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Protein homeostasis imposes a barrier on functional integration of horizontally transferred genes in bacteria

Shimon Bershtein, Adrian W.R. Serohijos, Sanchari Bhattacharyya, Michael Manhart, Jeong-Mo Choi, Wanmeng Mu, Jingwen Zhou, Eugene I. Shakhnovich
doi: https://doi.org/10.1101/025841
Shimon Bershtein
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
2Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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Adrian W.R. Serohijos
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
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Sanchari Bhattacharyya
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
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Michael Manhart
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
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Jeong-Mo Choi
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
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Wanmeng Mu
3State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China
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Jingwen Zhou
4School of Biotechnology and Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, Jiangsu, China
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Eugene I. Shakhnovich
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA
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Abstract

Horizontal gene transfer (HGT) plays a central role in bacterial evolution, yet the molecular and cellular constraints on functional integration of the foreign genes are poorly understood. Here we performed inter-species replacement of the chromosomal folA gene, encoding an essential metabolic enzyme dihydrofolate reductase (DHFR), with orthologs from 35 other mesophilic bacteria. The orthologous inter-species replacements caused a marked drop (in the range 10-90%) in bacterial growth rate despite the fact that most orthologous DHFRs are as stable as E.coli DHFR at 37° C and are more catalytically active than E. coli DHFR. Although phylogenetic distance between E. coli and orthologous DHFRs as well as their individual molecular properties correlate poorly with growth rates, the product of the intracellular DHFR abundance and catalytic activity (kcat/KM), correlates strongly with growth rates, indicating that the drop in DHFR abundance constitutes the major fitness barrier to HGT. Serial propagation of the orthologous strains for ∼600 generations dramatically improved growth rates by largely alleviating the fitness barriers. Whole genome sequencing and global proteome quantification revealed that the evolved strains with the largest fitness improvements have accumulated mutations that inactivated the ATP-dependent Lon protease, causing an increase in the intracellular DHFR abundance. In one case DHFR abundance increased further due to mutations accumulated in folA promoter, but only after the lon inactivating mutations were fixed in the population. Thus, by apparently distinguishing between self and non-self proteins, protein homeostasis imposes an immediate and global barrier to the functional integration of foreign genes by decreasing the intracellular abundance of their products. Once this barrier is alleviated, more fine-tuned evolution occurs to adjust the function/expression of the transferred proteins to the constraints imposed by the intracellular environment of the host organism.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 01, 2015.
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Protein homeostasis imposes a barrier on functional integration of horizontally transferred genes in bacteria
Shimon Bershtein, Adrian W.R. Serohijos, Sanchari Bhattacharyya, Michael Manhart, Jeong-Mo Choi, Wanmeng Mu, Jingwen Zhou, Eugene I. Shakhnovich
bioRxiv 025841; doi: https://doi.org/10.1101/025841
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Protein homeostasis imposes a barrier on functional integration of horizontally transferred genes in bacteria
Shimon Bershtein, Adrian W.R. Serohijos, Sanchari Bhattacharyya, Michael Manhart, Jeong-Mo Choi, Wanmeng Mu, Jingwen Zhou, Eugene I. Shakhnovich
bioRxiv 025841; doi: https://doi.org/10.1101/025841

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