Analyses of allele age and fitness impact reveal human beneficial alleles to be older than neutral controls DOI Creative Commons
Alyssa M. Pivirotto, Alexander Platt, Ravi Patel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 10, 2023

Abstract A classic population genetic prediction is that alleles experiencing directional selection should swiftly traverse allele frequency space, leaving detectable reductions in variation linked regions. However, despite this expectation, identifying clear footprints of beneficial passage has proven to be surprisingly challenging. We addressed the basic premise underlying expectation by estimating ages large numbers and deleterious a human genomic data set. Deleterious were found young, on average, given their frequency. older average than non-coding, non-regulatory same This finding not consistent with instead indicates some type balancing selection. Among derived alleles, those fixed show higher local recombination rates still segregating, model which new experience an initial period due linkage disequilibrium recessive alleles. Alleles ultimately fix following will leave modest ‘soft’ sweep impact variation, overall paucity species-wide ‘hard’ sweeps genomes. Impact Statement Analyses age evolutionary reveal are often neutral controls, suggesting role for adaptation.

Language: Английский

SeqDance: A Protein Language Model for Representing Protein Dynamic Properties DOI Creative Commons
Chao Hou, Yufeng Shen

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 15, 2024

Abstract Proteins perform their functions by folding amino acid sequences into dynamic structural ensembles. Despite the important role of protein dynamics, complexity and absence efficient representation methods have limited integration studies on function mutation fitness, especially in deep learning applications. To address this, we present SeqDance, a language model designed to learn properties directly from sequence alone. SeqDance is pre-trained biophysical derived over 30,400 molecular dynamics trajectories 28,600 normal mode analyses. Our results show that effectively captures local interactions, co-movement patterns, global conformational features, even for proteins lacking homologs pre-training set. Additionally, showed enhances prediction fitness landscapes, disorder-to-order transition binding regions, phase-separating proteins. By sequence, complements conventional evolution- static structure-based methods, offering new insights behavior function.

Language: Английский

Citations

3
Binding Evolution of the Dengue Virus Envelope Against DC-SIGN: A Combined Approach of Phylogenetics and Molecular Dynamics Analyses Over 30 Years of Dengue Virus in Brazil DOI
André Berndt Penteado, Geovani de Oliveira Ribeiro, Emerson Luiz Lima Araújo

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(11), P. 168577 - 168577

Published: April 18, 2024

Language: Английский

Citations

2
Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory DOI
Paul Campitelli, Tushar Modi, S. Banu Ozkan

et al.

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 7, 2024

We report a new approach that combines molecular dynamics trajectories with time-dependent linear response theory to compute the time evolution of residue fluctuation responses force perturbations exerted at functional sites. Applying this TEM-1 beta-lactamase, we observe time-resolved profiles allosteric sites active are distinct from those non-allosteric residues. Using Fourier transformations, convert domain frequency and demonstrate space representation perturbation can capture mutational behavior each site when applied deep sequencing data. Furthermore, show classification models built on accurately identify distal positions regulate antibiotic resistance. These findings provide insights into contributions specific residues resistance-encoded in highlight importance identifying mutations, opening avenues for potential characterization additional without extensive computational simulations.

Language: Английский

Citations

1
Some mechanistic underpinnings of molecular adaptations of SARS-COV-2 spike protein by integrating candidate adaptive polymorphisms with protein dynamics DOI Creative Commons
Nicholas J. Ose, Paul Campitelli, Tushar Modi

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Nov. 6, 2023

We integrate evolutionary predictions based on the neutral theory of molecular evolution with protein dynamics to generate mechanistic insight into adaptations SARS-COV-2 spike (S) protein. With this approach, we first identified candidate adaptive polymorphisms (CAPs) SARS-CoV-2 S and assessed impact these CAPs through analysis. Not only have found that frequently overlap well-known functional sites, but also, using several different dynamics-based metrics, reveal critical allosteric interplay between binding sites human ACE2 (hACE2) interact far differently hACE2 site residues in open conformation compared closed form. In particular, CAP control state, suggesting an binding. also explored characteristic mutations strains find dynamic hallmarks potential effects future mutations. Our analyses Delta strain-specific variants non-additive (i.e., epistatic) interactions whereas less pathogenic Omicron mostly additive Finally, our analysis suggests novel observed strain epistatically help escape antibody

Language: Английский

Citations

2
Biophysics at the dawn of exascale computers DOI Open Access
Abhishek Singharoy, Alberto Pérez,

Chris Chipot

et al.

Biophysical Journal, Journal Year: 2023, Volume and Issue: 122(14), P. E1 - E2

Published: July 1, 2023

Language: Английский

Citations

1
Analyses of allele age and fitness impact reveal human beneficial alleles to be older than neutral controls DOI Creative Commons
Alyssa M. Pivirotto, Alexander Platt, Ravi Patel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 10, 2023

Abstract A classic population genetic prediction is that alleles experiencing directional selection should swiftly traverse allele frequency space, leaving detectable reductions in variation linked regions. However, despite this expectation, identifying clear footprints of beneficial passage has proven to be surprisingly challenging. We addressed the basic premise underlying expectation by estimating ages large numbers and deleterious a human genomic data set. Deleterious were found young, on average, given their frequency. older average than non-coding, non-regulatory same This finding not consistent with instead indicates some type balancing selection. Among derived alleles, those fixed show higher local recombination rates still segregating, model which new experience an initial period due linkage disequilibrium recessive alleles. Alleles ultimately fix following will leave modest ‘soft’ sweep impact variation, overall paucity species-wide ‘hard’ sweeps genomes. Impact Statement Analyses age evolutionary reveal are often neutral controls, suggesting role for adaptation.

Language: Английский

Citations

0