Towards a theory of mutation in biology

K. P. Mohanan, Tara Mohanan

Like most of my other postings, this too is meant primarily for research students, especially graduate students in Biology. It is about the confusion generated by the use of the terms ‘mutation’ and ‘random mutation’. It is also a plea to research students to construct a theory of mutation (= a theory of change) in biology, comparable to the theories of mechanics in physics, which are theories of change (change of location in inanimate entities.)


1. THE TERM MUTATION

If we do an internet search on the word 'mutation', chances are that most entries would be on mutation in modern biology. And they would be on mutation as a change at the molecular level.

For instance, the article “Genetic Mutation” by Laurence Loewe in Nature Education 1(1):113 says

“Mutations are changes in the genetic sequence, and they are a main cause of diversity among organisms. ... For mutations to affect an organism's descendants, they must: 1) occur in cells that produce the next generation, and 2) affect the hereditary material. Ultimately, the interplay between inherited mutations and environmental pressures generates diversity among species... Although various types of molecular changes exist, the word "mutation" typically refers to a change that affects the nucleic acids. ("Genetic Mutation" https://www.nature.com/scitable/topicpage/genetic-mutation-1127/)”

This is not the dictionary meaning of the word ‘mutation’ outside biology, where it simply means ‘change’, and ‘immutable’ means unchangeable. In this sense, the term mutation can cover not only changes at the level of biomolecules, but also changes at the level of cells, tissues, organs, organisms, varieties, varieties/species, or the behaviour or habitat of a variety/species.

Interestingly, Darwin talks about mutability and immutability in terms of properties at the phenotypical level of varieties/species above the level of microbiology (molecules and cells):

"I have now recapitulated the chief facts and considerations which have thoroughly convinced me that species have changed, and are still slowly changing by the preservation and accumulation of successive slight favourable variations. Why, it may be asked, have all the most eminent living naturalists and geologists rejected this view of the mutability of species? It cannot be asserted that organic beings in a state of nature are subject to no variation; it cannot be proved that the amount of variation in the course of long ages is a limited quantity; no clear distinction has been, or can be, drawn between species and well-marked varieties. It cannot be maintained that species when intercrossed are invariably sterile, and varieties invariably fertile; or that sterility is a special endowment and sign of creation. The belief that species were immutable productions was almost unavoidable as long as the history of the world was thought to be of short duration; and now that we have acquired some idea of the lapse of time, we are too apt to assume, without proof, that the geological record is so perfect that it would have afforded us plain evidence of the mutation of species, if they had undergone mutation." (Origin of Species p.190)

In the context of evolution above the level of DNA, immutability translates as what is preserved in the course of evolution, shifting the focus of attention from variable to what is invariant. Thus, cell membranes and membranes have been preserved from bacteria to humans, so it makes sense to ask what the correlates of cell membranes are from bacteria to fungi to plants to worms, and humans. Likewise, what are the molecular correlates of the bone material preserved in vertebrates?


2. THE TRANSDISCIPLINARY CONCEPT OF MUTATION

If, following Darwin, we decide to use the term ‘mutation’ to refer to change, and decide to construct a theory of change as one of the components of a theory of evolution, it has far reaching consequences to biology, some of which are:

The concept of change: we need to place ‘change’ of structure and function (anatomy and physiology), behaviour, and habitat at the levels biomolecules, cells, tissues, organs, organisms and species. When we do that, it becomes obvious that physical changes, chemical changes, developmental changes, and historical changes are all instances of changes. And that means we need to place the biology specific concept of mutation in the larger perspective of change as a transdisciplinary concept.

Transfer of ideas for theory construction. It would be useful to look for ideas for theory construction in the theories of physical changes and chemical changes. A physical change from solid to liquid or liquid to gas is a change, and a change involved in a chemical reaction is a chemical change, or what the chemists call a change in the chemical species. And most importantly, what is called mechanics in physics as the study of motion seeks to understand change of location in inanimate entities. What can we learn from these theories that would be useful for theories of change in biology?

Change, cause, force, and inertia. The concept of force in mechanics in physics as that which causes change becomes directly relevant for the theory of change in biology. Aristotle conceptualised force as that which causes motion (that which causes a change of location), and inertia as the state (in his case, state of rest) in the absence of a cause. In contrast, Galileo (and Newton) conceptualised force as that which causes a change in velocity, inertia still being a state in the absence of a cause. Once conceptualised as change, the transdisciplinary concepts of force and inertia become directly relevant for the construction of a theory of mutation in biology, conceptualised as the biological counterpart of mechanics in physics.

Non-random mutation in biology. The investigation of mutation conceptualised as above becomes a study of what is NOT random in mutation. Mechanics in physics is the study of what is predictable, what is non-random, in the study of the motion of inanimate entities. It is unscientific to label mutation in biology as ‘random’, thereby generating the prejudice that there is nothing predictable/ regular that we need a scientific theory of mutation in biology for.


3. UNTENABILITY OF THE TEXTBOOK VIEW OF ‘RANDOM MUTATION’

As Laurence Loewe puts it,

“The statement that mutations are random is both profoundly true and profoundly untrue at the same time. The true aspect of this statement stems from the fact that, to the best of our knowledge, the consequences of a mutation have no influence whatsoever on the probability that this mutation will or will not occur. In other words, mutations occur randomly with respect to whether their effects are useful. Thus, beneficial DNA changes do not happen more often simply because an organism could benefit from them. Moreover, even if an organism has acquired a beneficial mutation during its lifetime, the corresponding information will not flow back into the DNA in the organism's germline. This is a fundamental insight that Jean-Baptiste Lamarck got wrong and Charles Darwin got right.

However, the idea that mutations are random can be regarded as untrue if one considers the fact that not all types of mutations occur with equal probability. Rather, some occur more frequently than others because they are favored by low-level biochemical reactions. These reactions are also the main reason why mutations are an inescapable property of any system that is capable of reproduction in the real world. Mutation rates are usually very low, and biological systems go to extraordinary lengths to keep them as low as possible, mostly because many mutational effects are harmful. Nonetheless, mutation rates never reach zero, even despite both low-level protective mechanisms, like DNA repair or proofreading during DNA replication, and high-level mechanisms, like melanin deposition in skin cells to reduce radiation damage. Beyond a certain point, avoiding mutation simply becomes too costly to cells. Thus, mutation will always be present as a powerful force in evolution. ("Genetic Mutation" https://www.nature.com/scitable/topicpage/genetic-mutation-1127/)

I would like to suggest that the idea that “the consequences of a mutation have no influence whatsoever on the probability that this mutation will or will not occur” can be true, if at all, only at the level of DNA. If we accept the ideas that

A) those properties which are preserved (i.e., left unchanged, relatively immutable) are the ones which have an adaptive function, and

B) mutation is the difference between the properties of the parent and those of the offspring,

then it follows that

most of those properties that make the organism not viable will be repaired above the DNA level (and hence such mutations are much less likely to occur), and

the remaining violations viability constraints (those that come under viability selection as distinct from fecundity selection) will not be passed down to the next generation (because an organism cannot reproduce after it dies) and hence those properties will not count as mutation.

In sum, those mutations which are relevant for reproduction are indeed non-random not only in the first but also the second sense of ‘random mutation’ that Loewe talks about.


4. THE NEED FOR A SCIENTIFIC THEORY OF MUTATION IN BIOLOGY

If we accept the idea that mutation is non-random, then those aspects of mutation that are predictable come under the scope of scientific explanation. They call for a theory of mutation that currently does not exist in biology. Hence this wake up call to research students in biology.