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Epistatic hotspots organize antibody fitness landscape and boost evolvability.

作者信息

Schulz Steven, Tan Timothy J C, Wu Nicholas C, Wang Shenshen

机构信息

Department of Physics and Astronomy, University of California, Los Angeles, CA 90095.

Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

出版信息

Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2413884122. doi: 10.1073/pnas.2413884122. Epub 2025 Jan 8.


DOI:10.1073/pnas.2413884122
PMID:39773024
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11745389/
Abstract

The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence-function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype. It is unclear to what extent local topography of a real epistatic landscape represents its global shape. Here, we demonstrate that epistatic landscapes can be heterogeneously rugged and this heterogeneity may render biomolecules more evolvable. By characterizing a multipeaked fitness landscape of a SARS-CoV-2 antibody mutant library, we show that heterogeneous ruggedness arises from sparse epistatic hotspots, whose mutation impacts the fitness effect of numerous sequence sites. Surprisingly, mutating an epistatic hotspot may enhance, rather than reduce, the accessibility of the fittest genotype, while increasing the overall ruggedness. Further, migratory constraints in real space alleviate mutational constraints in sequence space, which not only diversify direct paths taken but may also turn a road-blocking fitness peak into a stepping stone leading toward the global optimum. Our results suggest that a hierarchy of epistatic hotspots may organize the fitness landscape in such a way that path-orienting ruggedness confers global smoothness.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/2a7a470f0c5e/pnas.2413884122fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/093f51327b7f/pnas.2413884122fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/d3fbb8d78d49/pnas.2413884122fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/e6b5d97de462/pnas.2413884122fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/12f2c1e59aec/pnas.2413884122fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/6911e6bf7fbd/pnas.2413884122fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/61ff4e3feb57/pnas.2413884122fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/2a7a470f0c5e/pnas.2413884122fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/093f51327b7f/pnas.2413884122fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/d3fbb8d78d49/pnas.2413884122fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/e6b5d97de462/pnas.2413884122fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/12f2c1e59aec/pnas.2413884122fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/6911e6bf7fbd/pnas.2413884122fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/61ff4e3feb57/pnas.2413884122fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4b2/11745389/2a7a470f0c5e/pnas.2413884122fig07.jpg

相似文献

[1]
Epistatic hotspots organize antibody fitness landscape and boost evolvability.

Proc Natl Acad Sci U S A. 2025-1-14

[2]
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[3]
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[5]
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引用本文的文献

[1]
Convergent and clonotype-enriched mutations in the light chain drive affinity maturation of a public antibody.

bioRxiv. 2025-3-10

本文引用的文献

[1]
Epistasis facilitates functional evolution in an ancient transcription factor.

Elife. 2024-5-20

[2]
Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution.

PLoS Pathog. 2023-12

[3]
An oncogenic phenoscape of colonic stem cell polarization.

Cell. 2023-12-7

[4]
A rugged yet easily navigable fitness landscape.

Science. 2023-11-24

[5]
Rational design of a booster vaccine against COVID-19 based on antigenic distance.

Cell Host Microbe. 2023-8-9

[6]
Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody.

Elife. 2023-1-10

[7]
The structure of genotype-phenotype maps makes fitness landscapes navigable.

Nat Ecol Evol. 2022-11

[8]
Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies.

Elife. 2021-9-7

[9]
Global epistasis emerges from a generic model of a complex trait.

Elife. 2021-3-29

[10]
Emergence and propagation of epistasis in metabolic networks.

Elife. 2021-2-2

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