TY - JOUR AU - Liska, Orsolya AU - Boross, Gábor AU - Rocabert, Charles AU - Szappanos, Balázs AU - Tengölics, Roland AU - Papp, Balázs TI - Principles of metabolome conservation in animals JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 120 PY - 2023 IS - 35 PG - 12 SN - 0027-8424 DO - 10.1073/pnas.2302147120 UR - https://m2.mtmt.hu/api/publication/34202172 ID - 34202172 N1 - Funding Agency and Grant Number: "Lendlet" program of the Hungarian Academy of Sciences [LP2009-013/2012]; European Union [739593]; National Laboratory for Health Security [RRF-2.3.1-21-2022-00006]; National Laboratory of Biotechnology [NKFIH-871-3]; Hungarian Academy of Sciences Premium Postdoctoral Research Program [PREMIUM-2018-294]; Hungarian Academy of Sciences [BO/00728/21/8]; New National Excellence Program of the Ministry of Human Capacities [UNKP-21-5-SZTE-564, UNKP-22-5-SZTE-592]; National Research, Development and Innovation Office [PD 128271]; Tobacco-Related Disease Research Program of the University of California [T31FT1772] Funding text: by the National Research, Development and Innovation Office Elvonal Program KKP 129814 (B.P.) , the "Lenduelet" program of the Hungarian Academy of Sciences LP2009-013/2012 (B.P.) ,the European Union's Horizon 2020 research and innovation program Grant No. 739593 (B.P.) , the National Laboratory for Health Security Grant RRF-2.3.1-21-2022-00006 (B.P.) , the National Laboratory of Biotechnology Grant NKFIH-871-3/2020 (B.P.) , The Hungarian Academy of Sciences Premium Postdoctoral Research Program (PREMIUM-2018-294 to B.S.) ,Janos Bolyai Research Fellowship from the Hungarian Academy of Sciences (BO/00728/21/8 to B.S.) , New National Excellence Program of the Ministry of Human Capacities (Bolyai+, UNKP-21-5-SZTE-564 and UNKP-22-5-SZTE-592 to B.S.) , National Research, Development and Innovation Office (PD 128271 to R.T.) and the Tobacco-Related Disease Research Program of the University of California (T31FT1772 to G.B.) . AB - Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients. LA - English DB - MTMT ER - TY - JOUR AU - Yousefi, Maryam AU - Andrejka, Laura AU - Szamecz, Márton AU - Winslow, Monte M. AU - Petrov, Dmitri A. AU - Boross, Gábor TI - Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 120 PY - 2023 IS - 38 SN - 0027-8424 DO - 10.1073/pnas.2303224120 UR - https://m2.mtmt.hu/api/publication/34146082 ID - 34146082 AB - Cancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with the inactivation of additional tumor suppressor genes. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations that drive the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order. LA - English DB - MTMT ER - TY - GEN AU - Yousefi, Maryam AU - Andrejka, Laura AU - Winslow, Monte M AU - Petrov, Dmitri A AU - Boross, Gábor TI - Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma. PY - 2023 UR - https://m2.mtmt.hu/api/publication/33780517 ID - 33780517 AB - Cancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with additional tumor suppressor mutations. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations required for the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order. LA - English DB - MTMT ER - TY - JOUR AU - Yousefi, Maryam AU - Boross, Gábor AU - Weiss, Carly AU - Murray, Christopher W. AU - Hebert, Jess D. AU - Cai, Hongchen AU - Ashkin, Emily L. AU - Karmakar, Saswati AU - Andrejka, Laura AU - Chen, Leo AU - Wang, Minwei AU - Tsai, Min K. AU - Lin, Wen-Yang AU - Li, Chuan AU - Yakhchalian, Pegah AU - Colón, Caterina I. AU - Chew, Su-Kit AU - Chu, Pauline AU - Swanton, Charles AU - Kunder, Christian A. AU - Petrov, Dmitri A. AU - Winslow, Monte M. TI - Combinatorial Inactivation of Tumor Suppressors Efficiently Initiates Lung Adenocarcinoma with Therapeutic Vulnerabilities JF - CANCER RESEARCH J2 - CANCER RES VL - 82 PY - 2022 IS - 8 SP - 1589 EP - 1602 PG - 14 SN - 0008-5472 DO - 10.1158/0008-5472.CAN-22-0059 UR - https://m2.mtmt.hu/api/publication/33597875 ID - 33597875 LA - English DB - MTMT ER - TY - JOUR AU - Apjok, Gábor AU - Boross, Gábor AU - Nyerges, Ákos AU - Fekete, Gergely AU - Lázár, Viktória AU - Papp, Balázs AU - Pál, Csaba AU - Csörgő, Bálint TI - Limited evolutionary conservation of multidrug resistance and collateral sensitivity (vol 36, pg 1601, 2019) JF - MOLECULAR BIOLOGY AND EVOLUTION J2 - MOL BIOL EVOL VL - 38 PY - 2021 IS - 7 SP - 3029 EP - 3029 PG - 1 SN - 0737-4038 DO - 10.1093/molbev/msab116 UR - https://m2.mtmt.hu/api/publication/32106320 ID - 32106320 LA - English DB - MTMT ER - TY - JOUR AU - Dunai, Anett AU - Spohn, Réka AU - Farkas, Zoltán AU - Lázár, Viktória AU - Györkei, Ádám AU - Apjok, Gábor AU - Boross, Gábor AU - Szappanos, Balázs AU - Grézal, Gábor AU - Faragó, Anikó AU - Bodai, László AU - Papp, Balázs AU - Pál, Csaba TI - Rapid decline of bacterial drug-resistance in an antibiotic-free environment through phenotypic reversion. JF - ELIFE J2 - ELIFE VL - 8 PY - 2019 PG - 20 SN - 2050-084X DO - 10.7554/eLife.47088 UR - https://m2.mtmt.hu/api/publication/30776198 ID - 30776198 N1 - Funding Agency and Grant Number: H2020 European Research Council [H2020-ERC-2014-CoG 648364]; Gazdasagfejlesztesi es Innovacios Operativ Programm [GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.2-15-2016-00026]; Hungarian Academy of Sciences Momentum Programme [LP2017-10/2017]; National Research, Development and Innovation Office Elvonal Programme [KKP 126506]; Wellcome Trust [WT 098016/Z/11/Z, WT 084314/Z/07/Z]; National Research, Development and Innovation Office [FK 128775, NKFI-112294]; Magyar Tudomanyos Akademia Lendulet Programme [LP 2012-32/2018]; Magyar Tudomanyos Akademia Postdoctoral Programme [PD-007/2016, PD-038/2015, LP2009-013/2012] Funding text: H2020 European Research Council H2020-ERC-2014-CoG 648364 Resistance Evolution Csaba Pal; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00014 Csaba Pal; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00020 Csaba Pal; Hungarian Academy of Sciences Momentum Programme LP2017-10/2017 Csaba Pal; National Research, Development and Innovation Office Elvonal Programme KKP 126506 Csaba Pal; Wellcome Trust WT 098016/Z/11/Z Balazs Papp; Gazdasagfejlesztesi es Innovacios Operativ Programm GINOP-2.3.2-15-2016-00026 Balazs Papp; Wellcome Trust WT 084314/Z/07/Z Csaba Pal; National Research, Development and Innovation Office FK 128775 Zoltan Farkas; Magyar Tudomanyos Akademia Lendulet Programme LP 2012-32/2018 Csaba Pal; Magyar Tudomanyos Akademia Postdoctoral Programme PD-007/2016 Viktoria Lazar; Magyar Tudomanyos Akademia Postdoctoral Programme PD-038/2015 Zoltan Farkas; National Research, Development and Innovation Office NKFI-112294 Laszlo Bodai; Magyar Tudomanyos Akademia Lendulet Programme LP2009-013/2012 Balazs Papp; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. AB - Antibiotic resistance typically induces a fitness cost that shapes the fate of antibiotic-resistant bacterial populations. However, the cost of resistance can be mitigated by compensatory mutations elsewhere in the genome, and therefore the loss of resistance may proceed too slowly to be of practical importance. We present our study on the efficacy and phenotypic impact of compensatory evolution in Escherichia coli strains carrying multiple resistance mutations. We have demonstrated that drug-resistance frequently declines within 480 generations during exposure to an antibiotic-free environment. The extent of resistance loss was found to be generally antibiotic-specific, driven by mutations that reduce both resistance level and fitness costs of antibiotic-resistance mutations. We conclude that phenotypic reversion to the antibiotic-sensitive state can be mediated by the acquisition of additional mutations, while maintaining the original resistance mutations. Our study indicates that restricting antimicrobial usage could be a useful policy, but for certain antibiotics only. LA - English DB - MTMT ER - TY - JOUR AU - Apjok, Gábor AU - Boross, Gábor AU - Nyerges, Ákos AU - Fekete, Gergely AU - Lázár, Viktória AU - Papp, Balázs AU - Pál, Csaba AU - Csörgő, Bálint TI - Limited evolutionary conservation of the phenotypic effects of antibiotic resistance mutations JF - MOLECULAR BIOLOGY AND EVOLUTION J2 - MOL BIOL EVOL VL - 36 PY - 2019 IS - 8 SP - 1601 EP - 1611 PG - 11 SN - 0737-4038 DO - 10.1093/molbev/msz109 UR - https://m2.mtmt.hu/api/publication/30703953 ID - 30703953 LA - English DB - MTMT ER - TY - JOUR AU - Manczinger, Máté AU - Boross, Gábor AU - Kemény, Lajos AU - Müller, Viktor AU - Lenz, Tobias L. AU - Papp, Balázs AU - Pál, Csaba TI - Pathogen diversity drives the evolution of generalist MHC-II alleles in human populations JF - PLOS BIOLOGY J2 - PLOS BIOL VL - 17 PY - 2019 IS - 1 SN - 1544-9173 DO - 10.1371/journal.pbio.3000131 UR - https://m2.mtmt.hu/api/publication/30420930 ID - 30420930 N1 - Funding Agency and Grant Number: "Frontline" Research Excellence Programme of the National Research, Development and Innovation Office, Hungary [KKP_ 17]; "Lendulet" Programme of the Hungarian Academy of Sciences; Wellcome Trust [GINOP-2.3.2-15-2016-00014, GINOP-2.3.2-15-2016-00020, GINOP-2.3.3-15-2016-00001, GINOP-2.3.2-15-2016-00057]; German Research Foundation [LE 2593/3-1]; New National Excellence Program of the Ministry of Human Capacities [UNKP-18-4]; Bolyai Janos Research Fellowship of the Hungarian Academy of Sciences; ELTE Institutional Excellence Program - Hungarian Ministry of Human Capacities [1783-3/2018/FEKUTSRAT] Funding text: The authors acknowledge the following financial support: "Frontline" Research Excellence Programme of the National Research, Development and Innovation Office, Hungary (KKP_ 17), "Lendulet" Programme of the Hungarian Academy of Sciences and The Wellcome Trust (BP and CP), H2020 ERC-2014-CoG (CP), GINOP-2.3.2-15-2016-00014 (EVOMER, BP and CP), GINOP-2.3.2-15-2016-00020 (MolMedEx TUMORDNS, CP), GINOP-2.3.3-15-2016-00001 (CP), GINOP-2.3.2-15-2016-00057 ("Az evolucio fenyeben: elvek es megoldasok," VM), and German Research Foundation grant LE 2593/3-1 (TLL). MM was supported by the UNKP-18-4 New National Excellence Program of the Ministry of Human Capacities, MM and VM were supported by the Bolyai Janos Research Fellowship of the Hungarian Academy of Sciences, and VM was supported in the frame of the ELTE Institutional Excellence Program (1783-3/2018/FEKUTSRAT) funded by the Hungarian Ministry of Human Capacities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. AB - Whereas specialist major histocompatibility complex (MHC) molecules initiate immune response against only relatively few pathogens, generalists provide protection against a broad range. Accordingly, this study shows that the geographical distribution of generalist MHC alleles in human populations reflects exposure to diverse infectious diseases. LA - English DB - MTMT ER - TY - JOUR AU - Boross, Gábor Zoltán AU - Boross, Gábor TI - Káros és kompenzáló mutációk: lehet-e szerepük a biológiai sokféleség evolúciójában? JF - MAGYAR TUDOMÁNY J2 - MAGYAR TUDOMÁNY VL - 179 PY - 2018 SN - 0025-0325 DO - 10.1556/2065.179.2018.5.2 UR - https://m2.mtmt.hu/api/publication/34146093 ID - 34146093 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Manczinger, Máté AU - Boross, Gábor AU - Kemény, Lajos AU - Müller, Viktor AU - Tobias, L. Lenz AU - Papp, Balázs AU - Pál, Csaba TI - Pathogen diversity drives the evolution of generalist antigen presentation in human populations JF - IMMUNOLÓGIAI SZEMLE J2 - IMMUNOLÓGIAI SZEMLE VL - 10 PY - 2018 IS - 3 SP - 18 EP - 18 PG - 1 SN - 2061-0203 UR - https://m2.mtmt.hu/api/publication/30338873 ID - 30338873 LA - English DB - MTMT ER -