Cargando…

Local fitness landscape of the green fluorescent protein

Fitness landscapes1,2, depictions of how genotypes manifest at the phenotypic level, form the basis for our understanding of many areas of biology2–7 yet their properties remain elusive. Studies addressing this issue often consider specific genes and their function as proxy for fitness2,4, experimen...

Descripción completa

Detalles Bibliográficos
Autores principales: Sarkisyan, Karen S., Bolotin, Dmitry A., Meer, Margarita V., Usmanova, Dinara R., Mishin, Alexander S., Sharonov, George V., Ivankov, Dmitry N., Bozhanova, Nina G., Baranov, Mikhail S., Soylemez, Onuralp, Bogatyreva, Natalya S., Vlasov, Peter K., Egorov, Evgeny S., Logacheva, Maria D., Kondrashov, Alexey S., Chudakov, Dmitry M., Putintseva, Ekaterina V., Mamedov, Ilgar Z., Tawfik, Dan S., Lukyanov, Konstantin A., Kondrashov, Fyodor A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968632/
https://www.ncbi.nlm.nih.gov/pubmed/27193686
http://dx.doi.org/10.1038/nature17995
_version_ 1782445690099597312
author Sarkisyan, Karen S.
Bolotin, Dmitry A.
Meer, Margarita V.
Usmanova, Dinara R.
Mishin, Alexander S.
Sharonov, George V.
Ivankov, Dmitry N.
Bozhanova, Nina G.
Baranov, Mikhail S.
Soylemez, Onuralp
Bogatyreva, Natalya S.
Vlasov, Peter K.
Egorov, Evgeny S.
Logacheva, Maria D.
Kondrashov, Alexey S.
Chudakov, Dmitry M.
Putintseva, Ekaterina V.
Mamedov, Ilgar Z.
Tawfik, Dan S.
Lukyanov, Konstantin A.
Kondrashov, Fyodor A.
author_facet Sarkisyan, Karen S.
Bolotin, Dmitry A.
Meer, Margarita V.
Usmanova, Dinara R.
Mishin, Alexander S.
Sharonov, George V.
Ivankov, Dmitry N.
Bozhanova, Nina G.
Baranov, Mikhail S.
Soylemez, Onuralp
Bogatyreva, Natalya S.
Vlasov, Peter K.
Egorov, Evgeny S.
Logacheva, Maria D.
Kondrashov, Alexey S.
Chudakov, Dmitry M.
Putintseva, Ekaterina V.
Mamedov, Ilgar Z.
Tawfik, Dan S.
Lukyanov, Konstantin A.
Kondrashov, Fyodor A.
author_sort Sarkisyan, Karen S.
collection PubMed
description Fitness landscapes1,2, depictions of how genotypes manifest at the phenotypic level, form the basis for our understanding of many areas of biology2–7 yet their properties remain elusive. Studies addressing this issue often consider specific genes and their function as proxy for fitness2,4, experimentally assessing the impact on function of single mutations and their combinations in a specific sequence2,5,8–15 or in different sequences2,3,5,16–18. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here, we chart an extensive region of the local fitness landscape of the green fluorescent protein from Aequorea victoria (avGFP) by measuring the native function, fluorescence, of tens of thousands of derivative genotypes of avGFP. We find that its fitness landscape is narrow, with half of genotypes with two mutations showing reduced fluorescence and half of genotypes with five mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations arising mostly through the cumulative impact of slightly deleterious mutations causing a threshold-like decrease of protein stability and concomitant loss of fluorescence. A model of orthologous sequence divergence spanning hundreds of millions of years predicted the extent of epistasis in our data, indicating congruence between the fitness landscape properties at the local and global scales. The characterization of the local fitness landscape of avGFP has important implications for a number of fields including molecular evolution, population genetics and protein design.
format Online
Article
Text
id pubmed-4968632
institution National Center for Biotechnology Information
language English
publishDate 2016
record_format MEDLINE/PubMed
spelling pubmed-49686322016-11-11 Local fitness landscape of the green fluorescent protein Sarkisyan, Karen S. Bolotin, Dmitry A. Meer, Margarita V. Usmanova, Dinara R. Mishin, Alexander S. Sharonov, George V. Ivankov, Dmitry N. Bozhanova, Nina G. Baranov, Mikhail S. Soylemez, Onuralp Bogatyreva, Natalya S. Vlasov, Peter K. Egorov, Evgeny S. Logacheva, Maria D. Kondrashov, Alexey S. Chudakov, Dmitry M. Putintseva, Ekaterina V. Mamedov, Ilgar Z. Tawfik, Dan S. Lukyanov, Konstantin A. Kondrashov, Fyodor A. Nature Article Fitness landscapes1,2, depictions of how genotypes manifest at the phenotypic level, form the basis for our understanding of many areas of biology2–7 yet their properties remain elusive. Studies addressing this issue often consider specific genes and their function as proxy for fitness2,4, experimentally assessing the impact on function of single mutations and their combinations in a specific sequence2,5,8–15 or in different sequences2,3,5,16–18. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here, we chart an extensive region of the local fitness landscape of the green fluorescent protein from Aequorea victoria (avGFP) by measuring the native function, fluorescence, of tens of thousands of derivative genotypes of avGFP. We find that its fitness landscape is narrow, with half of genotypes with two mutations showing reduced fluorescence and half of genotypes with five mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations arising mostly through the cumulative impact of slightly deleterious mutations causing a threshold-like decrease of protein stability and concomitant loss of fluorescence. A model of orthologous sequence divergence spanning hundreds of millions of years predicted the extent of epistasis in our data, indicating congruence between the fitness landscape properties at the local and global scales. The characterization of the local fitness landscape of avGFP has important implications for a number of fields including molecular evolution, population genetics and protein design. 2016-05-11 /pmc/articles/PMC4968632/ /pubmed/27193686 http://dx.doi.org/10.1038/nature17995 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Sarkisyan, Karen S.
Bolotin, Dmitry A.
Meer, Margarita V.
Usmanova, Dinara R.
Mishin, Alexander S.
Sharonov, George V.
Ivankov, Dmitry N.
Bozhanova, Nina G.
Baranov, Mikhail S.
Soylemez, Onuralp
Bogatyreva, Natalya S.
Vlasov, Peter K.
Egorov, Evgeny S.
Logacheva, Maria D.
Kondrashov, Alexey S.
Chudakov, Dmitry M.
Putintseva, Ekaterina V.
Mamedov, Ilgar Z.
Tawfik, Dan S.
Lukyanov, Konstantin A.
Kondrashov, Fyodor A.
Local fitness landscape of the green fluorescent protein
title Local fitness landscape of the green fluorescent protein
title_full Local fitness landscape of the green fluorescent protein
title_fullStr Local fitness landscape of the green fluorescent protein
title_full_unstemmed Local fitness landscape of the green fluorescent protein
title_short Local fitness landscape of the green fluorescent protein
title_sort local fitness landscape of the green fluorescent protein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968632/
https://www.ncbi.nlm.nih.gov/pubmed/27193686
http://dx.doi.org/10.1038/nature17995
work_keys_str_mv AT sarkisyankarens localfitnesslandscapeofthegreenfluorescentprotein
AT bolotindmitrya localfitnesslandscapeofthegreenfluorescentprotein
AT meermargaritav localfitnesslandscapeofthegreenfluorescentprotein
AT usmanovadinarar localfitnesslandscapeofthegreenfluorescentprotein
AT mishinalexanders localfitnesslandscapeofthegreenfluorescentprotein
AT sharonovgeorgev localfitnesslandscapeofthegreenfluorescentprotein
AT ivankovdmitryn localfitnesslandscapeofthegreenfluorescentprotein
AT bozhanovaninag localfitnesslandscapeofthegreenfluorescentprotein
AT baranovmikhails localfitnesslandscapeofthegreenfluorescentprotein
AT soylemezonuralp localfitnesslandscapeofthegreenfluorescentprotein
AT bogatyrevanatalyas localfitnesslandscapeofthegreenfluorescentprotein
AT vlasovpeterk localfitnesslandscapeofthegreenfluorescentprotein
AT egorovevgenys localfitnesslandscapeofthegreenfluorescentprotein
AT logachevamariad localfitnesslandscapeofthegreenfluorescentprotein
AT kondrashovalexeys localfitnesslandscapeofthegreenfluorescentprotein
AT chudakovdmitrym localfitnesslandscapeofthegreenfluorescentprotein
AT putintsevaekaterinav localfitnesslandscapeofthegreenfluorescentprotein
AT mamedovilgarz localfitnesslandscapeofthegreenfluorescentprotein
AT tawfikdans localfitnesslandscapeofthegreenfluorescentprotein
AT lukyanovkonstantina localfitnesslandscapeofthegreenfluorescentprotein
AT kondrashovfyodora localfitnesslandscapeofthegreenfluorescentprotein