early 80's, as well as the differences caused by the geographic origins of the virus. Next, we developed an automated computational pipeline to comprehensively detect regions of the protein surface residues that were 100% conserved over multiple years and in multiple host species. We identified conserved regions on the surface of 10 influenza proteins spread across all avian, swine, and human strains; with the exception of a small group of isolated strains that affected the conservation of three proteins. Surprisingly, these regions were also unaffected by genetic variation in the pandemic 2009 H1N1 viral population data obtained from deep sequencing experiments. Finally, the conserved regions were intrinsically related to the intra-viral macromolecular interaction interfaces. Our study may provide further insights towards the identification of novel protein targets for influenza antivirals.

SUBMITTER: Warren S

PROVIDER: S-EPMC3839886 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Extreme evolutionary conservation of functionally important regions in H1N1 influenza proteome.

Warren Samantha S Wan Xiu-Feng XF Conant Gavin G Korkin Dmitry D

PloS one 20131125 11

The H1N1 subtype of influenza A virus has caused two of the four documented pandemics and is responsible for seasonal epidemic outbreaks, presenting a continuous threat to public health. Co-circulating antigenically divergent influenza strains significantly complicates vaccine development and use. Here, by combining evolutionary, structural, functional, and population information about the H1N1 proteome, we seek to answer two questions: (1) do residues on the protein surfaces evolve faster than ...[more]

PMID: 24282564

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Project description:The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R?W, R?C, E?K, R?H, R?Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased ?-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

Project description:The landscape of the human genome consists of millions of short islands of conservation that are 100% conserved across multiple vertebrate genomes (termed "bricks"), the majority of which are located in noncoding regions. Several hundred thousand bricks are deeply conserved reaching the genomes of amphibians and fish. Deep phylogenetic conservation of noncoding DNA has been reported to be strongly associated with the presence of gene regulatory elements, introducing bricks as a proxy to the functional noncoding landscape of the human genome. Here, we report a significant overrepresentation of bricks in the promoters of transcription factors and developmental genes, where the high level of phylogenetic conservation correlates with an increase in brick overrepresentation. We also found that the presence of a brick dictates a predisposition to evolutionary constraint, with only 0.7% of the amniota brick central nucleotides being diverged within the primate lineage--an 11-fold reduction in the divergence rate compared with random expectation. Human single-nucleotide polymorphism (SNP) data explains only 3% of primate-specific variation in amniota bricks, thus arguing for a widespread fixation of brick mutations within the primate lineage and prior to human radiation. This variation, in turn, might have been utilized as a driving force for primate- and hominoid-specific adaptation. We also discovered a pronounced deviation from the evolutionary predisposition in the human lineage, with over 20-fold increase in the substitution rate at brick SNP sites over expected values. In addition, contrary to typical brick mutations, brick variation commonly encountered in the human population displays limited, if any, signatures of negative selection as measured by the minor allele frequency and population differentiation (F-statistical measure) measures. These observations argue for the plasticity of gene regulatory mechanisms in vertebrates--with evidence of strong purifying selection acting on the gene regulatory landscape of the human genome, where widespread advantageous mutations in putative regulatory elements are likely utilized in functional diversification and adaptation of species.

Dataset Information

Extreme evolutionary conservation of functionally important regions in H1N1 influenza proteome.

Publications

Extreme evolutionary conservation of functionally important regions in H1N1 influenza proteome.

Similar Datasets

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