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:

Jacobs, Christopher ;

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Lambourne, Luke; Xia, Yu; Segrè, Daniel; Galli, ed., Alvaro

Publication Date:

2017-01-20

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:

Published Article

Journal Name:

PLoS ONE

Additional Journal Information:

Journal Name: PLoS ONE Journal Volume: 12 Journal Issue: 1; Journal ID: ISSN 1932-6203

Publisher:

Public Library of Science (PLoS)

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