Nature, volume 533, issue 7603, pages 397-401
Local fitness landscape of the green fluorescent protein
Karen S. Sarkisyan
1, 2, 3, 4, 5
,
Dmitry A. Bolotin
1, 3
,
Margarita V Meer
4, 5
,
Dinara R Usmanova
4, 5, 6
,
Alexander S. Mishin
1, 2
,
George V. Sharonov
1, 7
,
DMITRY N. IVANKOV
4, 5, 8
,
Nina G Bozhanova
1
,
Mikhail S Baranov
1, 9
,
Onuralp Soylemez
4, 5
,
NATALYA S. BOGATYREVA
4, 5, 8
,
Peter K Vlasov
4, 5
,
Evgeny S. Egorov
1
,
Maria D. Logacheva
9, 10, 11
,
Alexey S. Kondrashov
11, 12
,
Dmitry M. CHUDAKOV
1, 3
,
Ekaterina V. Putintseva
1, 3
,
Ilgar Z. Mamedov
1, 3
,
Dan S Tawfik
13
,
Konstantin A. Lukyanov
1, 2
,
Fyodor A. Kondrashov
4, 5, 14
2
Nizhny Novgorod State Medical Academy, Nizhny Novgorod, Russia
|
3
Central European Institute of Technology, Masaryk University, Brno, Czech republic
|
7
Faculty of Medicine, Moscow State University, Moscow, Russia
|
9
Pirogov Russian National Research Medical University, Moscow, Russia
|
11
Department of Bioinformatics and Bioengineering, Moscow State University, Moscow, Russia
|
Publication type: Journal Article
Publication date: 2016-05-10
PubMed ID:
27193686
Multidisciplinary
Abstract
Comprehensive genotype–phenotype mapping of the green fluorescent protein shows that the local fitness peak is narrow, shaped by a high prevalence of epistatic interactions, providing for the loss of fluorescence when the joint effect of mutations exceeds a threshold. Fyodor Kondrashov and colleagues report comprehensive genotype–phenotype mapping across an entire protein, based on analysis of the fitness landscape of green fluorescent protein (GFP) using a molecular barcoding and sequencing approach. They find that the fitness landscape is characterized by locally narrow regions, combined with a high prevalence of epistatic interactions, providing for the loss of fluorescence when the joint effect of mutations exceeds a threshold. Fitness landscapes1,2 depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology2,3,4,5,6,7, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness2,4, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence2,5,8,9,10,11,12,13,14,15 or in different sequences2,3,5,16,17,18. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here we visualize 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 show that the fitness landscape of avGFP is narrow, with 3/4 of the derivatives with a single mutation showing reduced fluorescence and half of the derivatives with four mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations and mostly occurred through the cumulative effect of slightly deleterious mutations causing a threshold-like decrease in protein stability and a 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 several fields including molecular evolution, population genetics and protein design.
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Sarkisyan K. S. et al. Local fitness landscape of the green fluorescent protein // Nature. 2016. Vol. 533. No. 7603. pp. 397-401.
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Sarkisyan K. S., Bolotin D. A., Meer M. V., Usmanova D. R., Mishin A. S., Sharonov G. V., IVANKOV D. N., Bozhanova N. G., Baranov M. S., Soylemez O., BOGATYREVA N. S., Vlasov P. K., Egorov E. S., Logacheva M. D., Kondrashov A. S., CHUDAKOV D. M., Putintseva E. V., Mamedov I. Z., Tawfik D. S., Lukyanov K. A., Kondrashov F. A. Local fitness landscape of the green fluorescent protein // Nature. 2016. Vol. 533. No. 7603. pp. 397-401.
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TY - JOUR
DO - 10.1038/nature17995
UR - https://doi.org/10.1038/nature17995
TI - Local fitness landscape of the green fluorescent protein
T2 - Nature
AU - Sarkisyan, Karen S.
AU - Bolotin, Dmitry A.
AU - Meer, Margarita V
AU - Usmanova, Dinara R
AU - Mishin, Alexander S.
AU - Sharonov, George V.
AU - IVANKOV, DMITRY N.
AU - Bozhanova, Nina G
AU - Baranov, Mikhail S
AU - Soylemez, Onuralp
AU - BOGATYREVA, NATALYA S.
AU - Vlasov, Peter K
AU - Egorov, Evgeny S.
AU - Logacheva, Maria D.
AU - Kondrashov, Alexey S.
AU - CHUDAKOV, Dmitry M.
AU - Putintseva, Ekaterina V.
AU - Mamedov, Ilgar Z.
AU - Tawfik, Dan S
AU - Lukyanov, Konstantin A.
AU - Kondrashov, Fyodor A.
PY - 2016
DA - 2016/05/10
PB - Springer Nature
SP - 397-401
IS - 7603
VL - 533
PMID - 27193686
SN - 0028-0836
SN - 1476-4687
ER -
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@article{2016_Sarkisyan,
author = {Karen S. Sarkisyan and Dmitry A. Bolotin and Margarita V Meer and Dinara R Usmanova and Alexander S. Mishin and George V. Sharonov and DMITRY N. IVANKOV and Nina G Bozhanova and Mikhail S Baranov and Onuralp Soylemez and NATALYA S. BOGATYREVA and Peter K Vlasov and Evgeny S. Egorov and Maria D. Logacheva and Alexey S. Kondrashov and Dmitry M. CHUDAKOV and Ekaterina V. Putintseva and Ilgar Z. Mamedov and Dan S Tawfik and Konstantin A. Lukyanov and Fyodor A. Kondrashov},
title = {Local fitness landscape of the green fluorescent protein},
journal = {Nature},
year = {2016},
volume = {533},
publisher = {Springer Nature},
month = {may},
url = {https://doi.org/10.1038/nature17995},
number = {7603},
pages = {397--401},
doi = {10.1038/nature17995}
}
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Sarkisyan, Karen S., et al. “Local fitness landscape of the green fluorescent protein.” Nature, vol. 533, no. 7603, May. 2016, pp. 397-401. https://doi.org/10.1038/nature17995.
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