--- _id: '6419' abstract: - lang: eng text: Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible. article_number: e1008079 article_processing_charge: No author: - first_name: Victoria full_name: Pokusaeva, Victoria id: 3184041C-F248-11E8-B48F-1D18A9856A87 last_name: Pokusaeva orcid: 0000-0001-7660-444X - first_name: Dinara R. full_name: Usmanova, Dinara R. last_name: Usmanova - first_name: Ekaterina V. full_name: Putintseva, Ekaterina V. last_name: Putintseva - first_name: Lorena full_name: Espinar, Lorena last_name: Espinar - first_name: Karen full_name: Sarkisyan, Karen id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Alexander S. full_name: Mishin, Alexander S. last_name: Mishin - first_name: Natalya S. full_name: Bogatyreva, Natalya S. last_name: Bogatyreva - first_name: Dmitry full_name: Ivankov, Dmitry id: 49FF1036-F248-11E8-B48F-1D18A9856A87 last_name: Ivankov - first_name: Arseniy full_name: Akopyan, Arseniy id: 430D2C90-F248-11E8-B48F-1D18A9856A87 last_name: Akopyan orcid: 0000-0002-2548-617X - first_name: Sergey full_name: Avvakumov, Sergey id: 3827DAC8-F248-11E8-B48F-1D18A9856A87 last_name: Avvakumov - first_name: Inna S. full_name: Povolotskaya, Inna S. last_name: Povolotskaya - first_name: Guillaume J. full_name: Filion, Guillaume J. last_name: Filion - first_name: Lucas B. full_name: Carey, Lucas B. last_name: Carey - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Pokusaeva V, Usmanova DR, Putintseva EV, et al. An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape. PLoS Genetics. 2019;15(4). doi:10.1371/journal.pgen.1008079 apa: Pokusaeva, V., Usmanova, D. R., Putintseva, E. V., Espinar, L., Sarkisyan, K., Mishin, A. S., … Kondrashov, F. (2019). An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape. PLoS Genetics. Public Library of Science. https://doi.org/10.1371/journal.pgen.1008079 chicago: Pokusaeva, Victoria, Dinara R. Usmanova, Ekaterina V. Putintseva, Lorena Espinar, Karen Sarkisyan, Alexander S. Mishin, Natalya S. Bogatyreva, et al. “An Experimental Assay of the Interactions of Amino Acids from Orthologous Sequences Shaping a Complex Fitness Landscape.” PLoS Genetics. Public Library of Science, 2019. https://doi.org/10.1371/journal.pgen.1008079. ieee: V. Pokusaeva et al., “An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape,” PLoS Genetics, vol. 15, no. 4. Public Library of Science, 2019. ista: Pokusaeva V, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan K, Mishin AS, Bogatyreva NS, Ivankov D, Akopyan A, Avvakumov S, Povolotskaya IS, Filion GJ, Carey LB, Kondrashov F. 2019. An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape. PLoS Genetics. 15(4), e1008079. mla: Pokusaeva, Victoria, et al. “An Experimental Assay of the Interactions of Amino Acids from Orthologous Sequences Shaping a Complex Fitness Landscape.” PLoS Genetics, vol. 15, no. 4, e1008079, Public Library of Science, 2019, doi:10.1371/journal.pgen.1008079. short: V. Pokusaeva, D.R. Usmanova, E.V. Putintseva, L. Espinar, K. Sarkisyan, A.S. Mishin, N.S. Bogatyreva, D. Ivankov, A. Akopyan, S. Avvakumov, I.S. Povolotskaya, G.J. Filion, L.B. Carey, F. Kondrashov, PLoS Genetics 15 (2019). date_created: 2019-05-13T07:58:38Z date_published: 2019-04-10T00:00:00Z date_updated: 2023-08-25T10:30:37Z day: '10' ddc: - '570' department: - _id: FyKo doi: 10.1371/journal.pgen.1008079 ec_funded: 1 external_id: isi: - '000466866000029' file: - access_level: open_access checksum: cf3889c8a8a16053dacf9c3776cbe217 content_type: application/pdf creator: dernst date_created: 2019-05-14T08:26:08Z date_updated: 2020-07-14T12:47:30Z file_id: '6445' file_name: 2019_PLOSGenetics_Pokusaeva.pdf file_size: 3726017 relation: main_file file_date_updated: 2020-07-14T12:47:30Z has_accepted_license: '1' intvolume: ' 15' isi: 1 issue: '4' language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '04' oa: 1 oa_version: Published Version project: - _id: 2564DBCA-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '665385' name: International IST Doctoral Program publication: PLoS Genetics publication_identifier: eissn: - '15537404' publication_status: published publisher: Public Library of Science quality_controlled: '1' related_material: record: - id: '9789' relation: research_data status: public - id: '9790' relation: research_data status: public - id: '9797' relation: research_data status: public scopus_import: '1' status: public title: An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 15 year: '2019' ... --- _id: '9790' article_processing_charge: No author: - first_name: Victoria full_name: Pokusaeva, Victoria id: 3184041C-F248-11E8-B48F-1D18A9856A87 last_name: Pokusaeva orcid: 0000-0001-7660-444X - first_name: Dinara R. full_name: Usmanova, Dinara R. last_name: Usmanova - first_name: Ekaterina V. full_name: Putintseva, Ekaterina V. last_name: Putintseva - first_name: Lorena full_name: Espinar, Lorena last_name: Espinar - first_name: Karen full_name: Sarkisyan, Karen id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Alexander S. full_name: Mishin, Alexander S. last_name: Mishin - first_name: Natalya S. full_name: Bogatyreva, Natalya S. last_name: Bogatyreva - first_name: Dmitry full_name: Ivankov, Dmitry id: 49FF1036-F248-11E8-B48F-1D18A9856A87 last_name: Ivankov - first_name: Arseniy full_name: Akopyan, Arseniy id: 430D2C90-F248-11E8-B48F-1D18A9856A87 last_name: Akopyan orcid: 0000-0002-2548-617X - first_name: Sergey full_name: Avvakumov, Sergey id: 3827DAC8-F248-11E8-B48F-1D18A9856A87 last_name: Avvakumov - first_name: Inna S. full_name: Povolotskaya, Inna S. last_name: Povolotskaya - first_name: Guillaume J. full_name: Filion, Guillaume J. last_name: Filion - first_name: Lucas B. full_name: Carey, Lucas B. last_name: Carey - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Pokusaeva V, Usmanova DR, Putintseva EV, et al. A statistical summary of segment libraries and sequencing results. 2019. doi:10.1371/journal.pgen.1008079.s011 apa: Pokusaeva, V., Usmanova, D. R., Putintseva, E. V., Espinar, L., Sarkisyan, K., Mishin, A. S., … Kondrashov, F. (2019). A statistical summary of segment libraries and sequencing results. Public Library of Science. https://doi.org/10.1371/journal.pgen.1008079.s011 chicago: Pokusaeva, Victoria, Dinara R. Usmanova, Ekaterina V. Putintseva, Lorena Espinar, Karen Sarkisyan, Alexander S. Mishin, Natalya S. Bogatyreva, et al. “A Statistical Summary of Segment Libraries and Sequencing Results.” Public Library of Science, 2019. https://doi.org/10.1371/journal.pgen.1008079.s011. ieee: V. Pokusaeva et al., “A statistical summary of segment libraries and sequencing results.” Public Library of Science, 2019. ista: Pokusaeva V, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan K, Mishin AS, Bogatyreva NS, Ivankov D, Akopyan A, Avvakumov S, Povolotskaya IS, Filion GJ, Carey LB, Kondrashov F. 2019. A statistical summary of segment libraries and sequencing results, Public Library of Science, 10.1371/journal.pgen.1008079.s011. mla: Pokusaeva, Victoria, et al. A Statistical Summary of Segment Libraries and Sequencing Results. Public Library of Science, 2019, doi:10.1371/journal.pgen.1008079.s011. short: V. Pokusaeva, D.R. Usmanova, E.V. Putintseva, L. Espinar, K. Sarkisyan, A.S. Mishin, N.S. Bogatyreva, D. Ivankov, A. Akopyan, S. Avvakumov, I.S. Povolotskaya, G.J. Filion, L.B. Carey, F. Kondrashov, (2019). date_created: 2021-08-06T08:50:15Z date_published: 2019-04-10T00:00:00Z date_updated: 2023-08-25T10:30:36Z day: '10' department: - _id: FyKo doi: 10.1371/journal.pgen.1008079.s011 month: '04' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '6419' relation: used_in_publication status: public status: public title: A statistical summary of segment libraries and sequencing results type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2019' ... --- _id: '9797' article_processing_charge: No author: - first_name: Victoria full_name: Pokusaeva, Victoria id: 3184041C-F248-11E8-B48F-1D18A9856A87 last_name: Pokusaeva orcid: 0000-0001-7660-444X - first_name: Dinara R. full_name: Usmanova, Dinara R. last_name: Usmanova - first_name: Ekaterina V. full_name: Putintseva, Ekaterina V. last_name: Putintseva - first_name: Lorena full_name: Espinar, Lorena last_name: Espinar - first_name: Karen full_name: Sarkisyan, Karen id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Alexander S. full_name: Mishin, Alexander S. last_name: Mishin - first_name: Natalya S. full_name: Bogatyreva, Natalya S. last_name: Bogatyreva - first_name: Dmitry full_name: Ivankov, Dmitry id: 49FF1036-F248-11E8-B48F-1D18A9856A87 last_name: Ivankov - first_name: Arseniy full_name: Akopyan, Arseniy id: 430D2C90-F248-11E8-B48F-1D18A9856A87 last_name: Akopyan orcid: 0000-0002-2548-617X - first_name: Inna S. full_name: Povolotskaya, Inna S. last_name: Povolotskaya - first_name: Guillaume J. full_name: Filion, Guillaume J. last_name: Filion - first_name: Lucas B. full_name: Carey, Lucas B. last_name: Carey - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Pokusaeva V, Usmanova DR, Putintseva EV, et al. A statistical summary of segment libraries and sequencing results. 2019. doi:10.1371/journal.pgen.1008079.s011 apa: Pokusaeva, V., Usmanova, D. R., Putintseva, E. V., Espinar, L., Sarkisyan, K., Mishin, A. S., … Kondrashov, F. (2019). A statistical summary of segment libraries and sequencing results. Public Library of Science. https://doi.org/10.1371/journal.pgen.1008079.s011 chicago: Pokusaeva, Victoria, Dinara R. Usmanova, Ekaterina V. Putintseva, Lorena Espinar, Karen Sarkisyan, Alexander S. Mishin, Natalya S. Bogatyreva, et al. “A Statistical Summary of Segment Libraries and Sequencing Results.” Public Library of Science, 2019. https://doi.org/10.1371/journal.pgen.1008079.s011. ieee: V. Pokusaeva et al., “A statistical summary of segment libraries and sequencing results.” Public Library of Science, 2019. ista: Pokusaeva V, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan K, Mishin AS, Bogatyreva NS, Ivankov D, Akopyan A, Povolotskaya IS, Filion GJ, Carey LB, Kondrashov F. 2019. A statistical summary of segment libraries and sequencing results, Public Library of Science, 10.1371/journal.pgen.1008079.s011. mla: Pokusaeva, Victoria, et al. A Statistical Summary of Segment Libraries and Sequencing Results. Public Library of Science, 2019, doi:10.1371/journal.pgen.1008079.s011. short: V. Pokusaeva, D.R. Usmanova, E.V. Putintseva, L. Espinar, K. Sarkisyan, A.S. Mishin, N.S. Bogatyreva, D. Ivankov, A. Akopyan, I.S. Povolotskaya, G.J. Filion, L.B. Carey, F. Kondrashov, (2019). date_created: 2021-08-06T11:08:20Z date_published: 2019-04-10T00:00:00Z date_updated: 2023-08-25T10:30:36Z day: '10' department: - _id: FyKo doi: 10.1371/journal.pgen.1008079.s011 month: '04' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '6419' relation: used_in_publication status: public status: public title: A statistical summary of segment libraries and sequencing results type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2019' ... --- _id: '9789' article_processing_charge: No author: - first_name: Victoria full_name: Pokusaeva, Victoria id: 3184041C-F248-11E8-B48F-1D18A9856A87 last_name: Pokusaeva orcid: 0000-0001-7660-444X - first_name: Dinara R. full_name: Usmanova, Dinara R. last_name: Usmanova - first_name: Ekaterina V. full_name: Putintseva, Ekaterina V. last_name: Putintseva - first_name: Lorena full_name: Espinar, Lorena last_name: Espinar - first_name: Karen full_name: Sarkisyan, Karen id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Alexander S. full_name: Mishin, Alexander S. last_name: Mishin - first_name: Natalya S. full_name: Bogatyreva, Natalya S. last_name: Bogatyreva - first_name: Dmitry full_name: Ivankov, Dmitry id: 49FF1036-F248-11E8-B48F-1D18A9856A87 last_name: Ivankov - first_name: Arseniy full_name: Akopyan, Arseniy id: 430D2C90-F248-11E8-B48F-1D18A9856A87 last_name: Akopyan orcid: 0000-0002-2548-617X - first_name: Sergey full_name: Avvakumov, Sergey id: 3827DAC8-F248-11E8-B48F-1D18A9856A87 last_name: Avvakumov - first_name: Inna S. full_name: Povolotskaya, Inna S. last_name: Povolotskaya - first_name: Guillaume J. full_name: Filion, Guillaume J. last_name: Filion - first_name: Lucas B. full_name: Carey, Lucas B. last_name: Carey - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Pokusaeva V, Usmanova DR, Putintseva EV, et al. Multiple alignment of His3 orthologues. 2019. doi:10.1371/journal.pgen.1008079.s010 apa: Pokusaeva, V., Usmanova, D. R., Putintseva, E. V., Espinar, L., Sarkisyan, K., Mishin, A. S., … Kondrashov, F. (2019). Multiple alignment of His3 orthologues. Public Library of Science. https://doi.org/10.1371/journal.pgen.1008079.s010 chicago: Pokusaeva, Victoria, Dinara R. Usmanova, Ekaterina V. Putintseva, Lorena Espinar, Karen Sarkisyan, Alexander S. Mishin, Natalya S. Bogatyreva, et al. “Multiple Alignment of His3 Orthologues.” Public Library of Science, 2019. https://doi.org/10.1371/journal.pgen.1008079.s010. ieee: V. Pokusaeva et al., “Multiple alignment of His3 orthologues.” Public Library of Science, 2019. ista: Pokusaeva V, Usmanova DR, Putintseva EV, Espinar L, Sarkisyan K, Mishin AS, Bogatyreva NS, Ivankov D, Akopyan A, Avvakumov S, Povolotskaya IS, Filion GJ, Carey LB, Kondrashov F. 2019. Multiple alignment of His3 orthologues, Public Library of Science, 10.1371/journal.pgen.1008079.s010. mla: Pokusaeva, Victoria, et al. Multiple Alignment of His3 Orthologues. Public Library of Science, 2019, doi:10.1371/journal.pgen.1008079.s010. short: V. Pokusaeva, D.R. Usmanova, E.V. Putintseva, L. Espinar, K. Sarkisyan, A.S. Mishin, N.S. Bogatyreva, D. Ivankov, A. Akopyan, S. Avvakumov, I.S. Povolotskaya, G.J. Filion, L.B. Carey, F. Kondrashov, (2019). date_created: 2021-08-06T08:38:50Z date_published: 2019-04-10T00:00:00Z date_updated: 2023-08-25T10:30:36Z day: '10' department: - _id: FyKo doi: 10.1371/journal.pgen.1008079.s010 month: '04' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '6419' relation: used_in_publication status: public status: public title: Multiple alignment of His3 orthologues type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2019' ... --- _id: '5780' abstract: - lang: eng text: Bioluminescence is found across the entire tree of life, conferring a spectacular set of visually oriented functions from attracting mates to scaring off predators. Half a dozen different luciferins, molecules that emit light when enzymatically oxidized, are known. However, just one biochemical pathway for luciferin biosynthesis has been described in full, which is found only in bacteria. Here, we report identification of the fungal luciferase and three other key enzymes that together form the biosynthetic cycle of the fungal luciferin from caffeic acid, a simple and widespread metabolite. Introduction of the identified genes into the genome of the yeast Pichia pastoris along with caffeic acid biosynthesis genes resulted in a strain that is autoluminescent in standard media. We analyzed evolution of the enzymes of the luciferin biosynthesis cycle and found that fungal bioluminescence emerged through a series of events that included two independent gene duplications. The retention of the duplicated enzymes of the luciferin pathway in nonluminescent fungi shows that the gene duplication was followed by functional sequence divergence of enzymes of at least one gene in the biosynthetic pathway and suggests that the evolution of fungal bioluminescence proceeded through several closely related stepping stone nonluminescent biochemical reactions with adaptive roles. The availability of a complete eukaryotic luciferin biosynthesis pathway provides several applications in biomedicine and bioengineering. article_processing_charge: No author: - first_name: Alexey A. full_name: Kotlobay, Alexey A. last_name: Kotlobay - first_name: Karen full_name: Sarkisyan, Karen id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Yuliana A. full_name: Mokrushina, Yuliana A. last_name: Mokrushina - first_name: Marina full_name: Marcet-Houben, Marina last_name: Marcet-Houben - first_name: Ekaterina O. full_name: Serebrovskaya, Ekaterina O. last_name: Serebrovskaya - first_name: Nadezhda M. full_name: Markina, Nadezhda M. last_name: Markina - first_name: Louisa full_name: Gonzalez Somermeyer, Louisa id: 4720D23C-F248-11E8-B48F-1D18A9856A87 last_name: Gonzalez Somermeyer orcid: 0000-0001-9139-5383 - first_name: Andrey Y. full_name: Gorokhovatsky, Andrey Y. last_name: Gorokhovatsky - first_name: Andrey full_name: Vvedensky, Andrey last_name: Vvedensky - first_name: Konstantin V. full_name: Purtov, Konstantin V. last_name: Purtov - first_name: Valentin N. full_name: Petushkov, Valentin N. last_name: Petushkov - first_name: Natalja S. full_name: Rodionova, Natalja S. last_name: Rodionova - first_name: Tatiana V. full_name: Chepurnyh, Tatiana V. last_name: Chepurnyh - first_name: Liliia full_name: Fakhranurova, Liliia last_name: Fakhranurova - first_name: Elena B. full_name: Guglya, Elena B. last_name: Guglya - first_name: Rustam full_name: Ziganshin, Rustam last_name: Ziganshin - first_name: Aleksandra S. full_name: Tsarkova, Aleksandra S. last_name: Tsarkova - first_name: Zinaida M. full_name: Kaskova, Zinaida M. last_name: Kaskova - first_name: Victoria full_name: Shender, Victoria last_name: Shender - first_name: Maxim full_name: Abakumov, Maxim last_name: Abakumov - first_name: Tatiana O. full_name: Abakumova, Tatiana O. last_name: Abakumova - first_name: Inna S. full_name: Povolotskaya, Inna S. last_name: Povolotskaya - first_name: Fedor M. full_name: Eroshkin, Fedor M. last_name: Eroshkin - first_name: Andrey G. full_name: Zaraisky, Andrey G. last_name: Zaraisky - first_name: Alexander S. full_name: Mishin, Alexander S. last_name: Mishin - first_name: Sergey V. full_name: Dolgov, Sergey V. last_name: Dolgov - first_name: Tatiana Y. full_name: Mitiouchkina, Tatiana Y. last_name: Mitiouchkina - first_name: Eugene P. full_name: Kopantzev, Eugene P. last_name: Kopantzev - first_name: Hans E. full_name: Waldenmaier, Hans E. last_name: Waldenmaier - first_name: Anderson G. full_name: Oliveira, Anderson G. last_name: Oliveira - first_name: Yuichi full_name: Oba, Yuichi last_name: Oba - first_name: Ekaterina full_name: Barsova, Ekaterina last_name: Barsova - first_name: Ekaterina A. full_name: Bogdanova, Ekaterina A. last_name: Bogdanova - first_name: Toni full_name: Gabaldón, Toni last_name: Gabaldón - first_name: Cassius V. full_name: Stevani, Cassius V. last_name: Stevani - first_name: Sergey full_name: Lukyanov, Sergey last_name: Lukyanov - first_name: Ivan V. full_name: Smirnov, Ivan V. last_name: Smirnov - first_name: Josef I. full_name: Gitelson, Josef I. last_name: Gitelson - first_name: Fyodor full_name: Kondrashov, Fyodor id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 - first_name: Ilia V. full_name: Yampolsky, Ilia V. last_name: Yampolsky citation: ama: Kotlobay AA, Sarkisyan K, Mokrushina YA, et al. Genetically encodable bioluminescent system from fungi. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(50):12728-12732. doi:10.1073/pnas.1803615115 apa: Kotlobay, A. A., Sarkisyan, K., Mokrushina, Y. A., Marcet-Houben, M., Serebrovskaya, E. O., Markina, N. M., … Yampolsky, I. V. (2018). Genetically encodable bioluminescent system from fungi. Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences. https://doi.org/10.1073/pnas.1803615115 chicago: Kotlobay, Alexey A., Karen Sarkisyan, Yuliana A. Mokrushina, Marina Marcet-Houben, Ekaterina O. Serebrovskaya, Nadezhda M. Markina, Louisa Gonzalez Somermeyer, et al. “Genetically Encodable Bioluminescent System from Fungi.” Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 2018. https://doi.org/10.1073/pnas.1803615115. ieee: A. A. Kotlobay et al., “Genetically encodable bioluminescent system from fungi,” Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 50. National Academy of Sciences, pp. 12728–12732, 2018. ista: Kotlobay AA, Sarkisyan K, Mokrushina YA, Marcet-Houben M, Serebrovskaya EO, Markina NM, Gonzalez Somermeyer L, Gorokhovatsky AY, Vvedensky A, Purtov KV, Petushkov VN, Rodionova NS, Chepurnyh TV, Fakhranurova L, Guglya EB, Ziganshin R, Tsarkova AS, Kaskova ZM, Shender V, Abakumov M, Abakumova TO, Povolotskaya IS, Eroshkin FM, Zaraisky AG, Mishin AS, Dolgov SV, Mitiouchkina TY, Kopantzev EP, Waldenmaier HE, Oliveira AG, Oba Y, Barsova E, Bogdanova EA, Gabaldón T, Stevani CV, Lukyanov S, Smirnov IV, Gitelson JI, Kondrashov F, Yampolsky IV. 2018. Genetically encodable bioluminescent system from fungi. Proceedings of the National Academy of Sciences of the United States of America. 115(50), 12728–12732. mla: Kotlobay, Alexey A., et al. “Genetically Encodable Bioluminescent System from Fungi.” Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 50, National Academy of Sciences, 2018, pp. 12728–32, doi:10.1073/pnas.1803615115. short: A.A. Kotlobay, K. Sarkisyan, Y.A. Mokrushina, M. Marcet-Houben, E.O. Serebrovskaya, N.M. Markina, L. Gonzalez Somermeyer, A.Y. Gorokhovatsky, A. Vvedensky, K.V. Purtov, V.N. Petushkov, N.S. Rodionova, T.V. Chepurnyh, L. Fakhranurova, E.B. Guglya, R. Ziganshin, A.S. Tsarkova, Z.M. Kaskova, V. Shender, M. Abakumov, T.O. Abakumova, I.S. Povolotskaya, F.M. Eroshkin, A.G. Zaraisky, A.S. Mishin, S.V. Dolgov, T.Y. Mitiouchkina, E.P. Kopantzev, H.E. Waldenmaier, A.G. Oliveira, Y. Oba, E. Barsova, E.A. Bogdanova, T. Gabaldón, C.V. Stevani, S. Lukyanov, I.V. Smirnov, J.I. Gitelson, F. Kondrashov, I.V. Yampolsky, Proceedings of the National Academy of Sciences of the United States of America 115 (2018) 12728–12732. date_created: 2018-12-23T22:59:18Z date_published: 2018-12-11T00:00:00Z date_updated: 2023-09-11T14:04:05Z day: '11' ddc: - '580' department: - _id: FyKo doi: 10.1073/pnas.1803615115 external_id: isi: - '000452866000068' file: - access_level: open_access checksum: 46b2c12185eb2ddb598f4c7b4bd267bf content_type: application/pdf creator: dernst date_created: 2019-02-05T15:21:40Z date_updated: 2020-07-14T12:47:11Z file_id: '5926' file_name: 2018_PNAS_Kotlobay.pdf file_size: 1271988 relation: main_file file_date_updated: 2020-07-14T12:47:11Z has_accepted_license: '1' intvolume: ' 115' isi: 1 issue: '50' language: - iso: eng license: https://creativecommons.org/licenses/by-nc-nd/4.0/ month: '12' oa: 1 oa_version: Published Version page: 12728-12732 publication: Proceedings of the National Academy of Sciences of the United States of America publication_identifier: issn: - '00278424' publication_status: published publisher: National Academy of Sciences quality_controlled: '1' scopus_import: '1' status: public title: Genetically encodable bioluminescent system from fungi tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 115 year: '2018' ... --- _id: '850' abstract: - lang: eng text: 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. acknowledgement: We thank Y. Kulikova and G. Filion for discussion on statistical analysis and I. Osterman, R. Moretti and J. Meiler for technical assistance and M. Friesen for a critical reading of the manuscript. We thank H. Himmelbauer, CRG Genomic Unit and the Russian Science Foundation project (14-50-00150) for sequencing. Experiments were partially carried out using the equipment provided by the IBCH core facility (CKP IBCH). The work was supported by HHMI International Early Career Scientist Program (55007424), the EMBO Young Investigator Programme, MINECO (BFU2012-31329), Spanish Ministry of Economy and Competitiveness Centro de Excelencia Severo Ochoa 2013-2017 grant (SEV-2012-0208), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat's AGAUR program (2014 SGR 0974), Russian Science Foundation (14-25-00129) and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013, ERC grant agreement, 335980-EinME). author: - first_name: Karen full_name: Karen Sarkisyan id: 39A7BF80-F248-11E8-B48F-1D18A9856A87 last_name: Sarkisyan orcid: 0000-0002-5375-6341 - first_name: Dmitry full_name: Bolotin, Dmitry A last_name: Bolotin - first_name: Margarita full_name: Meer, Margarita V last_name: Meer - first_name: Dinara full_name: Usmanova, Dinara R last_name: Usmanova - first_name: Alexander full_name: Mishin, Alexander S last_name: Mishin - first_name: George full_name: Sharonov, George V last_name: Sharonov - first_name: Dmitry full_name: Ivankov, Dmitry N last_name: Ivankov - first_name: Nina full_name: Bozhanova, Nina G last_name: Bozhanova - first_name: Mikhail full_name: Baranov, Mikhail S last_name: Baranov - first_name: Onuralp full_name: Soylemez, Onuralp last_name: Soylemez - first_name: Natalya full_name: Bogatyreva, Natalya S last_name: Bogatyreva - first_name: Peter full_name: Vlasov, Peter K last_name: Vlasov - first_name: Evgeny full_name: Egorov, Evgeny S last_name: Egorov - first_name: Maria full_name: Logacheva, Maria D last_name: Logacheva - first_name: Alexey full_name: Kondrashov, Alexey S last_name: Kondrashov - first_name: Dmitriy full_name: Chudakov, Dmitriy M last_name: Chudakov - first_name: Ekaterina full_name: Putintseva, Ekaterina V last_name: Putintseva - first_name: Ilgar full_name: Mamedov, Ilgar Z last_name: Mamedov - first_name: Dan full_name: Tawfik, Dan S last_name: Tawfik - first_name: Konstantin full_name: Lukyanov, Konstantin A last_name: Lukyanov - first_name: Fyodor full_name: Fyodor Kondrashov id: 44FDEF62-F248-11E8-B48F-1D18A9856A87 last_name: Kondrashov orcid: 0000-0001-8243-4694 citation: ama: Sarkisyan K, Bolotin D, Meer M, et al. Local fitness landscape of the green fluorescent protein. Nature. 2016;533:397-401. doi:10.1038/nature17995 apa: Sarkisyan, K., Bolotin, D., Meer, M., Usmanova, D., Mishin, A., Sharonov, G., … Kondrashov, F. (2016). Local fitness landscape of the green fluorescent protein. Nature. Nature Publishing Group. https://doi.org/10.1038/nature17995 chicago: Sarkisyan, Karen, Dmitry Bolotin, Margarita Meer, Dinara Usmanova, Alexander Mishin, George Sharonov, Dmitry Ivankov, et al. “Local Fitness Landscape of the Green Fluorescent Protein.” Nature. Nature Publishing Group, 2016. https://doi.org/10.1038/nature17995. ieee: K. Sarkisyan et al., “Local fitness landscape of the green fluorescent protein,” Nature, vol. 533. Nature Publishing Group, pp. 397–401, 2016. ista: Sarkisyan K, Bolotin D, Meer M, Usmanova D, Mishin A, Sharonov G, Ivankov D, Bozhanova N, Baranov M, Soylemez O, Bogatyreva N, Vlasov P, Egorov E, Logacheva M, Kondrashov A, Chudakov D, Putintseva E, Mamedov I, Tawfik D, Lukyanov K, Kondrashov F. 2016. Local fitness landscape of the green fluorescent protein. Nature. 533, 397–401. mla: Sarkisyan, Karen, et al. “Local Fitness Landscape of the Green Fluorescent Protein.” Nature, vol. 533, Nature Publishing Group, 2016, pp. 397–401, doi:10.1038/nature17995. short: K. Sarkisyan, D. Bolotin, M. Meer, D. Usmanova, A. Mishin, G. Sharonov, D. Ivankov, N. Bozhanova, M. Baranov, O. Soylemez, N. Bogatyreva, P. Vlasov, E. Egorov, M. Logacheva, A. Kondrashov, D. Chudakov, E. Putintseva, I. Mamedov, D. Tawfik, K. Lukyanov, F. Kondrashov, Nature 533 (2016) 397–401. date_created: 2018-12-11T11:48:50Z date_published: 2016-05-11T00:00:00Z date_updated: 2021-01-12T08:19:42Z day: '11' doi: 10.1038/nature17995 extern: 1 intvolume: ' 533' month: '05' page: 397 - 401 publication: Nature publication_status: published publisher: Nature Publishing Group publist_id: '6799' quality_controlled: 0 status: public title: Local fitness landscape of the green fluorescent protein type: journal_article volume: 533 year: '2016' ...