# Comments on Sanford and Carter respond to PS participants

**URL:** <https://discourse.peacefulscience.org/t/comments-on-sanford-and-carter-respond-to-ps-participants/12656>\
**Category:** Side Conversation\
**Created:** [December 2, 2020, 5:20am UTC](https://discourse.peacefulscience.org/t/comments-on-sanford-and-carter-respond-to-ps-participants/12656 "2020-12-02T05:20:53Z")\
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**Author:** ![Rumraket](https://sea2.discourse-cdn.com/flex016/user_avatar/discourse.peacefulscience.org/rumraket/32/9328_2.png) [@Rumraket](https://discourse.peacefulscience.org/u/Rumraket)\
**Post date:** [December 3, 2020, 5:36pm UTC](https://discourse.peacefulscience.org/t/comments-on-sanford-and-carter-respond-to-ps-participants/12656/62 "2020-12-03T17:36:28Z")

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> [@PDPrice](#):
>
> You cannot arbitrarily draw the line where you’d like to stop. It won’t stop at 1 million iron molecules. Mutations are ongoing, forever and ever. The trend is down.

The shape of the curve physically cannot remain constant. As you go lower, the effects of mutations increase in magnitude, and the distribution moves more mutations into the beneficial category. This has to happen at the physical and biochemical level.

Diminishing returns epistasis, a demonstrably real empirical phenomenon, means that adding one more gene copy when you have few will matter a lot more than if you already have many. Increasing the catalytic rate by some X amount will matter much more as a proportion of total when the rate is low, than if the rate is high. Etc. etc.

Simultaneously, as you move closer to a fitness peak, you get closer to having exhausted the total pool of beneficial mutations, which lowers their subsequent probability of occurrence, which means more mutations shift from beneficial to deleterious. Conversely as you accumulate deleterious mutations and move further down in absolute fitness, now more mutations shift back into the beneficial category.

The scenario that GE entails is physically impossible. It cannot occur in reality. It is based on imagining a fixed spectrum of mutations under all circumstances. It is an imaginary mathematical abstraction that does not reflect the real physical reality we inhabit.

Even if one grants that the current DFE of mutations for most organisms look like you describe it, that would only tell us that most organisms are highly adapted, it would not follow from this that inevitable and indefinite fitness decline is the fate of any form of life, as the demonstrable reality of the physical phenomena I described would come into play.

Here are some references for the reality of these effects:  
[https://science.sciencemag.org/content/332/6034/1190.abstract](https://science.sciencemag.org/content/332/6034/1190.abstract)

[https://science.sciencemag.org/content/332/6034/1193.abstract](https://science.sciencemag.org/content/332/6034/1193.abstract)

> **[Global Epistasis Makes Adaptation Predictable Despite Sequence-Level...](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314286/)**
>
> Epistatic interactions between mutations can make evolutionary trajectories contingent on the chance occurrence of initial mutations. We used experimental evolution in Saccharomyces cerevisiae to quantify this contingency, finding differences in...

> **[Changes in the distribution of fitness effects and adaptive mutational...](https://www.biorxiv.org/content/10.1101/2020.06.12.148833v1.full)**
>
> The fitness effects of random mutations are contingent upon the genetic and environmental contexts in which they occur, and this contributes to the unpredictability of evolutionary outcomes at the molecular level. Despite this unpredictability, the...

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