#72. Why There is Sex [evolution]

EV

Red, theory; black, fact.

The flower Coronilla varia L.

Sex is an evolvability adaptation

There are always two games in town: reproduction and evolution. Since we live on an unstable planet where the environment can change capriciously, species here have been selected for rapid evolvability per se to enable them to adapt to the occasional rapid environment changes and not go extinct. Apparently, mutations, the starting point for evolutionary adaptation, become more common when the organism is stressed, and stress may partly be a forecast of loss of fertility due to a developing genome-environment mismatch. Bacteria exhibit the large mutation of transformation under stress conditions, and 3 types of stress all increased the meiotic recombination rate of fruit flies (Stress-induced recombination and the mechanism of evolvability. Zhong W, Priest NK. Behavioral ecology and sociobiology. 2011;65:493-502). Recombination can involve unequal crossing-over in which changes in gene dose can occur due to gene duplication or deletion. However, since most mutations are deleterious (there are more ways to do something wrong than to do it better) many mutations will also reduce fertility, and at precisely the wrong moment: when a reduction in fertility is impending due to environment change. The answer was to split the population into two halves: the reproduction specialists and the selection specialists, and remix their respective genomes at each generation.

The roles of the two sexes

Females obviously do the heavy lifting of reproduction, and males seem to be the gene testers. So if a guy gets a bad gene, he dies, ha ha, and the luckier guy next to him then gets two wives. The phenomenon of greater male variability (Greater male than female variability in regional brain structure across the lifespan. Wierenga LM, Doucet GE, Dima D, Agartz I, Aghajani M, Akudjedu TN, Albajes‐Eizagirre A, Alnæs D, Alpert KI, Andreassen OA, Anticevic A. Karolinska Schizophrenia Project (KaSP) Consortium. Hum. Brain Mapp., doi. 2020;10, and I have never seen so many authors on a paper: 160.) suggests that mutations have more penetrance in males, as befits the male role of cannon fodder/selectees. What the male brings to the marriage bed, then, is field-tested genetic information. Male promiscuity can therefore be seen as a necessary part of this system, which allows many mutations to be field tested with minimal loss of whole-population fertility, because it is the females who are the limiting factor in population fertility.

Chromosomal mechanisms of greater male variability

Chromosomal diploidy may be a system for sheltering females from mutations, assuming that the default process is for the phenotype that develops to be the average of the phenotypes individually specified by the paternal and maternal chromosome sets. Averaging tends to mute the extremes. The males, however, may set up a winner-take-all competition between homologous chromosomes early in development, with inactivation of one of them chosen at random. The molecular machinery for this may be similar to that of random x-inactivation in females. The result will be greater penetrance of mutations through to the phenotype and thus greater male variability. 

Quantitative prediction

This reasoning predicts that on a given trait, male variability (as standard deviation) will be 41% greater than the female variability, a testable prediction. 41% = [SQRT(2) -1] × 100. Already in my reading I have found a figure of 30%, which is suggestive. 

Now all I have to do is reconcile all this with the laws of Mendelian inheritance. 

Mechanistic reconciliation with Mendel's laws

09-16-2021: This reconciliation seems to require an exemption mechanism built into the postulated chromosome inactivation process that operates on genes present in only one copy per parent. The effect of this mechanism will be to double the penetrance of dominant alleles at that gene. Therefore, in males, at single-copy genes, evolution of the machinery of sex is driven by the favorable mutations.

A lovers' heart drawn in dust

#61. Stress and Schizophrenia [neuroscience]

NE

Red, theory; black, fact.

Introduction

The main positive symptoms of schizophrenia, namely hallucinations, word salad, and loosening of associations, all seem to be variations of the latter, so loosening of associations will here be taken as the primary disorder. Stress and the brain's dopaminergic system are strongly implicated in the causation of schizophrenia. In connection with stress, psychologists speak of "the affective [emotional] pathway to schizophrenia." 

Stress and madness in culture and history

For an example of this from literature, recall that Shakespeare's King Lear "went mad" when his lofty status disintegrated as a result of his mishandling the succession to the throne. In the film Little Big Man, General Custer becomes delusional on the battlefield during the debacle for which he is famous, immediately before taking an arrow from an equally disturbed Pawnee character. It must be even more humiliating when an animal brings you down, as happened to Captain Ahab, who was not notably on an even keel towards the end of the story. In real life, one suspects a case of stress-induced madness in Adolf Hitler toward the end of WWII.

Organismal responses to stress

Stress is known to increase genetic variability in bacteria, a process known as transformation. Stress is likewise known to increase the meiotic recombination rate in sexually reproducing organisms such as fruit flies. (Stress-induced recombination and the mechanism of evolvability. Zhong W, Priest NK. Behavioral ecology and sociobiology. 2011;65:493-502.) It seems that when an organism is in trouble, it begins casting about ever more widely for solutions. If evolution is the only mode of adaptation available, this casting about will take the form of an increase in the size and frequency of mutations. In conscious humans, however, this casting about in search of solutions in the face of stress may well take the form of a loosening of associations during thought. Should the person find the solution he or she needs, then presumably the stress levels go down and the thought process tightens up again, so we have a negative feedback operating that eventually renormalizes the thought process and all is well. In optimization theory, this process is called "simulated annealing."

Disorder of a cognitive stress response

But what if the person does not find the solution they need? Then, presumably the loosening of associations gets more and more pronounced ("reverse annealing") until it begins to interfere with the activities of daily living and thus begins to contribute net stress, thus making matters worse, not better. Now we have a pernicious positive feedback operating, and it rapidly worsens the state of the sufferer in what is known as a psychotic break, resulting in hospitalization. That these psychotic breaks are associated with tremendous stress is made clear by the fact that post-traumatic stress disorder is a common sequel of a psychotic episode.

 

Stress: Molecular aspects

01-06-2020: Messenger substances (i.e., hormones and neuromodulators) known to carry the stress signal are: CRF, ACTH, cortisol, noradrenaline, adrenaline, dopamine, NGF, and prolactin. The well-known phenomenon of stress sensitization, <05-31-2020: which may be part of the disease mechanism of schizophrenia,> probably inheres in long-term changes in protein expression and will not be apparent in a simple blood test for any of the above substances without a prior standardized stress challenge. (Could that be the process of getting the needle itself? In that case, you would install a catheter through the needle to permit repeated blood sampling and collect the baseline sample long after the intervention sample, not before, as is customary in research.)

Take home 

If you are under stress and noticing a loosening of associations, see a doctor, take a valium or whatever he prescribes, and focus intently on solving that problem; you may not have a lot of time to solve it. Don't go off and paint pictures, as Van Gogh did. We all know what happened to him.

02-15-2020: Is society as a whole becoming "schizophrenic" at this time, by the mechanism of stress-induced reverse annealing? (The stress in question would be coming from overpopulation.) Food for thought.

Other mental illnesses

05-31-2020: Bipolar disorder may result from an analogous positive feedback affecting another problem solving adaptation of the brain, which would be modelled by the alternation of brainstorming sessions (mania) with sessions in which the brainstormed productions are soberly critiqued (depression).

Brain mechanisms

12-04-2020: How does the loosening of associations of schizophrenia arise? I conjecture that one activated sensory memory represented in the posterior cortex does not activate another directly, but indirectly via an anatomically lengthy but fast relay through the prefrontal cortex, which has a well known dopaminergic input from the ventral tegmental area of the midbrain. Imagine that a higher vertebrate has a free-will spectrum, with machine-like performance and high dopaminergic tone at one end, and at the other, a carefully considered performance verging on overthinking, with low dopaminergic tone. Persons with schizophrenia have presumably pushed past the latter end of the spectrum into dysfunction. Dopamine could orchestrate movement along the free-will spectrum by a dual action on the prefrontal cortex: inhibiting associational reflexes passing back to posterior cortex while facilitating direct outputs to the motor system. Dual actions of neuromodulators are a neuroscientific commonplace (e.g., my PhD thesis) and dopamine is a neuromodulator. It remains to be explained how the NMDA receptor, which is also strongly implicated in schizophrenia, enters the picture. <03-07-2021: It could simply be the source of excitation of the ventral tegmental area.>

Photo by Ameer Basheer on Unsplash

#45. The Denervation-supersensitivity Theory of Mental Illness [neuroscience, evolution, genetics]

NE     EV     GE     

Red, theory; black, fact.

People get mental illness but animals seemingly do not, or at least not outside of artificial laboratory models such as the unpredictable, mild-stress rodent model of depression. A simple theory to account for this cites the paleontological fact that the human brain has been expanding at breakneck speed over recent evolutionary time and postulates that this expansion is ongoing at the present time, and that mental illness is the price we are paying for all this brain progress.

In other words, the mentally ill carry the unfavorable mutations that have to be selected out during this progress, and the mutation rate in certain categories of mutation affecting human brain development is elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes here to indicate that the adaptation inheres in changes in the standard deviation of traits, not the average, and is therefore not Lamarkian.

In brain evolution, the growth changes in the various parts very probably have to be coordinated somehow. I conjecture that there is no master program doing this coordination. Rather, I conceive of the human brain as comprising scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. (This idea is consistent with the finding of about 400 genes in humans that participate in establishing body size.) All harmonious symmetry, even left-right symmetry, would have to be painstakingly created by brute-force selection, involving the early deaths of millions of asymmetrical individuals. This idea was outlined in post 10.

Assuming that left and right sides must functionally cooperate to produce a fitness improvement, mutations affecting parcel growth must occur in linked, left-right pairs to avoid irreducible-complexity paradoxes. I have previously conjectured in these pages that the crossing-over phenomenon of egg and sperm maturation serves to create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. (See "Can Irreducible Complexity Evolve?")

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which I conjecture implements if-then rules, like those making up the knowledge bases familiar from the field of artificial intelligence. The "if" part of the rule would be evaluated in post-Rolandic cortex, i.e., in temporal and parietal association cortices, and the "then" part of the rule would be created by the pre-Rolandic association cortex, i.e., the prefrontal cortex. The white matter tracts running forward in the brain would connect the "if" part with the "then" part, and the backward running white-matter tracts would carry priming signals to get other rules ready to "fire" if they are commonly used after the rule in question.

Due to such tight coordination, I would expect that the ideal brain will have a fixed ratio of prefrontal cortex to post-Rolandic association cortex. However, the random nature of the growth-gene bi-mutations (perhaps at mutational hot-spots) permitting human brain evolution will routinely violate this ideal ratio, leading to the creation of individuals having either too much prefrontal cortex or too much temporal/parietal cortex. In the former case, you will have prefrontal cortex starved of sensory input. In the latter case, you will have sensory association cortex starved of priming signals feeding back from motoric areas.

Denervation supersensitivity occurs when the normal nerve supply to a muscle is interrupted, resulting in a rapid overexpression of acetylcholine receptors on the muscle. This can be seen as an attempt to compensate for weak nerve transmission with a tremendous re-amplification of the signal by the muscle. Analogous effects have been found in areas of the cerebral cortex deprived of their normal supply of sensory signals, so the effect seems to be quite general.

In cases of genetically-determined frontal-parietal/temporal imbalance, I conjecture that the input-starved side develops something like denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in a person with schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia. Depression may originally have been an adaptation to the presence of a man-eating predator in the neighborhood, but in civilized contexts, it can get activated by the unpredictable (to the sufferer) punishments resulting from manic activity. If the mania is sufficiently mild to co-exist with depression, as in type II bipolar disorder, then the overall effect of the depressive component may be like a band-aid on the mania.

The non-overgrown association cortex might even secondarily develop the opposite of denervation supersensitivity as the result of continual bombardment with autonomous activity from the other side of the Rolandic fissure. This could account for the common observation of hypoprefrontality in cases of schizophrenia.

#39. Can Irreducible Complexity Evolve? [genetics, evolution]

EV     GE     

Red, theory; black, fact.

5-26-2018: Influential biologist Richard Dawkins wrote in "The God Delusion" that a genuine case of irreducible complexity will never be found in biology. A case of irreducible complexity would be some adaptation that would require an intelligent designer because it could never evolve one mutation at a time, and Dawkins believes there is no such intelligent designer in biology.

In classic natural selection, each mutation must be individually beneficial to its possessor in order for selection to increase its prevalence in the population to the point where the next incremental, one-mutation improvement becomes statistically possible. In this way, all manner of wondrous things are supposed to evolve bit by tiny bit.

However, I am seeing irreducible complexity all over the place these days. For example, your upper-jaw dentition must mesh pretty accurately with that of your lower jaw or you can't eat. Thus, the process of evolutionary foreshortening of the muzzle of the great apes to the flat human face could never have happened, assuming that a single mutation affects only the upper or lower jaw. But it did. (Let us gloss over the fact that that is an assumption, because the contrary seems to require non-local rules in development.)

Furthermore, how can any instinctive signaling system evolve one mutation at a time? At a minimum, you always need both the transmitter adaptation and the receiver adaptation, not to mention further mutations to connect the receiver circuit to something useful. The evolution of altruism presents a similar problem. The lonely first altruist in the population is always at a disadvantage in competition with the more selfish non-mutants unless it also has a signaling system that lets it recognize fellow altruists (initially, close relatives) and a further mutation that places the altruistic behavior under the control of the receiver part of this system. Thus, altruists would only be altruistic to their own kind, the requirement for altruism to be selected in the presence of selfishness. Finally, the various parts of this system must be indissolubly linked in a way that the non-altruists cannot fake.

My solution is to label the crossing-over events that occur during meiosis as "tetra-mutations." In crossing over, two homologous chromosomes pair up along their length and swap a long segment of DNA, a process requiring four double chain breaks and their corresponding repairs. Because of the presence of single-nucleotide polymorphisms, the homologous chromosomes are not exactly the same, so that each of the upstream sides of the four chain breaks ends up in a subtly different genetic environment. If the break point falls between a cis-acting regulatory element and the corresponding structural gene, for instance, the former may now control the expression of a slightly different protein. Thus, there could be as many as four distinct functional consequences of one crossing-over event. Why not call that a tetra-mutation?

In this way, a concerted change affecting four distinct sites becomes possible. The two ends of the recombinant segment can in principle be functionally unrelated initially. They become related if both are affected by the same tetra-mutation and the entire change increases fitness and is thus selected.

A single tetra-mutation could in principle produce viable altruism at one stroke because of the number of simultaneous changes involved. 

The probability of a combination of simultaneous local changes being beneficial to the organism is much smaller on mathematical grounds than is the probability of a given single-nucleotide change being beneficial. However, these unfavorable statistics are at least partly offset by the existence of a dedicated system for producing tetra-mutations in large numbers, namely meiosis, part of the process of maturation of egg cells and sperm cells.

In the big picture, tetra-mutations provide a way for a species to discontinuously jump into new niches as they open up, possibly explaining how a capacity for this kind of mutation could spread and become characteristic of surviving species over time. This idea also provides a ready explanation for the lack of transitional forms in the fossil record.

5-30-2018: Here is the search description again, in case you missed it or could not see all of it: Sexual reproduction may allow the evolution of irreducible complexity by increasing the intrinsic complexity of the basic building block of change, the mutation.

6-12-2018: Upon further reflection, it seems that the tetramutation construct described above lacks validity because during gamete maturation it falls apart into two bi-mutations, both of which cannot contribute to the same zygote. The bi-mutation is stable, however, because of the intervening translocated DNA segment. It is harder to see how a complex adaptation like altruism could evolve out of nothing but mono-mutations and bi-mutations, but that does not mean the theory put forward in this post is necessarily wrong. One must not argue from lack of imagination. It is an interesting question, actually, what is the minimum set of all mutation types necessary to account for all known adaptations.

8-27-2019: In my ignorance, I have undersold the bi-mutation idea. A very far-reaching change to the genetic information can occur during crossing-over that is not at all subtle and is termed unequal crossing-over. This form of the process arises because of inaccuracies, sometimes major, in the initial alignment of the homologous chromosomes prior to crossing-over. When the process is finished, one chromosome has been shortened and the other has been lengthened, with gene duplication. This is the major source of gene duplication, which, in turn, is a major source of junk DNA, the part that is classified as broken genes. Two questions come to mind. The first is, are anatomical features such as jaw length and axon targets somehow controlled by variations in gene dose? The second, which is a tangent, is, are broken genes really broken or just temporarily switched off by genetic drift at some mutational hot spot in the recognition site of some transcription factor? The analogy here is to a generator in a power plant that has been placed in stand-down mode because of a temporary decrease in the demand for electrical power.

#6. Mental Illness as Communication [neuroscience, genetics]

NE     GE     

Red, theory; black, fact.

The effects of most deleterious mutations are compensated by negative feedback processes occurring during development in utero. However, if the population is undergoing intense Darwinian selection, many of these mutations become unmasked and therefore contribute variation for selection. (Jablonka and Lamb, 2005, The MIT Press, "Evolution in Four Dimensions")

However, since most mutations are harmful, a purely random process for producing them, with no pre-screening, is wasteful. Raw selection alone is capable of scrubbing out a mistake that gets as far as being born, at great cost in suffering, only to have, potentially, the very same random mutation happen all over again the very next day, with nothing learnt. Repeat ad infinitum. This is Absurd, and quarrels with the engineer in me, and I like to say that evolution is an engineer. Nowadays, evolution itself is thought to evolve. A simple example of this would be the evolution of DNA repair enzymes, which were game-changers, allowing much longer genes to be transmitted to the next generation, resulting in the emergence of more-complex lifeforms.

An obvious, further improvement would be a screening, or vetting process for genetic variation. Once a bad mutation happens, you mark the offending stretch of DNA epigenetically in all the close relatives of the sufferer, to suppress further mutations there for a few thousand years, until the environment has had time to change significantly.

Obviously, you also want to oppositely mark the sites of beneficial mutations, and even turn them into recombinant hot spots for a few millennia, to keep the party going. Hot spots may even arise randomly and spontaneously, as true, selectable epi-mutations. The downside of all this is that even in a hot spot, most mutations will still be harmful, leading to the possibility of "hitchhiker" genetic diseases that cannot be efficiently selected against because they are sheltered in a hot spot. Cystic fibrosis may be such a disease, and as the hitchhiker mechanism would predict, it is caused by many different mutations, not just one. It would be a syndrome defined by the overlap of a vital structural gene and a hot spot, not by a single DNA mutation. I imagine epigenetic hot spots to be much more extended along the DNA than a classic point mutation.

It is tempting to suppose that the methylation islands found on DNA are these hot spots, but the scanty evidence available so far is that methylation suppresses recombinant hot spots, which are generally defined non-epigenetically, by the base-pair sequence.

The human brain has undergone rapid, recent evolutionary expansion, presumably due to intense selection, presumably unmasking many deleterious mutations affecting brain development that were formerly silent. Since the brain is the organ of behavior, we expect almost all these mutations to indirectly affect behavior for the worse. That explains mental illness, right?

I'm not so sure; mental illnesses are not random, but cluster into definable syndromes. My reading suggests the existence of three such syndromes: schizoid, depressive, and anxious. My theory is that each is defined by a different recombinant hot spot, as in the case of CF, and may even correspond to the three recently-evolved association cortices of the brain, namely parietal, prefrontal, and temporal, respectively. The drama of mental illness would derive from its communication role in warning nearby relatives that they may be harbouring a bad hot spot, causing them to find it and cool it by wholly unconscious processes. Mental illness would then be the push back against the hot spots driving human brain evolution, keeping them in check and deleting them as soon as they are no longer pulling their weight fitness-wise. The variations in the symptoms of mental illness would encode the information necessary to find the particular hot spot afflicting a particular family.

Now all we need is a communication link from brain to gonads. The sperm are produced by two rounds of meiosis and one of mitosis from the stem-like, perpetually self-renewing spermatogonia, that sit just outside the blood-testes barrier and are therefore exposed to blood-borne hormones. These cells are known to have receptors for the hypothalamic hormone orexin A*, as well as many other receptors for signaling molecules that do or could plausibly originate in the brain as does orexin. Some of these receptors are:

• retinoic acid receptor α
• glial cell-derived neurotrophic factor (GDNF) receptor
• CB2 (cannabinoid type 2) receptor
• p75 (For nerve growth factor, NGF)
• kisspeptin receptor.

*Gen Comp Endocrinol. 2016 May 9. pii: S0016-6480(16)30127-7. doi: 10.1016/j.ygcen.2016.05.006. [Epub ahead of print] Localization and expression of Orexin A and its receptor in mouse testis during different stages of postnatal development. Joshi D1, Singh SK2.

PS: for brevity, I left out mention of three sub-functions necessary to the pathway: an intracellular gonadal process transducing receptor activation into germ line-heritable epigenetic changes, a process for exaggerating the effects of bad mutations into the development of monsters or behavioral monsters for purposes of communication, and a process of decoding the communication located in the brains of the recipients.