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Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways.

ABSTRACT: Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino acid replacements affecting protein folding or stability, or variations affecting gene copy number. In experimentally exploring the adaptive landscape of the evolution of resistance to beta-lactam antibiotics in enteric bacteria, we noted that a regulatory mutation that increases beta-lactamase expression by about 2-fold has a very strong tendency to be fixed at or near the end of the evolutionary pathway. This pattern contrasts with previous experiments selecting for the utilization of novel substrates, in which regulatory mutations that increase expression are often fixed early in the process. To understand the basis of the difference, we carried out experiments in which the expression of beta-lactamase was under the control of a tunable arabinose promoter. We find that the fitness effect of an increase in gene expression is highly dependent on the catalytic activity of the coding sequence. An increase in expression of an inefficient enzyme has a negligible effect on drug resistance; however, the effect of an increase in expression of an efficient enzyme is very large. The contrast in the temporal incorporation of regulatory mutants between antibiotic resistance and the utilization of novel substrates is related to the nature of the function that relates enzyme activity to fitness. A mathematical model of beta-lactam resistance is examined in detail and shown to be consistent with the observed results.

SUBMITTER: Brown KM

PROVIDER: S-EPMC2912465 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways.

Brown Kyle M KM Depristo Mark A MA Weinreich Daniel M DM Hartl Daniel L DL

Molecular biology and evolution 20090714 11

Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino acid replacements affecting protein folding or stability, or variations affecting gene copy number. In experimentally exploring the adaptive landscape of the evolution of resistance to beta-lactam antibiotics in enteric bacteria, we noted that a ...[more]

PMID: 19602543

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Project description:BACKGROUND: The structure of regulatory networks remains an open question in our understanding of complex biological systems. Interactions during complete viral life cycles present unique opportunities to understand how host-parasite network take shape and behave. The Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) is a large double-stranded DNA virus, whose genome may encode for 152 open reading frames (ORFs). Here we present the analysis of the ordered cascade of the AgMNPV gene expression. RESULTS: We observed an earlier onset of the expression than previously reported for other baculoviruses, especially for genes involved in DNA replication. Most ORFs were expressed at higher levels in a more permissive host cell line. Genes with more than one copy in the genome had distinct expression profiles, which could indicate the acquisition of new functionalities. The transcription gene regulatory network (GRN) for 149 ORFs had a modular topology comprising five communities of highly interconnected nodes that separated key genes that are functionally related on different communities, possibly maximizing redundancy and GRN robustness by compartmentalization of important functions. Core conserved functions showed expression synchronicity, distinct GRN features and significantly less genetic diversity, consistent with evolutionary constraints imposed in key elements of biological systems. This reduced genetic diversity also had a positive correlation with the importance of the gene in our estimated GRN, supporting a relationship between phylogenetic data of baculovirus genes and network features inferred from expression data. We also observed that gene arrangement in overlapping transcripts was conserved among related baculoviruses, suggesting a principle of genome organization. CONCLUSIONS: Albeit with a reduced number of nodes (149), the AgMNPV GRN had a topology and key characteristics similar to those observed in complex cellular organisms, which indicates that modularity may be a general feature of biological gene regulatory networks.

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Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways.

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Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways.

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