Why is natural selection hard to beat and when do you need to beat it?

[This is a stub entry I'm making for John under his name. He should re-edit it with his own words. -- Eric]

Here’s a brief review I just wrote with Dan.

Why is natural selection hard to beat and when do you need to beat it?
John R. Roth and Dan I. Andersson

Bacterial genetics defeats natural selection — it uses positive selection to detect large-phenotype mutants without influencing their frequency.  Metazoans maintain organism integrity by defeating natural selection on somatic cell growth.  Bacterial genetics relies on selection strong enough to prevent growth of both the parent and common slightly-improved mutants.  When selective stringency is reduced, frequent small-effect mutations allow growth and initiate a cascade of successive improvements.  This rapid response rests on the unexpectedly high formation rate of small-effect mutations (particularly duplications and amplifications). Duplications form at a rate 104 times that of null mutations.  The high frequency of small-effect mutations reflects features of replication, repair and coding that minimize the costs of mutation.
The striking effect of small-effect mutations is seen in a system designed by John Cairns to test the effect of growth limitation on mutation rate.  A leaky E. coli mutant (lac) is plated on lactose medium.  Revertant (Lac+) colonies appear over 6 days above a lawn of (108) non-growing parent cells. These colonies have been attributed to stress-induced mutagenesis of the non-growing parent. This conclusion ignores natural selection, assuming that only large-effect mutants appear– as is true for lab genetic selections.  However, selection is not stringent in the Cairns system — small increases in lac enzymes allow growth.  Common cells with a lac duplication (and 2x the mutant enzyme level) initiate slow-growing colonies, in which selection drives a multi-step adaptation process – higher amplification, reversion to lac+ and loss of mutant lac alleles.  The high yield of revertant colonies under selection does not reflect mutagenesis, but rather the high spontaneous rate of gene duplication (10-5), amplification (10-2/step) and the selective addition of mutation targets (more cells with more mutant lac copies/cell).
Metazoan somatic cells may escape natural selection by the same mechanism.  Metazoans reduce the basal level of unexpressed genes 1000-fold (compared to bacteria) by their epi-genetic modification of DNA and histones – making it impossible for small-effect mutations to provide growth.

-- John Roth

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