#68. A Tripartite Genetic Code [genetics]

GE

Red, theory; black, fact

The filamentous alga Cladophora.

There are three genetic codes, not one. Conventional thinking holds that there is just one code, which encodes the amino acid sequence of proteins into DNA. Here are the two new ones:

A morphology code for the multicellular level

In the context of a growing embryo, control of the orientation of mitosis is arguably at the origin of organ and body morphology. For example, all cell division planes parallel will result in a filamentous organism like Cladophora. Planes free to vary in only one angle (azimuth or elevation) will produce a sheet of cells, a common element in vertebrate embryology. Programmed variation in both angles can produce a complex 3D morphology like the vertebrate skeleton. Thus we begin to see a genetic code for morphology, distinct from the classical genetic code that specifies amino acid sequences. 

The nucleus is tethered by cytoskeletal elements such as lamin, nesprin, actin, and tubulin to focal adhesions on the cell membrane, non-rotatably, so that all angle information can be referred to the previous mitotic orientation.

Observational Support 

The nucleus is usually spherical or ovoid and is about ten times more rigid than the surrounding cytoplasm, features which may be related to the demands of the morphology read-out process. Consistent with this, blood is a tissue without a morphology, and the nucleated cells of the blood have nuclei that are mostly irregular and lobate. The lymphocytes found in the blood have round nuclei, however, but these cells commonly form aggregates that can be considered to possess a simple morphology.

A morphology code for the single-cell level in cells with nuclei

A third genetic code would be a code for single-cell morphology, and cell morphology can be very elaborate, especially in neurons. This will probably involve storing information about cytoskeleton morphology in DNA. Neurons express especially many long noncoding RNAs (lncRNA), so I suggest that these transcripts can carry morphological information about cytoskeletal elements. This information could be read out by using the lncRNA as a template on which to assemble the cytoskeletal element, then removing the template by enzymic hydrolysis or by some enzyme analogous to a helicase. Greater efficiencies could be achieved by introducing some analog of transfer RNAs. LncRNAs are already implicated in transcriptional regulation, and this might be done indirectly by an action on the protein scaffolding of the chromatin. Moreover, as predicted, lncRNAs are abundant in cytoplasm as well as in the nucleus, and the cytoplasm contains the most conspicuous cytoskeletal structures. The template idea is similar to but goes beyond the already-established idea that lncRNAs act as scaffolds for ribonucleoprotein complexes. Since cytoskeletal elements are made from monomers of few kinds, we would expect the template to be highly repetitious, and lncRNAs are decidedly repetitious. Indeed, transposons and tandem repeats are thought to drive lncRNA evolution. See https://doi.org/10.1038/s41598-018-23334-1, in Results, subsection: "Repetitive sequences in lncRNAs," p. 4 in the PDF.

Why Three Codes?

The issue driving the evolution of the two additional genetic codes may be parsimony in coding (advantageously fewer and shorter protein-coding genes).

Disclaimer 

This next paragraph was written for researchers, not for patients or those at risk for cancer who may be seeking a cure outside the medical mainstream. 

Cancer Research May Be Held Back by the One-Code View

Mutations in the proposed cytoskeletal genome could be at the origin of cancer. Cancer cells will proliferate in a culture dish past the point of confluence, unlike healthy cells. If the cytoskeleton is required to sense confluence, as seems likely, a defective cytoskeleton incapable of performing this function could lead directly to uncontrolled growth and thus cancer. It is not clear how the immune system could detect a mutation like this, since no amino acid sequence is affected. Possibly, a special evolved system or reflex exists that telegraphs such mutations to the cell surface where the immune system has a chance of detecting them. The clustering of antigens on the cell surface is already known to enhance immunogenicity, so this hypothetical system may output a clustering signal on the cell surface that talks to the cytoskeletons of circulating immune-system cells. Alternatively, the immune-system cells may directly interrogate the body cells’ ability to detect confluence. For these ideas to apply to blood-borne cells such as leukocytes, the failure event would have to happen during maturation in the bone marrow while the cell is still part of a solid tissue.

YAP1 protein, which promotes cell proliferation when localized to the nucleus, may be gated through the nuclear pores by some kind of operculum attached to the lamin component of the nuclear envelope. The operculum would move down from the pore, thus unblocking it, when a region of nuclear membrane flattens in response to a localized loss of tensile forces in the cytoskeleton. The flattening causes a local excess of lamin area, which leads to buckling and delamination, which is coupled to operculum movement. A mutation that makes the operculum leaky to YAP1 when closed could lead to cancer. This mutation could be in an lncRNA that scaffolds key components of the nuclear membrane’s supporting proteins. A more subtle mechanism would be for the buckling and delamination to happen on a molecular scale and lead to a uniform regional increase in the porosity of the lamin layer, which would gate YAP1 permeation.

Loss of tissue adjacent to the cell would cause a loss of cytoskeletal tension on the nucleus not only on that side of the nucleus, but also on the side opposite. If these two slack regions directly dictate centriole placement on the next round of mitosis, then the new cell will automatically be placed to fill in the tissue hole. (This may constitute an important mechanism of wound healing and suggests a link between morphology and carcinogenesis.)

Evolutionary Considerations 

The multicellular morphology code was postulated to arise from precise control of the orientation of the plane of mitotic division. It now seems likely that this control will be implemented via bespoke cytoskeletal elements, since complex single-cell morphology and its genetic code probably preceded complex multicellular morphology in evolution. 

Mechanism of Multicellular Morphology Readout

These bespoke elements might be inserted into a cytoskeletal apparatus surrounding the nucleus that has commonalities with devices such as gimbals and armillary spheres. The centrioles are likely to be key components of this apparatus. Each centriole may create a hoop of microtubules encircling the nucleus, and the two hoops would be at right angles, like the centrioles themselves when parked outside the nucleus between cell divisions. During mitosis, in-plane revolution of one of the hoops through 180 degrees would be responsible for separating the centrioles. After this, both centrioles must be on this same hoop. Alternatively, the centrioles may move by synthesis at the new locations followed by disassembly of the old centrioles. Each hoop then forms a circular track for adjusting azimuth and elevation, respectively, relative to anchor points left over from the previous round of mitosis. The bespoke elements would lie along these tracks and function as variable-length shims. The remainder of the apparatus would translate these lengths into angles. The inner hoop would pass through two protein eyelets connected to the outer hoop and the outer hoop would pass through an eyelet connected to the anchor. The shims would fix the along-track distances between an inner eyelet and the outer eyelet and between an inner eyelet and a centriole (Fig. 1).

Figure 1. A hypothetical cytoskeletal apparatus for orienting mitosis; C, centrioles; zigzag, shims; dotted, a nuclear diameter; double line, anchor to cell membrane; EL, elevation; AZ, azimuth 

Top picture credit: Cladophora flavescens, Phycologia Britannica, William Henry Harvey, 1851.

#65. Why There is Sex [evolution, genetics]

EV  GE

Red, theory; black, fact

The flower Coronilla varia L.

Sex as 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 three 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:10.1002/hbm.25204, 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. This system 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. 

Mechanistic reconciliation with Mendel's laws

The postulated chromosome inactivation process may feature an exemption mechanism that operates on genes present in only one copy per parent. The effect will be to double the penetrance of dominant alleles at that gene. 

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

EP   NE   GE

Red, theory; black, fact

A Genetics Theory 

All sexually reproducing species may have a long-range guidance system that that could be called proxy natural selection, or preferably, post-zygotic gamete selection (PGS). This is basically a fast form of evolution in which particular body 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.

Emotions Represent Fitness 

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.

The Corresponding Mechanistic Theory 

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 may 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 we have all the essential ingredients of classical natural selection, and all the potential, in a process that solves problems on an historical timescale.

The Limited Scope of Crossing-over

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.

Do Chromosome-specific Signaling Pathways Exist?

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. In the literature, I already find a strange diversity of cell-surface receptors on the spermatogonia. 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 traits, not their averages.

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. Five second-messenger systems are known, these being based on: cyclic AMP, inositol triphosphate, cyclic GMP, arachidonic acid, and small GTPases (e.g., ras). The AND-element that would be required for decoding could be implemented straightforwardly as a linear sequence of transcription-factor binding sites along the DNA strand. However, many mammalian species have many more than the 32 chromosome pairs needed to saturate a 5-bit address space. 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.

It Gets Bigger

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.

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.

Illustration credit: By Edmund Beecher Wilson - Figure 2 of: Wilson, Edmund B. (1900) The cell in Development and Inheritance (2nd ed.), Category:New York: The Macmillan Company, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3155599

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

EV   GE

Red, theory; black, fact

The Problem and My Solution 

Some entity must be 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, "post-zygotic gamete selection" (PGS) is DNA-based.

Background 

First, a refresher on how standard natural selection works. DNA undergoes various mutations 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.

My Solution, Big Picture 

PGS 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.

The PGS Mechanism 

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 oligo-generational timescale. On such a timescale, neither standard natural selection nor synapse-based learning systems are serviceable.

Female PGS Is Different 

However, egg cells mature in utero and therefore face a selection disconnect or delay. 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 PGS.

A Better Theory of Female PGS 

First, a definition. PGS focus: a function that is the target of most PGS. Thus, in trees, the PGS focus might be bio-elaboration of natural pesticides. In human males, the PGS focus might be brain development and the broad outlines of emotional reactivity, and thus behaviour. In human females, the PGS focus might be 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.

Experimental evidence for the proposed recombination mechanism of PGS 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

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 signalling pathways, itself  evolves, by species-replacement group selection.

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

EN   GE

Red: theory; black, fact

The Known Intelligences 

There may be three intelligences: the genetic, the synaptic, and the artificial. The first includes genetic phenomena and may be 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 understand it. Thus, it can provide a wealth of insights into the nature of the other two intelligences and a vocabulary for discussing them.

The Artificial Intelligence 

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.

DNA Through an AI Lens

A genome can be compared to a KB in that it contains structural genes and cis-acting control elements. The latter 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 control element evaluates the “if” condition and the conditionally translated protein enables the “action” taken by the cell if the condition is true.

Avoiding Slowdowns at Scale

Note that the structural gene of one rule precedes the control element of the next rule along the DNA strand. 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.

A Rule-ordering Mechanism 

The process of putting the rules into an efficient sequence may involve trial-and-error, with transposon jumping providing the random variation on which selection operates. 

A variant on this process would involve the enhancement by de-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 such as competition. It would then be converted into patterns of DNA de-methylation in the germ line. DNA methylation is known to be able to cool recombination hot spots, so de-methylation should do the opposite.

Rule Creation 

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.

Implementing Jump Instructions In DNA 

How would the genetic intelligence handle conditional rule firing probabilities in the medium to low range, which would call for jump instructions as opposed to merely incrementing the instruction pointer?

This could be done by cross linking nucleosomes via the histone side chains in such a way as to cluster the cis control elements 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.

A Possible Mechanism of Jump Instructions 

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. A variety of such changes are possible.

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.

Evolutionary History of Jump Instructions 

If the eukaryotic cell is descended from a spheriodal 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.