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Transcription control reprogramming in genetic backup circuits

Nature Genetics volume 37, pages 295–299 (2005)Cite this article

Abstract

A key question in molecular genetics is why severe mutations often do not result in a detectably abnormal phenotype. This robustness was partially ascribed to redundant paralogs1,2 that may provide backup for one another in case of mutation. Mining mutant viability and mRNA expression data in Saccharomyces cerevisiae, we found that backup was provided predominantly by paralogs that are expressed dissimilarly in most growth conditions. We considered that this apparent inconsistency might be resolved by a transcriptional reprogramming mechanism that allows the intact paralog to rescue the organism upon mutation of its counterpart. We found that in wild-type cells, partial coregulation across growth conditions predicted the ability of paralogs to alter their transcription patterns and to provide backup for one another. Notably, the sets of regulatory motifs that controlled the paralogs with the most efficient backup activity deliberately overlapped only partially; paralogs with highly similar or dissimilar sets of motifs had suboptimal backup activity. Such an arrangement of partially shared regulatory motifs reconciles the differential expression of paralogs with their ability to back each other up.

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Figure 1: Dependence of backup on expression similarity between paralogs.
Figure 2: Gene dispensability as a function of the regulatory motif–content overlap O between genes and their closest paralogs.
Figure 3: Transcriptional response of backup-providing genes to the deletion of the counterparts.
Figure 4: Difference in the number of motifs regulating paralogous pair members as a function of the difference in the growth rates of mutants lacking them.
Figure 5: Confirmation and characterization of genetic backup circuits.
Figure 6: Schematic and dynamics of the reprogramming switch.

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Acknowledgements

We thank all members of the laboratory of Y.P. for discussions; I. Pechersky for computational assistance; and Y. Garten, N. Barkai, J. Berman, B. Shilo, A.M. Dudley, I. Yanai, O. Man, S. Shen-Orr, D. Graur, D. Lancet, M. Levy and D. Artzi for critical review of the manuscript. Y.P. is an incumbent of the Aser Rothstein Career Development Chair in Genetic Diseases and is a Fellow of the Hurwitz Foundation for Complexity Sciences. We thank the Leo and Julia Forchheimer Center for Molecular Genetics and the Ben May Foundation for grant support. This paper is dedicated to the memory of I. Kafri.

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Authors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 76100, Israel

    Ran Kafri, Arren Bar-Even & Yitzhak Pilpel

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  1. Ran Kafri
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  2. Arren Bar-Even
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Correspondence to Yitzhak Pilpel.

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Supplementary information

Supplementary Fig. 1

The proportion of dispensable genes among genes that constitute a set of paralogous pairs with high functional similarity. (PDF 60 kb)

Supplementary Fig. 2

Effects of GO-annotated molecular function similarity on dispensability (and hence on backup potential) of paralogs. (PDF 80 kb)

Supplementary Fig. 3

Prevalence of predicted paralogous backup within and between organelles. (PDF 70 kb)

Supplementary Fig. 4

Dependence of protein-protein interactions on expression similarity and on Ks. (PDF 58 kb)

Supplementary Fig. 5

Negative correlation between expression similarity and protein function similarity of paralogs. (PDF 78 kb)

Supplementary Fig. 6

Regulatory motif content overlap, 'O' as a function of their divergence quantified by Ks. (PDF 44 kb)

Supplementary Fig. 7

Dependence of regulatory motif content similarity on Ks. (PDF 235 kb)

Supplementary Fig. 8

The proportion of paralogous isozymes within sets of paralogous gene pairs as a function of mean expression similarity and PCoR. (PDF 50 kb)

Supplementary Fig. 9

Dependence of the trends shown in Fig 1B & C on the particular choice of Ks threshold. (PDF 139 kb)

Supplementary Fig. 10

Effect of bin size in Fig 1 on results and statistics. (PDF 153 kb)

Supplementary Fig. 11

Linear fit for the viability and growth rate data of deletion mutants (as opposed to fraction of dispensable genes in each expression bin size) as a function of the mean expression similarity and PCoR between homologs. (PDF 489 kb)

Supplementary Fig. 12

Proportion of dispensable genes among the close paralogs (red), i.e. Ks <1, and duplicates arising from the whole genome duplication (blue) against the mean expression similarity and PCoR of the paralogous pairs. (PDF 65 kb)

Supplementary Note (PDF 99 kb)

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Kafri, R., Bar-Even, A. & Pilpel, Y. Transcription control reprogramming in genetic backup circuits. Nat Genet 37, 295–299 (2005). https://doi.org/10.1038/ng1523

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