Showing posts with label genome. Show all posts
Showing posts with label genome. Show all posts

Monday, September 13, 2021

#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, so long, 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






Sunday, December 17, 2017

#34. Emotions [evolutionary psychology, genetics, neuroscience]

EP    NE    GE
Red, theory; black, fact.

12-17-2017: In previous posts, I theorized that humans, along with all other sexually-reproducing species, have a long-range guidance system that I called proxy natural selection, or preferably, post-zygotic gamete selection (PGS), that is basically a fast form of evolution in which individual cells, the gametes, are the units of selection, not individuals. Selection is conjectured to happen post-zygotically (i.e., sometime after the beginning of development, or even in adulthood) but is retroactive to the egg and sperm that came together to create the individual. Each gamete is potentially unique because of the crossing-over genetic rearrangements that happen during its maturation. This theory explains the biological purpose of this further layer of uniqueness beyond that due to the sexual mixing of chromosomes, which would otherwise appear to be redundant.

Our emotions are conjectured to be programmed by species-replacement group selection and to serve as proxies for increases and decreases in the fitness of our entire species.

A further correlate of an emotion beyond the cognitive and autonomic-nervous-system components would be the neurohumoral component, expressed as chemical releasing and inhibiting factors that enter the general circulation via the portal vessels of the hypothalamus, blood vessels which are conventionally described as affecting only the anterior pituitary gland. These factors are theorized to reach the stem-like cells that mature into egg and sperm, where they set reversible epigenetic controls on the level of crossing-over that will occur during differentiation. Large amounts of crossing-over are viewed as retroactively penalizing the gametes leading to the individual by obfuscating or overwriting with noise specifically the genetic uniqueness of said original gametes. In contrast, low levels of further crossing-over reward the original gametes with high penetrance into the next generation. Here, I believe you have all the essential ingredients of classical natural selection, and all the potential, in a process that solves problems on an historical timescale.

Crossing-over happens only between homologous chromosomes, which are the paternal and maternal copies of the same chromosome. Human cells have 46 chromosomes because they have 23 pairs of homologous chromosomes. The homologous-chromosome-specificity of crossing-over suggests that the grand optimization problem that is human evolution has been broken down into 23 smaller sub-problems for the needs of the PGS process, each of which can be solved independently, without interactions with any of the other 22, and which involves a 23-fold reduction in the number of variables that must be simultaneously optimized. In computing, this problem-fragmentation strategy greatly increases the speed of optimization. I conjecture that it is one of the features that makes PGS faster than classical natural selection.

However, we now need 23 independent neurohumoral factors descending in the bloodstream from brain to testis or (fetal) ovary, each capable of setting the crossing-over propensity of one specific pair of homologous chromosomes. Each one will require its own specific receptor on the surface of the target oogonia or spermatogonia. Check this out in the literature, and you will already find a strange diversity of cell-surface receptors on the spermatogonia. (I haven't looked at oogonia yet.&&) I predict that the number of such receptors known to science will increase to at least 23. None of this is Lamarkism, because nervous-system control would be over the standard deviation of behavioral traits, not their averages.

1-09-2018: Naively, this theory also appears to require 23 second messengers to transfer the signals from cell surface to nucleus, which sounds excessive. Perhaps the second messengers form a combinatorial code, which would reduce the number required by humans to log2 (23) = 4.52, or 5 in round numbers. This is much better. Exactly five second-messenger systems are known, these being based on: cyclic AMP, inositol triphosphate, cyclic GMP, arachidonic acid, and small GTPases (e.g., ras). However, many mammalian species have many more than the 32 chromosome pairs needed to saturate a 5-bit address space.

1-10-2018: If we expand the above list of second messengers with the addition of the calcium/calmodulin complex, the address space expands to 64 pairs of homologous chromosomes, for a total ploidy of 128. This seems sufficient to accommodate all the mammals. Thus, a combinatorial second-messenger code representable as a five- or six-bit binary integer in most organisms would control the deposition of the epigenetic marks controlling crossing-over propensity.

If the above code works for transcription as well as epigenetic modification, then applying whatever stimuli it takes to produce a definite combinatorial second-messenger state inside the cell will activate one specific chromosome for transcription, so that the progeny of the affected cell will develop into whatever that chromosome specifies, be it an organ, a system, or something else. And there you may have the long-sought key to programming stem cells. You're welcome.

Each pair of homologous chromosomes may correspond to what in an earlier post was called a "PNS focus." The requirement that the evolution of each chromosome contribute independently to the total increase in fitness suggests that a chromosome specifies a system, like the nervous system or the digestive system. We seem to have only 11 systems, not 23, but more may be defined in the future.

A related concept is that a chromosome specifies an ancestral, generic cell type, like glial cells (4 subtypes known) or muscle cells (3 subtypes known). The great diversity of the neurons suggest that they must be reclassified into multiple basic types, perhaps along the lines suggested by the functional classification of the cranial nerves: general somatic, general visceral, and special somatic (i.e., specific senses).

1-09-2018: A third concept for function assignment to homologous pairs of chromosomes postulates a hypothetical maximally divided genome in which each cell type has its own chromosome pair, a state conjectured to seldom occur in nature. Co-evolution of clusters of cell types (e.g., neurons and glia; bone and cartilage) would create selection pressure for the underlying cell-type-specific chromosomes to become covalently linked into the larger chromosomes that we see in the actual karyotypes. Thus, each observed homologous pair would correspond to a few cell types that are currently co-evolving, which seems to return us to the system or organ concept. 

01-08-2019: The system specified by a chromosome may be called a cooperation system, and these may be organized in a hierarchy, following the general principles of spatial organization outlined in my post: "The Pictures in Your Head.Chromosomes activated earlier in development will specify system-like entities and those activated late in development will specify organ-like entities. Only the first-activated chromosome will apply to the entire organism.

Humans depend on complex social structures for their survival, and this comes out of our individual behavioral tendencies. Probably, most PGS adaptations to environmental fluctuations involve modifying these structures, which would come out of subtle modifications of individual behaviors. I think I am just repeating E.O. Wilson here. Our hard-wired species-fitness definitions would give rise to the primary emotions, perhaps in the hypothalamus or limbic system, by connecting specific stimuli to primary emotions in the manner of an if-then rule. 

Further out on the cortex, the specific stimuli being connected would get progressively more complex and learning-dependent, and progressively less concerned with the "what" of behavior (i.e., our species-specific taxes) and more with the "how" of behavior. In "how" mode, the complex stimuli become more like signposts to be consulted on a journey. PGS adaptations of our behavior would affect the hardwired aspects of this hypothetical transition zone. The primary emotions would then be like the highest hierarchical level of our motor program, or like the least-indented instructions of a conventional high-level computer program.

I conjecture that religion is important because it goes straight for this highest level. We all know that religion is kind of an emotional business, what with the organ music and the stained glass and all such as that, and this is why. I therefore conjecture that words spoken often from the pulpit, such as God, sin, forgiveness, devil, angel, soul, salvation, etc., all enclose a secret that writers such as Dawkins do not grasp: the emotions are the message. To illustrate this, let us attempt an emotional definition of the master symbol, "God."

God: feeling loved and secure to the point of invulnerability; feeling small in an agreeable way, as in the presence of mountains; feeling brotherly/sisterly towards one's fellow humans; blossoming in confidence into one's full potential; fearing nothing.

Perhaps that's enough to give the general idea. No doubt a whole dictionary could be compiled along these lines. When the priest strings these emotion-words together, he creates an experience for the congregation that could fairly be called a form letter from "God," assuming that the word "God" points to the PGS process itself. The job of the priest is to help the congregation relate on a deep level to the sacred texts and to see/feel how they apply to the challenges of the here and now.

7-05-2018: Another term for PGS would be "Yahwetion," from "Yahweh," the conventional modern spelling of the name of the god of ancient Israel, and the "tion" ending indicating a process, like evolution. This neologism advantageously steers people away from category errors like attempting to worship it, or appease it, or what have you.

The conventionally religious will complain that this would make prayer to God impossible, but not if prayer itself is re conceived as "auto socialization," following the educational theory of prayer. Then prayer becomes a fantasy conversation with anyone, living or dead, that you would like to have as a mentor, if it were possible.

Monday, February 6, 2017

#23. Proxy Natural Selection: The God-shaped Gap at the Heart of Biology [genetics, evolution]

EV    GE    
Red, theory; black, fact.

2-06-2017
As promised, here is my detailed and hypothetical description of the entity responsible for compensating for the fact that our microbial, insect, and rodent competitors evolve much faster than we do because of their shorter generation times. In these pages, I have been variously calling this entity the intermind, the collective unconscious, the mover of the zeitgeist, and the real, investigable system that the word "God" points to. I here recant my former belief that epigenetic marks are likely to be the basis of an information storage system sufficient to support an independent evolution-like process. I will assume that the new system, "proxy natural selection" (PNS) is DNA-based.

11-20-2017
The acronym PNS is liable to be confused with "peripheral nervous system," so a better acronym would be "PGS," meaning "post-zygotic gamete selection."

2-06-2017
First, a refresher on how standard natural selection works. DNA undergoes point mutations (I will deal with the other main type of mutation later) that add diversity to the genome. The developmental process translates the various genotypes into a somewhat diverse set of phenotypes. Existential selection then ensues from the interaction of these phenotypes with the environment, made chronically stringent by population pressure. Differential reproduction of phenotypes then occurs, leading to changes in gene frequencies in the population gene pool. Such changes are the essence of evolution.

PNS assumes that the genome contains special if-then rules, perhaps implemented as cis-control-element/structural gene partnerships, that collectively simulate the presence of an objective function that dictates the desiderata of survival and replaces or stands in for existential selection. A given objective function is species-specific but has a generic resemblance across the species of a genus. The genus-averaged objective function evolves by species-replacement group selection, and can thus theoretically produce altruism between individuals. The if-then rules instruct the wiring of the hypothalamus during development, which thereby comes to dictate the organism's likes and dislikes in a way leading to species survival as well as (usually) individual survival. Routinely, however, some specific individuals end up sacrificed for the benefit of the species.

Here is how PNS may work. Crossing-over mutations during meiosis to produce sperm increase the diversity of the recombinotypes making up the sperm population. During subsequent fertilization and brain development, each recombinotype instructs a particular behavioral temperament, or idiosyncratotype. Temperament is assumed to be a set of if-then rules connecting certain experiences with the triggering of specific emotions. An emotion is a high-level, but in some ways stereotyped, motor command, the details of which are to be fleshed out during conscious planning before anything emerges as overt behavior. Each idiosyncratotype interacts with the environment and the result is proxy-evaluated by the hypothalamus to produce a proxy-fitness (p-fitness) measurement. The measurement is translated into blood-borne factors that travel from the brain to the gonads where they activate cell-surface receptors on the spermatogonia. Good p-fitness results in the recombination hot spots of the spermatogonia being stabilized, whereas poor p-fitness results in their further destabilization. 

Thus, good p-fitness leads to good penetrance of the paternal recombinotype into viable sperm, whereas poor p-fitness leads to poor penetrance, because of many further crossing-over events. Changes in hotspot activity could possibly be due to changes in cytosine methylation status. The result is within-lifetime changes in idiosyncratotype frequencies in the population, leading to changes in the gross behavior of the population in a way that favors species survival in the face of environmental fluctuations on an oligogenerational timescale. On such a timescale, neither standard natural selection nor synapse-based learning systems are serviceable.

2-07-2017
The female version of crossing over may set up a slow, random process of recombination that works in the background to gradually erase any improbable statistical distribution of recombinotypes that is not being actively maintained by PNS.

7-29-2017
Here is a better theory of female PNS. First, we need a definition. PNS focus: a function that is the target of most PNS. Thus, in trees, the PNS focus is bio elaboration of natural pesticides. In human males, the PNS focus is brain development and the broad outlines of emotional reactivity, and thus behavior. In human females, the PNS focus is the digestive process. The effectiveness of the latter could be evaluated while the female fetus is still in the womb, when the eggs are developing. The proxy fitness measure would be how well nourished the fetus is, which requires no sensory experience. This explains the developmental timing difference between oogenesis and spermatogenesis. Digestion would be fine tuned by the females for whatever types of food happen to be available in a given time and place.

8-18-2017
Experimental evidence for my proposed recombination mechanism of proxy natural selection has been available since 2011, as follows:

Stress-induced recombination and the mechanism of evolvability
by Weihao Zhong; Nicholas K. Priest
Behavioral Ecology and Sociobiology, 03/2011, Volume 65, Issue 3

permalink:

Abstract:
"The concept of evolvability is controversial. To some, it is simply a measure of the standing genetic variation in a population and can be captured by the narrow-sense heritability (h2). To others, evolvability refers to the capacity to generate heritable phenotypic variation. Many scientists, including Darwin, have argued that environmental variation can generate heritable phenotypic variation. However, their theories have been difficult to test.
 Recent theory on the evolution of sex and recombination provides a much simpler framework for evaluating evolvability. It shows that modifiers of recombination can increase in prevalence whenever low fitness individuals produce proportionately more recombinant offspring. Because recombination can generate heritable variation, stress-induced recombination might be a plausible mechanism of evolvability if populations exhibit a negative relationship between fitness and recombination. Here we use the fruit fly, Drosophila melanogaster, to test for this relationship.
We exposed females to mating stress, heat shock or cold shock and measured the temporary changes that occurred in reproductive output and the rate of chromosomal recombination. We found that each stress treatment increased the rate of recombination and that heat shock, but not mating stress or cold shock, generated a negative relationship between reproductive output and recombination rate. The negative relationship was absent in the low-stress controls, which suggests that fitness and recombination may only be associated under stressful conditions. Taken together, these findings suggest that stress-induced recombination might be a mechanism of evolvability."

However, my theory also has a macro aspect, namely that the definition of what constitutes "stress," in terms of neuron interconnections or chemical signaling pathways, itself  evolves, by species-replacement group selection. Support for that idea is the next thing I must search for in the literature. &&

Monday, July 4, 2016

#7. What is Intelligence? Part I. DNA as Knowledge Base [genetics, engineering]

EN     GE     
Red: theory; black, fact.

I have concluded that the world contains three intelligences: the genetic, the synaptic, and the artificial. The first includes (See Deprecated, Part 10) genetic phenomena and is the scientifically-accessible reality behind the concept of God. The synaptic is the intelligence in your head, and seems to be the hardest to study and the one most in need of elucidation. The artificial is the computer, and because we built it ourselves, we presumably understand it. Thus, it can provide a wealth of insights into the nature of the other two intelligences and a vocabulary for discussing them.

Artificial intelligence systems are classically large knowledge bases (KBs), each animated by a relatively small, general-purpose program, the "inference engine." The knowledge bases are lists of if-then rules. The “if” keyword introduces a logical expression (the condition) that must be true to prevent control from immediately passing to the next rule, and the “then” keyword introduces a block of actions the computer is to take if the condition is true. Classical AI suffers from the problem that as the number of if-then rules increases, operation speed decreases dramatically due to an effect called the combinatorial explosion.

A genome can be compared to a KB in that it contains structural genes and cis-acting control elements.(CCEs). The CCEs trigger the transcription of the structural genes into messenger RNAs in response to environmental factors and these are then translated into proteins that have some effect on cell behavior. The analogy to a list of if-then rules is obvious. A CCE evaluates the “if” condition and the conditionally translated protein enables the “action” taken by the cell if the condition is true.

Note that the structural gene of one rule precedes the CCE of the next rule along the DNA strand. Surely, would this circumstance not also represent information? However, what could it be used for? It could be used to order the rules along the DNA strand in the same sequence as the temporal sequence in which the rules are normally applied, given the current state of the organism’s world. This seems to be a possible solution to the combinatorial explosion problem, leading to much shorter delays on average for the transcriptase complex to arrive where it is needed. I suspect that someday, it will be to this specific arrangement that the word “intelligence” will refer.
The process of putting the rules into such a sequence may involve trial-and-error, with transposon jumping providing the random variation on which selection operates. A variant on this process would involve stabilization by methylation of recombination sites that have recently produced successful results. These results would initially be encoded in the organism's emotions, as a proxy to reproductive success. In this form, the signal can be rapidly amplified by inter individual positive feedback effects. It would then be converted into DNA methylation signals in the germ line. (See my post on mental illness for possible mechanisms.) DNA methylation is known to be able to cool recombination hot spots.

A longer-timescale process involving meiotic crossing-over may create novel rules of conduct by breaking DNA between promoter and structural gene of the same rule, a process analogous to the random-move generation discussed in my post on dreaming. Presumably, the longest-timescale process would be creating individual promoters and structural genes with new capabilities of recognition and effects produced, respectively. This would happen by point mutation and classical selection.
How would the genetic intelligence handle conditional firing probabilities in the medium to low range? This could be done by cross linking nucleosomes via the histone side chains in such a way as to cluster the CCEs of likely-to-fire-next rules near the end of the relevant structural gene, by drawing together points on different loops of DNA. The analogy here would be to a science-fictional “wormhole” from one part of space to another via a higher-dimensional embedding space. In this case, “space” is the one-dimensional DNA sequence with distances measured in kilobases, and the higher-dimensional embedding space is the three-dimensional physical space of the cell nucleus.

The cross linking is presumably created and/or stabilized by the diverse epigenetic marks known to be deposited in chromatin. Most of these marks will certainly change the electric charge and/or the hydrophobicity of amino acid residues on the histone side chains. Charge and hydrophobicity are crucial factors in ionic bonding between proteins. The variety of such changes that are possible.

Mechanistically, there seems to be a great divide between the handling of high and of medium-to-low conditional probabilities. This may correspond with the usual block structure of algorithms, with transfer of control linear and sequential within a block, and by jump instruction between blocks.

Another way of accounting for the diversity of epigenetic marks, mostly due to the diversity of histone marks, is to suppose that they can be paired up into negative-positive, lock-key partnerships, each serving to stabilize by ionic bonding all the wormholes in a subset of the chromatin that deals with a particular function of life. The number of such pairs would equal the number of functions.

Their lock-key specificity would prevent wormholes, or jumps, from forming between different functions, which would cause chaos. If the eukaryotic cell is descended from a glob-like array of prokaryotes, with internal division of labor and specialization, then by one simple scheme, the specialist subtypes would be defined and organized by something like mathematical array indexes. For parsimony, assume that these array indexes are the different kinds of histone marks, and that they simultaneously are used to stabilize specialist-specific wormholes. A given lock-key pair would wormhole specifically across regions of the shared genome not needed by that particular specialist.

 A secondary function of the array indexes would be to implement wormholes that execute between-blocks jumps within the specialist's own program-like KB. With consolidation of most genetic material in a nucleus, the histone marks would serve only to produce these secondary kind of jumps while keeping functions separate and maintaining an informational link to the ancestral cytoplasmic compartment. The latter could be the basis of sorting processes within the modern eukaryotic cell.