How does molecular biology overthrow the Modern Synthesis?

I think the hardened version of the Modern Synthesis is inadequate to describe 21st century evolutionary biology. I think that it didn't adequately recognize Neutral Theory and random genetic drift and it didn't place enough emphasis on macroevolution and the possibility of hierarchical modes of evolution.

There are a whole host of scientists who want to overthrow the Modern Synthesis for a variety of other (stupid) reasons. Most of them have no idea that the Modern Synthesis has (or should have) been replaced 40 years ago.

Here's another example from last week's issue Science (March 7, 2014). Susan M. Rosenberg and Christine Queitsch have an article entitled "Combating Evolution
to Fight Disease" (Rosenberg and Queitsch, 2014). They begin with ....

Traditional evolutionary biology began in the 1930s with the "modern synthesis," which fused Darwin’s theses on phenotypic variation and selection with Mendel’s concepts of genetic inheritance to explain the source of biological diversity. This synthesis predated knowledge that genes were made of DNA and of the structure of DNA and how it replicates. Thus, molecular mechanisms could not be integrated into concepts about how phenotypic variation is generated. Instead, assumptions had to be made about the origins of the variation that drives evolution. Among the cornerstone assumptions were that mutations are the sole drivers of evolution; mutations occur randomly, constantly, and gradually; and the transmission of genetic information is vertical from parent to offspring, rather than horizontal (infectious) between individuals and species (as is now apparent throughout the tree of life). But discoveries of molecular mechanisms are modifying these assumptions.

This is fairly typical of modern critics of evolution. They begin with the assumption that evolutionary theory hasn't changed since the 1930s. What that tells us is that, right from the beginning, they don't know what they are talking about.

So, what are the "new" revelations that molecular mechanisms have uncovered?

In at least two ways, heritable variation can be generated by proteins, not DNA (1). Spontaneously self-aggregating alternative conformations of some proteins—prions—can flip into their aggregated state and change a cell’s phenotype in an environmentally responsive manner with no change to DNA. The change is transmissible vertically, parent to offspring cell, as well as horizontally, to other cells in which the proteins come in contact. Another mechanism involves chaperones such as heat shock protein 90 (Hsp90), proteins that massage subideal (mutant) proteins into functional conformations but abandon their regular client proteins during heat and other stresses that destabilize proteins. This causes a stress-inducible release of phenotypic diversity, which may drive evolution (with phenotypes ultimately stabilized by subsequent genetic changes). Both of these molecular mechanisms of protein-based inheritance are major departures from the modern synthesis views of solely mutation directed variation, solely genetic inheritance, and independence of the generation of variation from environmental conditions.

Yawn. We've known about prions for 25 years. The proteins are encoded by genes and certain variants in certain species can adopt different conformations depending on conditions within the cell. Move along folks, there's nothing to see here.

We've known about the role of molecular chaperones for thirty years. We've known for almost twenty years that chaperones can assist in protein folding so that some polypeptides that cannot fold spontaneously on their own in a reasonable length of time can nevertheless function due to chaperones. Chaperones are very ancient proteins. This means that "subideal" folders have been around for several billion years. In times of stress these "subideal" proteins may not be able to fold correctly. If the proteins are important then this could be lethal and the genes will be eliminated. If the function of particular, properly folded, proteins is not essential then cells can survive short periods of stress.

This has nothing to do with "protein-based inheritance" and the existence of prions and chaperones does not challenge the old-fashioned 1930s view of evolutionary theory. It also doesn't challenge the updated view of evolutionary theory that arose after 1968. Anyone who thinks that prions and chaperones have a serious impact on our understanding of evolutionary theory is really grasping at straws.

If, at the same time, they fail to mention molecular clocks, the evidence of junk from genome sequences, and the massive amount of data supporting Neutral Theory as an explanation for variation, then they have not only grasped the wrong straws but failed to notice the haystack.

Similarly, transient errors in mRNA synthesis can also cause heritable non–DNAbased phenotypic change. This is observed when low-abundance transcriptional regulators are affected by transcription errors. This disruption can cause a cell to alter its gene expression, resulting in a phenotype that may be heritable (2).

There are times when errors in transcription or translation can cause problems. These are quite rare since most of the time there are dozens of copies of functional RNAs and the loss of one doesn't make a difference. Similarly, the loss of a single protein is very unlikely to make much of a difference except under highly unusual circumstances. It's difficult to imagine scenarios where errors in transcription and translation could routinely affect the evolution of a population.

Even the assumption that mutations are random, constant, and gradual has been revised on the basis of molecular mechanisms of mutagenesis. For example, in bacteria, responses to environmental stress can activate mutagenesis mechanisms that increase mutation rate, which can potentially increase the ability of a cell to evolve, specifically when it is poorly adapted to its environment (when stressed). Most of a 93-gene network that promotes mutagenesis in Escherichia coli is devoted to sensing stress and activating stress responses that direct the bacterium to mutate when stressed (3). Stress responses also up-regulate mutagenesis in yeast (4) and human cancer cells (5) and underlie mutations induced by antibiotics that cause resistance to those very drugs, and others (6).

It's true that transient changes in mutation rate caused by mutations in repair and replication genes are commonly observed in evolving populations that are under extreme selection pressure. (For example, in Lenski's long-term evolution experiment.)

It's also true that the vast majority of observed changes during evolution are consistent with the idea that mutations rates are roughly constant over millions of years. I don't think that the 1930s version of the Modern Synthesis necessarily assumed that "mutations are random, constant, and gradual" but even if it did, that's still pretty much what we observe today. (Where "random" means "non-directed.")

It's not obvious to me that we need to revise our 21st century understanding of evolution in order to account for some increases in mutation rates from time to time.

Mutations are also nonrandom in genomic space—for example, forming hot spots at DNA double-strand breaks, as demonstrated in bacteria (7) and suggested by local clusters of mutations in cancer genomes (8, 9).

We've known for at least 45 years about hot spots and we've known for almost as long that certain DNA sequences are more susceptible to mutation than others. The classic example is adjacent pyrimidines, especially TT. There's only one reason why this would cause a fuss and that's if you believe that the probability of mutation is exactly the same for every single nucleotide in a genome. If that's what you believe then you've probably got lots of serious issues about understanding evolution and you should go back and read the literature on mutagenesis from the 1970s.

The long-standing assumption of random, constant, and gradual mutagenesis is refuted by observations that mutations occur more frequently when cells are maladapted to their environments, together with the discoveries of mechanisms by which mutations are targeted to specific genomic structures. These modifications of the modern synthesis assumptions could not have been predicted or found without exploration of molecular mechanisms.

As far as I know, it was never a requirement of the Modern Synthesis that all mutations are completely random and occur all the time at a constant rate. It WAS part of the Modern Synthesis to claim that evolution occurred gradually over long periods of time. That may not be strictly true but it's not because of mutation rates.

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Rosenberg, S.M. and C. Queitsch (2014) Combating Evolution to Fight Disease. Science 343:1088-1089. [doi: 10.1126/science.1247472]