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Title: Upon accounting for the impact of isoenzyme loss, gene deletion costs anticorrelate with their evolutionary rates

Abstract

Here, system-level metabolic network models enable the computation of growth and metabolic phenotypes from an organism's genome. In particular, flux balance approaches have been used to estimate the contribution of individual metabolic genes to organismal fitness, offering the opportunity to test whether such contributions carry information about the evolutionary pressure on the corresponding genes. Previous failure to identify the expected negative correlation between such computed gene-loss cost and sequence-derived evolutionary rates in Saccharomyces cerevisiae has been ascribed to a real biological gap between a gene's fitness contribution to an organism "here and now"º and the same gene's historical importance as evidenced by its accumulated mutations over millions of years of evolution. Here we show that this negative correlation does exist, and can be exposed by revisiting a broadly employed assumption of flux balance models. In particular, we introduce a new metric that we call "function-loss cost", which estimates the cost of a gene loss event as the total potential functional impairment caused by that loss. This new metric displays significant negative correlation with evolutionary rate, across several thousand minimal environments. We demonstrate that the improvement gained using function-loss cost over gene-loss cost is explained by replacing the base assumption thatmore » isoenzymes provide unlimited capacity for backup with the assumption that isoenzymes are completely non-redundant. We further show that this change of the assumption regarding isoenzymes increases the recall of epistatic interactions predicted by the flux balance model at the cost of a reduction in the precision of the predictions. In addition to suggesting that the gene-to-reaction mapping in genome-scale flux balance models should be used with caution, our analysis provides new evidence that evolutionary gene importance captures much more than strict essentiality.« less

Authors:
ORCiD logo [1];  [2];  [2];  [1];  [3]
  1. Boston Univ., Boston, MA (United States)
  2. Boston Univ., Boston, MA (United States); McGill Univ., Montreal, QC (Canada)
  3. CNR (Italy)
Publication Date:
Research Org.:
Boston Univ., MA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1340026
Alternate Identifier(s):
OSTI ID: 1347524
Grant/Contract Number:
SC0012627
Resource Type:
Journal Article: Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 12; Journal Issue: 1; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; evolutionary rate; deletion mutation; Saccharomyces cerevisiae; enzyme metabolism; enzymes; gene mapping; evolutionary genetics; epistasis

Citation Formats

Jacobs, Christopher, Lambourne, Luke, Xia, Yu, Segrè, Daniel, and Galli, Alvaro. Upon accounting for the impact of isoenzyme loss, gene deletion costs anticorrelate with their evolutionary rates. United States: N. p., 2017. Web. doi:10.1371/journal.pone.0170164.
Jacobs, Christopher, Lambourne, Luke, Xia, Yu, Segrè, Daniel, & Galli, Alvaro. Upon accounting for the impact of isoenzyme loss, gene deletion costs anticorrelate with their evolutionary rates. United States. doi:10.1371/journal.pone.0170164.
Jacobs, Christopher, Lambourne, Luke, Xia, Yu, Segrè, Daniel, and Galli, Alvaro. Fri . "Upon accounting for the impact of isoenzyme loss, gene deletion costs anticorrelate with their evolutionary rates". United States. doi:10.1371/journal.pone.0170164.
@article{osti_1340026,
title = {Upon accounting for the impact of isoenzyme loss, gene deletion costs anticorrelate with their evolutionary rates},
author = {Jacobs, Christopher and Lambourne, Luke and Xia, Yu and Segrè, Daniel and Galli, Alvaro},
abstractNote = {Here, system-level metabolic network models enable the computation of growth and metabolic phenotypes from an organism's genome. In particular, flux balance approaches have been used to estimate the contribution of individual metabolic genes to organismal fitness, offering the opportunity to test whether such contributions carry information about the evolutionary pressure on the corresponding genes. Previous failure to identify the expected negative correlation between such computed gene-loss cost and sequence-derived evolutionary rates in Saccharomyces cerevisiae has been ascribed to a real biological gap between a gene's fitness contribution to an organism "here and now"º and the same gene's historical importance as evidenced by its accumulated mutations over millions of years of evolution. Here we show that this negative correlation does exist, and can be exposed by revisiting a broadly employed assumption of flux balance models. In particular, we introduce a new metric that we call "function-loss cost", which estimates the cost of a gene loss event as the total potential functional impairment caused by that loss. This new metric displays significant negative correlation with evolutionary rate, across several thousand minimal environments. We demonstrate that the improvement gained using function-loss cost over gene-loss cost is explained by replacing the base assumption that isoenzymes provide unlimited capacity for backup with the assumption that isoenzymes are completely non-redundant. We further show that this change of the assumption regarding isoenzymes increases the recall of epistatic interactions predicted by the flux balance model at the cost of a reduction in the precision of the predictions. In addition to suggesting that the gene-to-reaction mapping in genome-scale flux balance models should be used with caution, our analysis provides new evidence that evolutionary gene importance captures much more than strict essentiality.},
doi = {10.1371/journal.pone.0170164},
journal = {PLoS ONE},
number = 1,
volume = 12,
place = {United States},
year = {Fri Jan 20 00:00:00 EST 2017},
month = {Fri Jan 20 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1371/journal.pone.0170164

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  • Here, system-level metabolic network models enable the computation of growth and metabolic phenotypes from an organism's genome. In particular, flux balance approaches have been used to estimate the contribution of individual metabolic genes to organismal fitness, offering the opportunity to test whether such contributions carry information about the evolutionary pressure on the corresponding genes. Previous failure to identify the expected negative correlation between such computed gene-loss cost and sequence-derived evolutionary rates in Saccharomyces cerevisiae has been ascribed to a real biological gap between a gene's fitness contribution to an organism "here and now"º and the same gene's historical importance asmore » evidenced by its accumulated mutations over millions of years of evolution. Here we show that this negative correlation does exist, and can be exposed by revisiting a broadly employed assumption of flux balance models. In particular, we introduce a new metric that we call "function-loss cost", which estimates the cost of a gene loss event as the total potential functional impairment caused by that loss. This new metric displays significant negative correlation with evolutionary rate, across several thousand minimal environments. We demonstrate that the improvement gained using function-loss cost over gene-loss cost is explained by replacing the base assumption that isoenzymes provide unlimited capacity for backup with the assumption that isoenzymes are completely non-redundant. We further show that this change of the assumption regarding isoenzymes increases the recall of epistatic interactions predicted by the flux balance model at the cost of a reduction in the precision of the predictions. In addition to suggesting that the gene-to-reaction mapping in genome-scale flux balance models should be used with caution, our analysis provides new evidence that evolutionary gene importance captures much more than strict essentiality.« less
  • Mutational inactivation of the retinoblastoma/ gene (RB) is found in all retinoblastomas and in a subset of other human neoplasms, including sarcomas of bone or soft tissue and carcinomas of lung or breast. Exogenous copies of wild-type RB have been shown to suppress the tumorigenicity of several types of tumor cells with endogenous RB mutations, including a previously described human prostatic carcinoma cell line. To further support a role for RB inactivation in the genesis of prostate cancer, seven primary or metastatic prostate carcinoma specimens were examined for evidence of RB mutation. By the use of immunoblot analysis and immunostainingmore » of histologic sections, RB-encoded protein was readily detected in tumor cells of five specimens, was equivocally detected in one specimen, and was apparently absent from tumor cells of one specimen. RB mutations in the latter case were precisely characterized as (i) a deletion of 103 nucleotides containing transcriptional start sites and (ii) loss of the second RB allele. The 103-base-pair deletion was sufficient to abolish the promoter activity of upstream DNA sequences in a heterologous expression system. These results (i) demonstrate that RB can be inactivated in vivo by mutation of its promoter, (ii) confirm the existence of RB mutations in some human prostate carcinomas, and (iii) suggest the use of immunohistochemcial methods to screen for RB mutations in clinical samples of common adult neoplasms.« less
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