Epistatic drift causes gradual decay of predictability in protein evolution

Science, Journal Year: 2022, Volume and Issue: 376(6595), P. 823 - 830

Published: May 19, 2022

Epistatic interactions can make the outcomes of evolution unpredictable, but no comprehensive data are available on extent and temporal dynamics changes in effects mutations as protein sequences evolve. Here, we use phylogenetic deep mutational scanning to measure functional effect every possible amino acid mutation a series ancestral extant steroid receptor DNA binding domains. Across 700 million years evolution, epistatic caused most become decorrelated from their initial windows evolutionary accessibility open close transiently. Most changed gradually without bias at rates that were largely constant across time, indicating neutral process by many weak interactions. Our findings show drift inexorably into contingency unpredictability, is statistically predictable, given sufficient experimental data.

Language: Английский

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Functional differences between rodent and human PD-1 linked to evolutionary divergence

Science Immunology, Journal Year: 2025, Volume and Issue: 10(103)

Published: Jan. 3, 2025

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and share only 59.6% amino acid identity. Here, we found that more than PD-1, owing to stronger interactions with ligands PD-L1 PD-L2 efficient recruitment effector phosphatase Shp2. In a melanoma model adoptively transferred T cells, humanization intracellular domain disrupted antitumor activity CD8

Language: Английский

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Antibody optimization enabled by artificial intelligence predictions of binding affinity and naturalness

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 17, 2022

Abstract Traditional antibody optimization approaches involve screening a small subset of the available sequence space, often resulting in drug candidates with suboptimal binding affinity, developability or immunogenicity. Based on two distinct antibodies, we demonstrate that deep contextual language models trained high-throughput affinity data can quantitatively predict unseen variants. These variants span K D range three orders magnitude over large mutational space. Our reveal strong epistatic effects, which highlight need for intelligent approaches. In addition, introduce modeling “naturalness”, metric scores similarity to natural immunoglobulins. We show naturalness is associated measures and immunogenicity, it be optimized alongside using genetic algorithm. This approach promises accelerate improve engineering, may increase success rate developing novel related candidates.

Language: Английский

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In vivo hypermutation and continuous evolution

Nature Reviews Methods Primers, Journal Year: 2022, Volume and Issue: 2(1)

Published: May 19, 2022

Language: Английский

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A morphological basis for path-dependent evolution of visual systems

Science, Journal Year: 2024, Volume and Issue: 383(6686), P. 983 - 987

Published: Feb. 29, 2024

Path dependence influences macroevolutionary predictability by constraining potential outcomes after critical evolutionary junctions. Although it has been demonstrated in laboratory experiments, path is difficult to demonstrate natural systems because of a lack independent replicates. Here, we show that two types distributed visual recently evolved twice within chitons, demonstrating rapid and path-dependent evolution complex trait. The type system chiton lineage can evolve constrained the number openings for sensory nerves its shell plates. Lineages with more thousands eyespots, whereas those fewer hundreds eyes. These shaped are both deterministic stochastic possibilities restricted yet not entirely predictable.

Language: Английский

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Protein quality control is a master modulator of molecular evolution in bacteria

Genome Biology and Evolution, Journal Year: 2025, Volume and Issue: 17(2)

Published: Jan. 22, 2025

Abstract The bacterial protein quality control (PQC) network comprises a set of genes that promote proteostasis (proteome homeostasis) through proper folding and function via chaperones, proteases, translational machinery. It participates in vital cellular processes influences organismal development evolution. In this review, we examine the mechanistic bases for how PQC molecular We discuss relevance components to contemporary issues evolutionary biology including epistasis, evolvability, navigability space. other areas where affects aspects evolution physiology, host-parasite interactions. More generally, demonstrate study systems can aid broader efforts understand relationship between genotype phenotype across biosphere.

Language: Английский

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Prediction of designer-recombinases for DNA editing with generative deep learning

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Dec. 27, 2022

Site-specific tyrosine-type recombinases are effective tools for genome engineering, with the first engineered variants having demonstrated therapeutic potential. So far, adaptation to new DNA target site selectivity of designer-recombinases has been achieved mostly through iterative cycles directed molecular evolution. While effective, evolution methods laborious and time consuming. Here we present RecGen (Recombinase Generator), an algorithm intelligent generation designer-recombinases. We gather sequence information over one million Cre-like recombinase sequences evolved 89 different sites which train Conditional Variational Autoencoders generation. Experimental validation demonstrates that can predict activity on novel target-sites, indicating is useful accelerate development future

Language: Английский

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Molecular determinants of protein evolvability

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(9), P. 751 - 760

Published: June 15, 2023

Language: Английский

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The mutation effect reaction norm (mu‐rn) highlights environmentally dependent mutation effects and epistatic interactions

Evolution, Journal Year: 2022, Volume and Issue: 76(S1), P. 37 - 48

Published: Jan. 6, 2022

Since the modern synthesis, fitness effects of mutations and epistasis have been central yet provocative concepts in evolutionary population genetics. Studies how interactions between parcels genetic information can change as a function environmental context added layer complexity to these discussions. Here, I introduce "mutation effect reaction norm" (Mu-RN), new instrument through which one analyze phenotypic consequences across contexts. It embodies fusion measurements with norm, classic depiction performance genotypes environments. demonstrate utility Mu-RN case study: signature "compensatory ratchet" mutation that undermines reverse evolution antimicrobial resistance. In closing, argue norm may help us resolve dynamism unpredictability evolution, implications for theoretical biology, biotechnology, public health.

Language: Английский

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Simple mechanisms for the evolution of protein complexity

Protein Science, Journal Year: 2022, Volume and Issue: 31(11)

Published: Sept. 15, 2022

Abstract Proteins are tiny models of biological complexity: specific interactions among their many amino acids cause proteins to fold into elaborate structures, assemble with other higher‐order complexes, and change functions structures upon binding molecules. These complex features classically thought evolve via long gradual trajectories driven by persistent natural selection. But a growing body evidence from biochemistry, protein engineering, molecular evolution shows that naturally occurring often exist at or near the genetic edge multimerization, allostery, even new folds, so just one few mutations can trigger acquisition these properties. sudden transitions occur because physical properties underlie present in simpler as fortuitous by‐products architecture. Moreover, be encoded huge arrays sequences, they accessible different starting points possible paths. Because bridges both short numerous, random chance join selection key factor explaining complexity.

Language: Английский

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