Using global quantitative genetic datasets in yeast to examine the relationships among genetic, environmental and stochastic robustness.

<p>The effects of deletions in nearly all non-essential genes on environmental, mutational and stochastic robustness can be estimated using global experiments performed with the haploid gene deletion collection (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#s4" target="_blank">materials and methods</a>). This allows one to ask whether gene deletions tend to have similar (i.e. correlated) consequences for the three measures of robustness, or whether they tend to affect genetic, environmental or stochastic robustness independently.</p

The correlated affects of gene deletions on genetic and environmental robustness in yeast.

<p>The effects of mutations on environmental robustness (the number of different environmental conditions in which a gene is required for growth <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Hillenmeyer1" target="_blank">[31]</a>) and mutational robustness (the number of synthetic lethal interactions made by a mutation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Pan1" target="_blank">[9]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Tong1" target="_blank">[11]</a>) are compared across 4656 gene deletions in yeast. Data are plotted for ten equally sized bins of genes. Error bars are +/− one standard error. Spearman rank correlation coefficient (ρ) = 0.39, p<2.2×10⁻¹⁶.</p

The effects of mutations on mutational and environmental robustness are also correlated with reductions in stochastic robustness.

<p>Stochastic robustness is quantified as the variability of cellular morphology among individuals, as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#s4" target="_blank">materials and methods </a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Levy1" target="_blank">[29]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Ohya1" target="_blank">[32]</a>. The correlation of each measure of environmental or genetic robustness across mutant strains with morphological variability is shown. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone-0009035-t001" target="_blank">Table 1</a> for P-values. Datasets used are as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone-0009035-g003" target="_blank">Figure 3</a>.</p

Genes confer correlated robustness to genetic, environmental and stochastic perturbations in yeast.

<p>Spearman Rank Correlation coefficients (ρ), P-values (P) and number of genes considered (n) comparing different measures of genetic, environmental, and stochastic robustness for gene deletions in yeast. Datasets are referred to by first author–Tong <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Tong1" target="_blank">[11]</a>, Pan <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Pan1" target="_blank">[9]</a>, Hillenmeyer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Hillenmeyer1" target="_blank">[31]</a>, Dudley <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Dudley1" target="_blank">[30]</a>, Levy/Ohya <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Levy1" target="_blank">[29]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Ohya1" target="_blank">[32]</a>.</p

The correlation between the requirement of genes for mutational and environmental robustness is confirmed using multiple different datasets.

<p>Correlation coefficients between the effects of mutations on measures of robustness are represented as a heat-map. Datasets: genetic robustness–proportion of synthetic lethal interactions from Tong <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Tong1" target="_blank">[11]</a>, Pan <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Pan1" target="_blank">[9]</a>; environmental robustness–number of environmental conditions in which a strain is required for growth from Hillenmeyer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Hillenmeyer1" target="_blank">[31]</a>, and Dudley <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone.0009035-Dudley1" target="_blank">[30]</a>. ‘1’–synthetic lethal degree for ‘target’ genes, ‘2’–synthetic lethal degree for ‘bait’ genes. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009035#pone-0009035-t001" target="_blank">Table 1</a> for P-values.</p

A model for the evolution of mutational robustness.

<p>The coupling between the requirement of genes for genetic (‘G’) and environmental (‘E’) robustness means that during evolution, selection for adaptive increases in environmental resilience may often have the side-effect of increasing mutational robustness.</p

Nucleoid-Associated Proteins Affect Mutation Dynamics in <em>E. coli</em> in a Growth Phase-Specific Manner

<div><p>The binding of proteins can shield DNA from mutagenic processes but also interfere with efficient repair. How the presence of DNA-binding proteins shapes intra-genomic differences in mutability and, ultimately, sequence variation in natural populations, however, remains poorly understood. In this study, we examine sequence evolution in <em>Escherichia coli</em> in relation to the binding of four abundant nucleoid-associated proteins: Fis, H-NS, IhfA, and IhfB. We find that, for a subset of mutations, protein occupancy is associated with both increased and decreased mutability in the underlying sequence depending on when the protein is bound during the bacterial growth cycle. On average, protein-bound DNA exhibits reduced mutability compared to protein-free DNA. However, this net protective effect is weak and can be abolished or even reversed during stages of colony growth where binding coincides – and hence likely interferes with – DNA repair activity. We suggest that the four nucleoid-associated proteins analyzed here have played a minor but significant role in patterning extant sequence variation in <em>E. coli</em>.</p> </div

Mutability as a function of NAP occupancy.

<p>The upper panels depict mutability (changes per nucleotide at risk) as a function of NAP occupancy for all possible transitions and transversions. White: sequence bound by one of the four NAPs. Sequence is considered bound when at least one of the NAPs binds during at least one of the growth phases assayed (see main text). Blue: sequence not bound by any of the four NAPs throughout growth. The lower panels show odds ratios along with 95% confidence intervals. Values in excess of 1 indicate higher mutability in unbound sequence.</p

A simple principle concerning the robustness of protein complex activity to changes in gene expression-3

<p><b>Copyright information:</b></p><p>Taken from "A simple principle concerning the robustness of protein complex activity to changes in gene expression"</p><p>http://www.biomedcentral.com/1752-0509/2/1</p><p>BMC Systems Biology 2008;2():1-1.</p><p>Published online 2 Jan 2008</p><p>PMCID:PMC2242779.</p><p></p>iched amongst the subunits of protein complexes. In contrast genes with over-expression phenotypes are equally represented amongst protein complex subunits and other genes. The graph shows the percentage of genes found in MIPS protein complexes and the percentage of all other genes that have each phenotype. ** Chi square test p < 0.05 for difference between protein complex subunits and all genes

Growth phase dependency of mutability in NAP-bound sequence.

<p>The top left panel shows schematically when NAP binding was assayed by Chip-Seq during the <i>E. coli</i> growth cycle. The remaining panels depict mutability at 4-fold synonymous sites as a function of the binding of a specific NAP (or of all NAPs combined) at a specific stage during the growth cycle. The colour coding corresponds to the colours of the growth phase labels in the top left panel. Note that mutability estimates for a certain growth phase do not only include regions that are exclusively bound during that phase but also include regions that are bound at several stages during the growth cycle.</p