Dataset Information

Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection.

ABSTRACT:

Background

The mutation spectra of the TP53 gene and other tumor suppressors contain multiple hotspots, i.e., sites of non-random, frequent mutation in tumors and/or the germline. The origin of the hotspots remains unclear, the general view being that they represent highly mutable nucleotide contexts which likely reflect effects of different endogenous and exogenous factors shaping the mutation process in specific tissues. The origin of hotspots is of major importance because it has been suggested that mutable contexts could be used to infer mechanisms of mutagenesis contributing to tumorigenesis.

Results

Here we apply three independent tests, accounting for non-uniform base compositions in synonymous and non-synonymous sites, to test whether the hotspots emerge via selection or due to mutational bias. All three tests consistently indicate that the hotspots in the TP53 gene evolve, primarily, via positive selection. The results were robust to the elimination of the highly mutable CpG dinucleotides. By contrast, only one, the least conservative test reveals the signature of positive selection in BRCA1, BRCA2, and p16. Elucidation of the origin of the hotspots in these genes requires more data on somatic mutations in tumors.

Conclusion

The results of this analysis seem to indicate that positive selection for gain-of-function in tumor suppressor genes is an important aspect of tumorigenesis, blurring the distinction between tumor suppressors and oncogenes.

Reviewers

This article was reviewed by Sandor Pongor, Christopher Lee and Mikhail Blagosklonny.

SUBMITTER: Glazko GV

PROVIDER: S-EPMC1403748 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Publications

Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection.

Glazko Galina V GV Babenko Vladimir N VN Koonin Eugene V EV Rogozin Igor B IB

Biology direct 20060131

<h4>Background</h4>The mutation spectra of the TP53 gene and other tumor suppressors contain multiple hotspots, i.e., sites of non-random, frequent mutation in tumors and/or the germline. The origin of the hotspots remains unclear, the general view being that they represent highly mutable nucleotide contexts which likely reflect effects of different endogenous and exogenous factors shaping the mutation process in specific tissues. The origin of hotspots is of major importance because it has been ...[more]

PMID: 16542006

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Project description:Temperature regulation is an indispensable physiological activity critical for animal survival. However, relatively little is known about the origin of thermoregulatory regimes in a phylogenetic context, or the genetic mechanisms driving the evolution of these regimes. Using bats as a study system, we examined the evolution of three thermoregulatory regimes (hibernation, daily heterothermy, and homeothermy) in relation to the evolution of leptin, a protein implicated in regulation of torpor bouts in mammals, including bats. A threshold model was used to test for a correlation between lineages with positively selected lep, the gene encoding leptin, and the thermoregulatory regimes of those lineages. Although evidence for episodic positive selection of lep was found, positive selection was not correlated with lineages of heterothermic bats, a finding that contradicts results from previous studies. Evidence from our ancestral state reconstructions suggests that the most recent common ancestor of bats used daily heterothermy and that the presence of hibernation is highly unlikely at this node. Hibernation likely evolved independently at least four times in bats-once in the common ancestor of Vespertilionidae and Molossidae, once in the clade containing Rhinolophidae and Rhinopomatidae, and again independently in the lineages leading to Taphozous melanopogon and Mystacina tuberculata. Our reconstructions revealed that thermoregulatory regimes never transitioned directly from hibernation to homeothermy, or the reverse, in the evolutionary history of bats. This, in addition to recent evidence that heterothermy is best described along a continuum, suggests that thermoregulatory regimes in mammals are best represented as an ordered continuous trait (homeothermy ? ? daily torpor ? ? hibernation) rather than as the three discrete regimes that evolve in an unordered fashion. These results have important implications for methodological approaches in future physiological and evolutionary research.

Dataset Information

Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection.

Background

Results

Conclusion

Reviewers

Publications

Mutational hotspots in the TP53 gene and, possibly, other tumor suppressors evolve by positive selection.

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