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Transcription control reprogramming in genetic backup circuits Literature search. WANG Chao 4/6/2005. Why this question?. ► W hy severe mutations often do not result in a detectably abnormal phenotype. robustness was partially ascribed to redundant paralogs

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transcription control reprogramming in genetic backup circuits literature search

Transcription control reprogramming in geneticbackup circuitsLiterature search

WANG Chao 4/6/2005

why this question
Why this question?

► Why severe mutationsoften do not result in a detectably abnormal phenotype.

robustness was partially ascribed to redundant paralogs

► Understand both the relevance of transcription regulation to duplicateretention in evolution and its role in controlling expression of genesthat provide backup in case of mutation

definition
Definition
  • For each pair of paralogs, 40 correlation coefficients of mRNA expression corresponding to 40 different experiments
  • Mean expression similarity:

means of such correlations for each piar

  • Partial coregulation (PCoR) values:

standard deviations of such correlations for each pair

i nspected close and remote paralogous pairs separately and found markedly different trends
Inspected close and remoteparalogous pairs separately and found markedly different trends:
  • In remote pairs, backup was most efficient among transcriptionallynoncorrelated pairs, as their essentiality was substantiallylower than that of single genes.

These results provide a potential explanation for theobserved decrease in backup capacity with increased coexpression.

  • Incontrast to remote pairs, close pairs showed an almost opposite, moreintuitive trend.
example such reprogramming has been experimentally verified for the acs1 and acs2 isoenzymes

Backup among naturally dissimilarly expressed genes A and B maysuggest that, upon mutation in gene A, expression of gene B isreprogrammed to acquire a profile that is similar to the wild-typeexpression profile of gene A.

Example: Such reprogramming has been experimentally

verified for the Acs1 and Acs2 isoenzymes.

slide7

In search for a mechanism that may regulate switching betweendissimilar and similar expression in response to mutation, weexamined thedependence of gene essentiality on PCoR.

We found that PCoR was a very strong predictor ofbackup

i nvestigat e the promoter architecture of backup providing paralogs
Investigate the promoter architecture of backup-providingparalogs
  • Maximal backup coincided with intermediate levels of motif sharing
  • We propose that the uniquemotifs of each paralog provide differential expression in the wild typeand that the shared motifs allow paralogs to respond to the sameconditions. This situation allows for reprogramming in response tomutations.
slide9
Gene dispensability as a function of the regulatory motif–content overlap O between genes and their closest paralogs.
slide10
To corroborate the hypothesis that PCoR underlies reprogrammingand, ultimately, backup, we examined three predictions.
slide11

First, onemember of a pair with high PCoR should be upregulated transcriptionallyin response to the deletion of its paralog.Transcriptional response of backup-providing genes to the deletionof the counterparts.

slide12

Second, our reprogramming scenario predicts that themore motifs control a gene, the better itsreprogramming andbackup-providing capacity willbe.Difference in the number of motifs regulating paralogous pair members as afunction of the difference in the growth rates of mutants lacking them.

slide13

Third, our proposed model predicts synthetic lethal interactions.Backup was maximal among pairs with high PCoRand low coexpression.Confirmation and characterization of genetic backup circuits.

w hat controls reprogramming of a gene upon mutation of its paralog
What controls reprogramming of a gene uponmutation of its paralog.

Propose a kinetic model, or reprogrammingswitch.

conclusions
Conclusions
  • The different behavior of close and remote paralogs probably stemsfrom the profoundly different evolutionary regimens acting on them.
  • Wepropose that backup-providing duplicates may be retained duringevolution if their retention is coupled to other selectable traits, such asacquisition of new regulatory capabilities