Local fitness landscape of the green fluorescent protein

Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing t...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Karen S Sarkisyan [verfasserIn] Dmitry A Bolotin Margarita V Meer Dinara R Usmanova Alexander S Mishin George V Sharonov Dmitry N Ivankov Nina G Bozhanova Mikhail S Baranov Onuralp Soylemez Natalya S Bogatyreva Peter K Vlasov Evgeny S Egorov Maria D Logacheva Alexey S Kondrashov Dmitry M Chudakov Ekaterina V Putintseva Ilgar Z Mamedov Dan S Tawfik Konstantin A Lukyanov Fyodor A Kondrashov

Format:	Artikel
Sprache:	Englisch

Erschienen:	2016

Schlagwörter:	Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis

Übergeordnetes Werk:	Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 533(2016), 7603, Seite 397
Übergeordnetes Werk:	volume:533 ; year:2016 ; number:7603 ; pages:397

Links:	Volltext Link aufrufen Link aufrufen

DOI / URN:	10.1038/nature17995

Katalog-ID:	OLC1975207394

Internformat


LEADER	01000caa a2200265 4500
001	OLC1975207394
003	DE-627
005	20230714191636.0
007	tu
008	160609s2016 xx \|\|\|\|\| 00\| \|\|eng c
024	7		\|a 10.1038/nature17995 \|2 doi
028	5	2	\|a PQ20160610
035			\|a (DE-627)OLC1975207394
035			\|a (DE-599)GBVOLC1975207394
035			\|a (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0
035			\|a (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
082	0	4	\|a 070 \|a 500 \|q DNB
082	0	4	\|a 500 \|q AVZ
084			\|a BIODIV \|2 fid
100	0		\|a Karen S Sarkisyan \|e verfasserin \|4 aut
245	1	0	\|a Local fitness landscape of the green fluorescent protein
264		1	\|c 2016
336			\|a Text \|b txt \|2 rdacontent
337			\|a ohne Hilfsmittel zu benutzen \|b n \|2 rdamedia
338			\|a Band \|b nc \|2 rdacarrier
520			\|a Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.
650		4	\|a Proteins
650		4	\|a Genotype & phenotype
650		4	\|a Amino acids
650		4	\|a Fluorescence
650		4	\|a Mutation
650		4	\|a Mutagenesis
700	0		\|a Dmitry A Bolotin \|4 oth
700	0		\|a Margarita V Meer \|4 oth
700	0		\|a Dinara R Usmanova \|4 oth
700	0		\|a Alexander S Mishin \|4 oth
700	0		\|a George V Sharonov \|4 oth
700	0		\|a Dmitry N Ivankov \|4 oth
700	0		\|a Nina G Bozhanova \|4 oth
700	0		\|a Mikhail S Baranov \|4 oth
700	0		\|a Onuralp Soylemez \|4 oth
700	0		\|a Natalya S Bogatyreva \|4 oth
700	0		\|a Peter K Vlasov \|4 oth
700	0		\|a Evgeny S Egorov \|4 oth
700	0		\|a Maria D Logacheva \|4 oth
700	0		\|a Alexey S Kondrashov \|4 oth
700	0		\|a Dmitry M Chudakov \|4 oth
700	0		\|a Ekaterina V Putintseva \|4 oth
700	0		\|a Ilgar Z Mamedov \|4 oth
700	0		\|a Dan S Tawfik \|4 oth
700	0		\|a Konstantin A Lukyanov \|4 oth
700	0		\|a Fyodor A Kondrashov \|4 oth
773	0	8	\|i Enthalten in \|t Nature \|d London : Macmillan Publishers Limited, part of Springer Nature, 1869 \|g 533(2016), 7603, Seite 397 \|w (DE-627)129292834 \|w (DE-600)120714-3 \|w (DE-576)014473941 \|x 0028-0836 \|7 nnns
773	1	8	\|g volume:533 \|g year:2016 \|g number:7603 \|g pages:397
856	4	1	\|u http://dx.doi.org/10.1038/nature17995 \|3 Volltext
856	4	2	\|u http://www.ncbi.nlm.nih.gov/pubmed/27193686
856	4	2	\|u http://search.proquest.com/docview/1790506337
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_OLC
912			\|a FID-BIODIV
912			\|a SSG-OLC-PHY
912			\|a SSG-OLC-CHE
912			\|a SSG-OLC-MAT
912			\|a SSG-OLC-FOR
912			\|a SSG-OLC-SPO
912			\|a SSG-OLC-PHA
912			\|a SSG-OLC-DE-84
912			\|a SSG-OPC-FOR
912			\|a GBV_ILN_11
912			\|a GBV_ILN_22
912			\|a GBV_ILN_30
912			\|a GBV_ILN_40
912			\|a GBV_ILN_47
912			\|a GBV_ILN_55
912			\|a GBV_ILN_59
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_101
912			\|a GBV_ILN_110
912			\|a GBV_ILN_120
912			\|a GBV_ILN_154
912			\|a GBV_ILN_168
912			\|a GBV_ILN_170
912			\|a GBV_ILN_171
912			\|a GBV_ILN_211
912			\|a GBV_ILN_290
912			\|a GBV_ILN_294
912			\|a GBV_ILN_601
912			\|a GBV_ILN_647
912			\|a GBV_ILN_754
912			\|a GBV_ILN_2001
912			\|a GBV_ILN_2002
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2007
912			\|a GBV_ILN_2008
912			\|a GBV_ILN_2015
912			\|a GBV_ILN_2016
912			\|a GBV_ILN_2018
912			\|a GBV_ILN_2020
912			\|a GBV_ILN_2026
912			\|a GBV_ILN_2095
912			\|a GBV_ILN_2116
912			\|a GBV_ILN_2120
912			\|a GBV_ILN_2121
912			\|a GBV_ILN_2219
912			\|a GBV_ILN_2221
912			\|a GBV_ILN_2279
912			\|a GBV_ILN_2286
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4219
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4277
912			\|a GBV_ILN_4302
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4314
912			\|a GBV_ILN_4317
912			\|a GBV_ILN_4320
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 533 \|j 2016 \|e 7603 \|h 397

Indexfelder

author_variant	k s s kss
matchkey_str	article:00280836:2016----::oaftesadcpoterefur
hierarchy_sort_str	2016
publishDate	2016
allfields	10.1038/nature17995 doi PQ20160610 (DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Karen S Sarkisyan verfasserin aut Local fitness landscape of the green fluorescent protein 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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. Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis Dmitry A Bolotin oth Margarita V Meer oth Dinara R Usmanova oth Alexander S Mishin oth George V Sharonov oth Dmitry N Ivankov oth Nina G Bozhanova oth Mikhail S Baranov oth Onuralp Soylemez oth Natalya S Bogatyreva oth Peter K Vlasov oth Evgeny S Egorov oth Maria D Logacheva oth Alexey S Kondrashov oth Dmitry M Chudakov oth Ekaterina V Putintseva oth Ilgar Z Mamedov oth Dan S Tawfik oth Konstantin A Lukyanov oth Fyodor A Kondrashov oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 533(2016), 7603, Seite 397 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:533 year:2016 number:7603 pages:397 http://dx.doi.org/10.1038/nature17995 Volltext http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 533 2016 7603 397
spelling	10.1038/nature17995 doi PQ20160610 (DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Karen S Sarkisyan verfasserin aut Local fitness landscape of the green fluorescent protein 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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. Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis Dmitry A Bolotin oth Margarita V Meer oth Dinara R Usmanova oth Alexander S Mishin oth George V Sharonov oth Dmitry N Ivankov oth Nina G Bozhanova oth Mikhail S Baranov oth Onuralp Soylemez oth Natalya S Bogatyreva oth Peter K Vlasov oth Evgeny S Egorov oth Maria D Logacheva oth Alexey S Kondrashov oth Dmitry M Chudakov oth Ekaterina V Putintseva oth Ilgar Z Mamedov oth Dan S Tawfik oth Konstantin A Lukyanov oth Fyodor A Kondrashov oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 533(2016), 7603, Seite 397 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:533 year:2016 number:7603 pages:397 http://dx.doi.org/10.1038/nature17995 Volltext http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 533 2016 7603 397
allfields_unstemmed	10.1038/nature17995 doi PQ20160610 (DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Karen S Sarkisyan verfasserin aut Local fitness landscape of the green fluorescent protein 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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. Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis Dmitry A Bolotin oth Margarita V Meer oth Dinara R Usmanova oth Alexander S Mishin oth George V Sharonov oth Dmitry N Ivankov oth Nina G Bozhanova oth Mikhail S Baranov oth Onuralp Soylemez oth Natalya S Bogatyreva oth Peter K Vlasov oth Evgeny S Egorov oth Maria D Logacheva oth Alexey S Kondrashov oth Dmitry M Chudakov oth Ekaterina V Putintseva oth Ilgar Z Mamedov oth Dan S Tawfik oth Konstantin A Lukyanov oth Fyodor A Kondrashov oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 533(2016), 7603, Seite 397 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:533 year:2016 number:7603 pages:397 http://dx.doi.org/10.1038/nature17995 Volltext http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 533 2016 7603 397
allfieldsGer	10.1038/nature17995 doi PQ20160610 (DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Karen S Sarkisyan verfasserin aut Local fitness landscape of the green fluorescent protein 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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. Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis Dmitry A Bolotin oth Margarita V Meer oth Dinara R Usmanova oth Alexander S Mishin oth George V Sharonov oth Dmitry N Ivankov oth Nina G Bozhanova oth Mikhail S Baranov oth Onuralp Soylemez oth Natalya S Bogatyreva oth Peter K Vlasov oth Evgeny S Egorov oth Maria D Logacheva oth Alexey S Kondrashov oth Dmitry M Chudakov oth Ekaterina V Putintseva oth Ilgar Z Mamedov oth Dan S Tawfik oth Konstantin A Lukyanov oth Fyodor A Kondrashov oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 533(2016), 7603, Seite 397 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:533 year:2016 number:7603 pages:397 http://dx.doi.org/10.1038/nature17995 Volltext http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 533 2016 7603 397
allfieldsSound	10.1038/nature17995 doi PQ20160610 (DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Karen S Sarkisyan verfasserin aut Local fitness landscape of the green fluorescent protein 2016 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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. Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis Dmitry A Bolotin oth Margarita V Meer oth Dinara R Usmanova oth Alexander S Mishin oth George V Sharonov oth Dmitry N Ivankov oth Nina G Bozhanova oth Mikhail S Baranov oth Onuralp Soylemez oth Natalya S Bogatyreva oth Peter K Vlasov oth Evgeny S Egorov oth Maria D Logacheva oth Alexey S Kondrashov oth Dmitry M Chudakov oth Ekaterina V Putintseva oth Ilgar Z Mamedov oth Dan S Tawfik oth Konstantin A Lukyanov oth Fyodor A Kondrashov oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 533(2016), 7603, Seite 397 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:533 year:2016 number:7603 pages:397 http://dx.doi.org/10.1038/nature17995 Volltext http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 533 2016 7603 397
language	English
source	Enthalten in Nature 533(2016), 7603, Seite 397 volume:533 year:2016 number:7603 pages:397
sourceStr	Enthalten in Nature 533(2016), 7603, Seite 397 volume:533 year:2016 number:7603 pages:397
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis
dewey-raw	070
isfreeaccess_bool	false
container_title	Nature
authorswithroles_txt_mv	Karen S Sarkisyan @@aut@@ Dmitry A Bolotin @@oth@@ Margarita V Meer @@oth@@ Dinara R Usmanova @@oth@@ Alexander S Mishin @@oth@@ George V Sharonov @@oth@@ Dmitry N Ivankov @@oth@@ Nina G Bozhanova @@oth@@ Mikhail S Baranov @@oth@@ Onuralp Soylemez @@oth@@ Natalya S Bogatyreva @@oth@@ Peter K Vlasov @@oth@@ Evgeny S Egorov @@oth@@ Maria D Logacheva @@oth@@ Alexey S Kondrashov @@oth@@ Dmitry M Chudakov @@oth@@ Ekaterina V Putintseva @@oth@@ Ilgar Z Mamedov @@oth@@ Dan S Tawfik @@oth@@ Konstantin A Lukyanov @@oth@@ Fyodor A Kondrashov @@oth@@
publishDateDaySort_date	2016-01-01T00:00:00Z
hierarchy_top_id	129292834
dewey-sort	270
id	OLC1975207394
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1975207394</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230714191636.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">160609s2016 xx \|\|\|\|\| 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/nature17995</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20160610</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1975207394</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1975207394</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">070</subfield><subfield code="a">500</subfield><subfield code="q">DNB</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Karen S Sarkisyan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Local fitness landscape of the green fluorescent protein</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genotype & phenotype</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Amino acids</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Fluorescence</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mutation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mutagenesis</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry A Bolotin</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Margarita V Meer</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dinara R Usmanova</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alexander S Mishin</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">George V Sharonov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry N Ivankov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nina G Bozhanova</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mikhail S Baranov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Onuralp Soylemez</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Natalya S Bogatyreva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Peter K Vlasov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Evgeny S Egorov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Maria D Logacheva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alexey S Kondrashov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry M Chudakov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ekaterina V Putintseva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ilgar Z Mamedov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dan S Tawfik</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Konstantin A Lukyanov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Fyodor A Kondrashov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Nature</subfield><subfield code="d">London : Macmillan Publishers Limited, part of Springer Nature, 1869</subfield><subfield code="g">533(2016), 7603, Seite 397</subfield><subfield code="w">(DE-627)129292834</subfield><subfield code="w">(DE-600)120714-3</subfield><subfield code="w">(DE-576)014473941</subfield><subfield code="x">0028-0836</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:533</subfield><subfield code="g">year:2016</subfield><subfield code="g">number:7603</subfield><subfield code="g">pages:397</subfield></datafield><datafield tag="856" ind1="4" ind2="1"><subfield code="u">http://dx.doi.org/10.1038/nature17995</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.ncbi.nlm.nih.gov/pubmed/27193686</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://search.proquest.com/docview/1790506337</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_OLC</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHY</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-CHE</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-SPO</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-DE-84</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_30</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_47</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_55</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_59</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_154</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_168</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_211</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_290</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_294</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_601</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_647</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_754</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2002</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2008</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2016</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2018</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2095</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2116</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2121</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2219</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2221</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2279</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2286</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4219</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4277</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4302</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4314</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4317</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4320</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">533</subfield><subfield code="j">2016</subfield><subfield code="e">7603</subfield><subfield code="h">397</subfield></datafield></record></collection>
author	Karen S Sarkisyan
spellingShingle	Karen S Sarkisyan ddc 070 ddc 500 fid BIODIV misc Proteins misc Genotype & phenotype misc Amino acids misc Fluorescence misc Mutation misc Mutagenesis Local fitness landscape of the green fluorescent protein
authorStr	Karen S Sarkisyan
ppnlink_with_tag_str_mv	@@773@@(DE-627)129292834
format	Article
dewey-ones	070 - News media, journalism & publishing 500 - Natural sciences & mathematics
delete_txt_mv	keep
author_role	aut
collection	OLC
remote_str	false
illustrated	Not Illustrated
issn	0028-0836
topic_title	070 500 DNB 500 AVZ BIODIV fid Local fitness landscape of the green fluorescent protein Proteins Genotype & phenotype Amino acids Fluorescence Mutation Mutagenesis
topic	ddc 070 ddc 500 fid BIODIV misc Proteins misc Genotype & phenotype misc Amino acids misc Fluorescence misc Mutation misc Mutagenesis
topic_unstemmed	ddc 070 ddc 500 fid BIODIV misc Proteins misc Genotype & phenotype misc Amino acids misc Fluorescence misc Mutation misc Mutagenesis
topic_browse	ddc 070 ddc 500 fid BIODIV misc Proteins misc Genotype & phenotype misc Amino acids misc Fluorescence misc Mutation misc Mutagenesis
format_facet	Aufsätze Gedruckte Aufsätze
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	nc
author2_variant	d a b dab m v m mvm d r u dru a s m asm g v s gvs d n i dni n g b ngb m s b msb o s os n s b nsb p k v pkv e s e ese m d l mdl a s k ask d m c dmc e v p evp i z m izm d s t dst k a l kal f a k fak
hierarchy_parent_title	Nature
hierarchy_parent_id	129292834
dewey-tens	070 - News media, journalism & publishing 500 - Science
hierarchy_top_title	Nature
isfreeaccess_txt	false
familylinks_str_mv	(DE-627)129292834 (DE-600)120714-3 (DE-576)014473941
title	Local fitness landscape of the green fluorescent protein
ctrlnum	(DE-627)OLC1975207394 (DE-599)GBVOLC1975207394 (PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0 (KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein
title_full	Local fitness landscape of the green fluorescent protein
author_sort	Karen S Sarkisyan
journal	Nature
journalStr	Nature
lang_code	eng
isOA_bool	false
dewey-hundreds	000 - Computer science, information & general works 500 - Science
recordtype	marc
publishDateSort	2016
contenttype_str_mv	txt
container_start_page	397
author_browse	Karen S Sarkisyan
container_volume	533
class	070 500 DNB 500 AVZ BIODIV fid
format_se	Aufsätze
author-letter	Karen S Sarkisyan
doi_str_mv	10.1038/nature17995
dewey-full	070 500
title_sort	local fitness landscape of the green fluorescent protein
title_auth	Local fitness landscape of the green fluorescent protein
abstract	Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.
abstractGer	Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.
abstract_unstemmed	Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700
container_issue	7603
title_short	Local fitness landscape of the green fluorescent protein
url	http://dx.doi.org/10.1038/nature17995 http://www.ncbi.nlm.nih.gov/pubmed/27193686 http://search.proquest.com/docview/1790506337
remote_bool	false
author2	Dmitry A Bolotin Margarita V Meer Dinara R Usmanova Alexander S Mishin George V Sharonov Dmitry N Ivankov Nina G Bozhanova Mikhail S Baranov Onuralp Soylemez Natalya S Bogatyreva Peter K Vlasov Evgeny S Egorov Maria D Logacheva Alexey S Kondrashov Dmitry M Chudakov Ekaterina V Putintseva Ilgar Z Mamedov Dan S Tawfik Konstantin A Lukyanov Fyodor A Kondrashov
author2Str	Dmitry A Bolotin Margarita V Meer Dinara R Usmanova Alexander S Mishin George V Sharonov Dmitry N Ivankov Nina G Bozhanova Mikhail S Baranov Onuralp Soylemez Natalya S Bogatyreva Peter K Vlasov Evgeny S Egorov Maria D Logacheva Alexey S Kondrashov Dmitry M Chudakov Ekaterina V Putintseva Ilgar Z Mamedov Dan S Tawfik Konstantin A Lukyanov Fyodor A Kondrashov
ppnlink	129292834
mediatype_str_mv	n
isOA_txt	false
hochschulschrift_bool	false
author2_role	oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth oth
doi_str	10.1038/nature17995
up_date	2024-07-04T06:01:41.582Z
_version_	1803627162838761472
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a2200265 4500</leader><controlfield tag="001">OLC1975207394</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230714191636.0</controlfield><controlfield tag="007">tu</controlfield><controlfield tag="008">160609s2016 xx \|\|\|\|\| 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/nature17995</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">PQ20160610</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)OLC1975207394</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)GBVOLC1975207394</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(PRQ)g1106-b09c8c1cc03d6e233a610f605fc8ab38dbce1d8007b9a4ca228404134d29193c0</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(KEY)0072945020160000533760300397localfitnesslandscapeofthegreenfluorescentprotein</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">070</subfield><subfield code="a">500</subfield><subfield code="q">DNB</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">500</subfield><subfield code="q">AVZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">BIODIV</subfield><subfield code="2">fid</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Karen S Sarkisyan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Local fitness landscape of the green fluorescent protein</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">ohne Hilfsmittel zu benutzen</subfield><subfield code="b">n</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Band</subfield><subfield code="b">nc</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. 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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Proteins</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genotype & phenotype</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Amino acids</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Fluorescence</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mutation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mutagenesis</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry A Bolotin</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Margarita V Meer</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dinara R Usmanova</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alexander S Mishin</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">George V Sharonov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry N Ivankov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Nina G Bozhanova</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Mikhail S Baranov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Onuralp Soylemez</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Natalya S Bogatyreva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Peter K Vlasov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Evgeny S Egorov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Maria D Logacheva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Alexey S Kondrashov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dmitry M Chudakov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ekaterina V Putintseva</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ilgar Z Mamedov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Dan S Tawfik</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Konstantin A Lukyanov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Fyodor A Kondrashov</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Nature</subfield><subfield code="d">London : Macmillan Publishers Limited, part of Springer Nature, 1869</subfield><subfield code="g">533(2016), 7603, Seite 397</subfield><subfield code="w">(DE-627)129292834</subfield><subfield code="w">(DE-600)120714-3</subfield><subfield code="w">(DE-576)014473941</subfield><subfield code="x">0028-0836</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:533</subfield><subfield code="g">year:2016</subfield><subfield code="g">number:7603</subfield><subfield code="g">pages:397</subfield></datafield><datafield tag="856" ind1="4" ind2="1"><subfield code="u">http://dx.doi.org/10.1038/nature17995</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://www.ncbi.nlm.nih.gov/pubmed/27193686</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">http://search.proquest.com/docview/1790506337</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_OLC</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHY</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-CHE</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-MAT</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-SPO</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-DE-84</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_11</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_30</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_47</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_55</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_59</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_60</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_154</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_168</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_171</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_211</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_290</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_294</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_601</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_647</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_754</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2001</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2002</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2003</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2007</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2008</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2015</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2016</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2018</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2020</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2026</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2095</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2116</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2121</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2219</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2221</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2279</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2286</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4219</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4251</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4277</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4302</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4314</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4317</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4320</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">533</subfield><subfield code="j">2016</subfield><subfield code="e">7603</subfield><subfield code="h">397</subfield></datafield></record></collection>
score	7.4010277

Nicht das Richtige dabei?

Schreiben Sie uns!

Local fitness landscape of the green fluorescent protein

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?