An elephant in the room

Do you know the story of blind men and an elephant?

Each blind man touches a different part of an elephant. Then, they talk about what the elephant is. Each statement is correct and captures a piece of truth. However, none would directly associate what non-blind men think about an elephant in the first place. Nothing is incorrect. However, collecting all the small pieces cannot capture the real whole. Sometimes this can cause unnecessary battles between two blind men. Both can use a lot of logic to convince the other. They can accuse, ignore or despise each other. No commonality and imagination. At other times, this can create something that does not exist – imaginative monsters. All statements are taken seriously, and then they create something huge – an imaginary monster, not even resembling an elephant.

Then, this monster is the devil’s proof. No way to disprove that something doesn’t exist.

The search for the monster is justified. A significant amount of money is attracted, and vested interests and experts can emerge. More justification of the importance of the search, such as that the monster will be a future danger. More money.  Evidence is collected from here and there because elephants exist. However, no one realizes that the monster is a shadow of an elephant. The monster should exist because of evidence and statements collected from blind men.

I must confess that scientists are equivalent to blind men. We do not know what exactly we are dealing with. Therefore, we want to know. The topics could be the universe, molecules, life and so on. We have no idea how big or small the thing we are dealing with is. We wander, we grope, and we explore. We think and create words for that. Nothing is different from the story of blind men and an elephant. We have no idea which part of an elephant we are touching. We have no idea if the direction of exploration is correct or if the approaches we are taking are really useful. Groping in the dark. Only curiosity is the driving force.

Of course, not every step of groping yields meaningful outcomes. The process is trial and error.  If you try to make each step meaningful, it will be a disaster. Through the groping of trial and error, if you are lucky enough to have a light and be in a good position, you will have a chance to see the whole of an elephant. After all, scientists are not blinded. However, each person needs to justify their existence and correctness without knowing where they are. The monster gets larger and larger. More and more complicated with a lot of knowledge, because the monster is, and has never been, a real elephant. 

After all, an elephant in the room, but no one talks about it.  (I know I’m using this idiom a bit differently…)  

Some dogmatic views are like a monster. Each small statement associated with it is true. However, as a whole, they cannot reconstitute the actual reality, but rather falsify something huge – a monster. 

In the Evolution of Life. In Cancer. Both are considered issues of the DNA sequence.  Adaptation and selection. Two key concepts in both. They are believed to be causally involved. I want to challenge this dogmatic view. These two things apparently happen. Is this because of causality, or what if it is consequently involved?

There are two cold truths: that any genetic and genomic change occurs in a single cell. Any genetic and genomic event is personal in one DNA string of a single cell. Another is that all organisms, including prokaryotes and eukaryotes, exhibit a range of plasticity and adaptability in their phenotype through epigenetics and complex networks (i.e. many detours in town), without altering the DNA sequence.

Darwinian Natural Selection (population-based genetic selection) is a highly limited, unique event in nature.

1.        The cause of phenotypic variation is not limited to genetics.

The phenotypic variation has three types: (a) solely controlled by genes, (b) only controlled by epigenetics, (c) by both, (d) by the environment and (e) by all. Development from a zygote to an adult form is a great example of (b). A past injury or nutritional condition is an example of (d).  An example of (e) could be aging.  To population-based genetic selection to occur, the variation should be controlled solely by genes, and most likely by a single gene, i.e. monogenic and dominant.

2.        The genetic-based phenotypic trait may not be exhibited in the direct offspring. Inheritance of a genetically based phenotypic trait requires a specific condition.

The fundamental requirement of Neo-Darwinian natural selection is that the phenotypic variation is inherited from a parent to an offspring. This is not as easy as we accept, particularly in diploid organisms. Here, we need to think about Mendel’s law. A genetic phenotype can be due to one of the following: 1. monogenic dominant, 2. monogenic recessive, or 3. multigenic. For the inheritance of the parental phenotype, sexual reproduction is the worst strategy. Asexual reproduction, which is seen in haploid organisms and clonal budding in some diploid organisms, should be better for this purpose.

As I mentioned, any alteration in a DNA sequence occurs in one DNA strand of a single cell. If a phenotype is monogenic dominant, the same phenotype is exhibited in its offspring.

If a phenotype is recessive, the situation becomes more complicated. No phenotype will be observed in the first individual who has the genetic change.  Initially, the allele is always heterozygous, without an apparent phenotype. Through heterozygous intercross, homozygous individuals may emerge with the phenotype if the allele has spread in a population by then. Because the heterozygote of a recessive allele should not have the phenotype, its spread in a population is not guaranteed, but by chance. Even the recessive phenotype is highly advantageous for fitness, but there is no guarantee of inheritance by its offspring. It is interesting, isn’t it?  Here, the increase in allelic frequency in a population from the first single individual relies on luck.  In the current concept, a sizable variation should already exist in a population for no reason. Interesting. After that, even if homozygotes emerge with their unique phenotype, the inheritance of the phenotype is dependent on their mating partner. The partner can be homozygous for the new allele, heterozygous or wildtype. The probability of phenotype inheritance in offspring is 100%, 50% and 0%, respectively.

If a phenotype is multigenic, meaning it is a combination of dominant and recessive alleles, random mating has almost zero chance of inheritance. Domestication makes this type of phenomenon possible through selective breeding.  The restricted crossing of individuals showing selected phenotypes can make this type of inheritance possible. As far as they intercross within their subspecies or strains, the phenotype is consistently inherited. However, even with just one outcross, a mating cross between a selected individual and a non-selected one, the offspring will fail to inherit the phenotypic traits. To reconstitute the original traits, several generations of backcrossing are required.

3.        The phenotypic variation caused by non-genetic reasons is not inherited in the offspring. However, the range of phenotypic variation of a species is consistent and inherited. Commonality permitting the epigenetic variation is heritable, consistent and unique in each species.    

This is a very interesting point. When we discuss evolution, we focus on variation. However, the concept of species is based on their commonality. We have not explored the commonalities that underlie each species and how they permit the range of phenotypic variation.

4.        Why do animals have an embryonic or larval stage?

Development is a series of processes controlled by epigenetic regulation. During development, no DNA sequence alteration. However, the phenotype of an organism undergoes drastic changes from the zygote to the adult form. Except for vertebrates, most animals begin as larvae, undergo metamorphosis, and then develop into adults. This is a huge phenotypic variation, larger than any variation caused by genetic alteration. Is it possible to have population-based genetic selection in a population with a large range of non-genetic phenotypic variation?

5.        Who selects whom?

Darwin’s idea of natural selection is that an environment selects survivors within it through competition. Unidirectional selection. What if organisms select an environment where they live?  Bidirectional matching. Is it possible to have population-based genetic selection?

6.        Who is competing with whom?

In the current neo-Darwinian model, evolution is explained as the change in allelic frequency within a population responding to its environment. An individual competes with other individuals within the same species. A competition within the same species occurs because of sharing the same goal. Then, individuals with better genes are selected, and the frequency of better genes in the population increases.  This leads to adaptation.  Ok.  I understand the logical flow despite disagreeing.

But is it possible for a competition to cause population-based genetic selection in the first place? 

Then, how about two species? Do two different spices compete? How does it translate into the allelic frequency?

Lastly, how about species and environment? Is this a competition or filtration? 

7.        What are ‘adaptation’ and ‘selection’?

These two words are key to thinking about the current theory. Both implicate time and change. From the one original state to another. In ‘adaptation’, the direction of the change in response to something. Then, the direction should be better, whatever it means. In selection, from multiple in the original state to one or a few in the later state. Both words are primarily anthropological and presuppose the existence of a person with an intention and making a decision: ‘adapt’ and ‘select’.  On the other hand, ‘adaptation’ and ‘selection’ are explanations of the consequence change, implicating their process. For example, a select shop is a collection that its owner has personally curated. A table for lost items presents a collection of lost items. The former, we call ‘selection’, but not the latter.  A selection is not a simple collection.

‘Adaptation’ is an interesting word. It means that the process of changing from the original state in response to something to become better or suitable. There are two key parts in this concept. One is ‘in response to’. This should be the response to something else. Stimulation should exist. The other is that there should be a direction of better or suitable.

Several related words are ‘mal-adaptation’, ‘pre-adaptation’, ‘co-adaptation’, ‘re-adaptation’ and ‘dys-adaptation’. ‘Mal-adaptation’ is the change in response to something, but in the wrong direction. ‘Pre-adaptation’ is the change without stimulation, but the direction was correct retrospectively. Co-adaptation is the change in both entities, the one and the stimulus. Re-adaptation is the second change to the second stimulation. Dys-adaptation is characterized by no change even with stimulation.

The trickiness of this concept lies in who decides the direction of the change is good, and when this decision can be made. Before the change or after?

Both ‘adaptation’ and ‘selection’ omit the involvement of randomness but force us to consider an intention.  Can we use another word like ‘filtration’? Imagine a strainer. Whether something passed through it or not is not anyone’s intention, but is determined by the size of objects and the size of holes. This is binary, pass or not-pass. Is there ‘adaptation’ in a pass or not-pass context? 

8.        Is adaptation a personal process or a population process?

Lamarck thought that it was a personal process. Then, the adapted trait could be inherited by offspring. I believe that everyone can relate to the first part. We, humans, adapt to various environments based on training and education. There is a wide range of phenotypic variations through training and education. However, something gained by training or education is not inherited by the kids. Retraining is necessary.

Darwin thought that it was a populational event. There are heritable variations in individuals of a population. Not all individuals can survive and reproduce for the next generation. Only survivors can pass their heritable variation to the next generation. When heritable variation plays a decisive role in death or alive, heritable variation will be enriched in a population.

They are not mutually exclusive. Both are plausible. However, only when heritable genetic variation is more critical than the range of phenotypic variations, population-based genetic selection is plausible. It means that a baby and an adult face the same challenge, but the baby can survive due to its unique genetic variation. Can you imagine this?

9.        What do species and reproductive isolation mean?

A species is defined by anatomical and physiological commonality passed through generations. The species’ commonality is stable over time from the inception to the extinction of the species. Spatially, subspecies sometimes emerge with cosmetic variations and considerable commonality with the original one. 

In sexual reproduction, a male and a female within the same species can reproduce to produce offspring.  A male and a female from two different species theoretically should not reproduce. This is called reproductive isolation or barrier.

Speciation is the process of the emergence of a new species. Establishing a barrier between the original and a newly forming species. Various mechanisms have been proposed. 1. The foundation of sexual reproduction is the bumping between a male and a female. Physical isolation of two populations can suffice. 2. Temporal separation is another way. For successful reproduction, both a male and a female need to be competent for reproduction at the time of bumping - mating or breeding seasons. Shifts in these seasons prevent reproductive bumping. 3. Particularly, in internal fertilization species like insects, mechanical compatibility between a male and a female is important. Even if a male and a female bump each other in their reproductive season, their gametes, sperm and oocytes cannot bump. 4. The last one is biological incompatibility. Sperm and oocytes can bump. But (a) do not fertilize, (b) fertilize but do not grow into an adult, (c) grow into an adult but are infertile, (d)grow into an adult but with subfertility or no fertility issue. The conditions (c) and (d), those individuals are called hybrids.

For physical isolation, genetic/genomic changes are not required. Physically separate one population into two. Then, no further mixture. According to the current theory, these two groups are in two different environments, and they adapt to their environment differently. Consequently, they look different.

Important concepts to mention before going further are the founder effect (also known as the bottleneck effect) and genetic drift.  These impacts are very difficult to tease apart from the plausible consequences of natural selection.

A population consists of individuals with variation. The variation gets constantly mixed within a large enough population. Therefore, the variation pattern is always varied through generations. However, if a population size becomes extremely small, the size of variation becomes extremely small, like glass beads in a bottle passing through its neck one by one. Even if you have 30 colored glass beads in a bottle, the one you can get at a time is one colour. If a population is rebuilt from this small group, the variation is biased (or minimized) toward the variation that this group had at the time of passing through this narrow pass.  This passing through the neck could be because of genetic-based variation or a simple accident. But the consequence is the same. The new group is consistently slightly different from the original group.

Physical isolation from the original population can occur in either a large population or a very small group. With a long time, two populations may become two distinct species. Through adaptation, two species can become incompatible in reproduction, utilizing the mechanisms from 2-4, not just physical isolation. 

I strongly feel that this idea is naïve. For this to occur, genetic/genomic changes are required. As I mentioned, genetic/genomic changes occur in a single DNA strand in a single cell. No other way.  The genetic phenotype can be monogenic dominant, monogenic recessive, or multigenic. I cannot imagine how the new allele controlling reproductive changes spread in a population, unless the changes are absolutely essential for reproductive success.  A linear, gradual change like a slope road in reproduction is a delusion. The change should be a stepwise one, like stairs.

Temporal separation has the same issue, although this is possible as a possibility by controlling animal maturation in both males and females, for example. 

Mechanical incompatibility has another issue, in addition to the issues mentioned above.  The change in males and females should be mechanically compatible but sufficient enough to be incompatible with the original.

Biological incompatibility has two flavours. One is molecular incompatibility in fertilization and embryo survival. This has a similar issue with mechanical incompatibility. How can a new group be different from the original? The new males and females should be compatible but incompatible with the original. This cannot be a linear, gradual process, but a stepwise one.

The second type of biological incompatibility is the most interesting one. This type of fertility problem occurs during meiosis. During meiosis, two homologous chromosomes, paternal and maternal chromosomes, align with each other for meiotic recombination to exchange some DNA sequences between them. If they are not similar enough, they cannot align with each other. If a chromosome has a chromosomal rearrangement like translocation or inversion, the difference could impact this alignment process and result in meiosis failure. This is the cause of infertility or subfertility. Interestingly, not all rearrangements cause fertility issues, but some are fully tolerated.

As I mentioned over and over, genetic and genomic change only occur in a single DNA string in a single cell. Thus, chromosomal rearrangement occurs in one chromosome in a single cell. If its progeny can contribute to the germ lineage, the cells with heterozygous chromosomes will face the meiosis problem. If 10% of these cells go through meiosis and become sperm or oocytes, there is a chance of the birth of several heterozygotes since all mating partners should have two WT chromosomes. The original individual is likely a mosaic of WT and heterozygous cells. Its offspring will be several heterozygotes, dependent on the degrees of mosaicism and subfertility. By sibling mating of heterozygotes, there is a chance of the birth of some homozygotes in 25% despite heterozygous subfertility.  Interestingly, the homozygote will recover 100% fertility because the alignment problem of the two incompatible chromosomes is dissolved. Only heterozygotes have the fertility problem, but both WT and homozygotes of the rearranged chromosome have no fertility issue. 

In this way, no need for physical isolation. No need for pre-expansion of a new allele for selection.  With/without the phenotypic consequence of the rearrangement, a new small group is reproductively isolated from the original population. Due to the very narrow bottleneck effect, even without the phenotypic consequence by the rearrangement, the phenotype within a new group can be different from the original with less variation than the original.

An inversion means two breaking points and two new rejoining points. An intrachromosomal translocation means three breaking points with three new rejoining points.  One chromosomal event is equivalent to multiple point mutations without changing gene dosage.  Additionally, the rearrangement can lead to changes in gene expression in multiple genes adjacent to the break points. Recently, long-range interactions between enhancers and the gene body have been recognized and appreciated for their involvement in development and various human diseases. It is plausible that chromosomal recombination can induce gene expression changes and simultaneously generate a small reproductively isolated population.

The beauty of this process is that it is possible to inherit the recessive traits and fix them as homozygous alleles. The phenotypic traits not associated with survival are also fixed as passengers. Multigenic traits are fixed due to the strong founder effect. Heterozygotes may exhibit no specific phenotype but are subfertile. However, homozygotes can exhibit consistent, unique recessive and multigenic phenotypes created by recombination sites and the founder effect, without any fertility issues.

Another interesting point of this mechanistic process is that this reproductive isolation does not mean reproductive independence for all other species. For example, species B is separated from species A. Then, at a different time and place, species C is separated from species A. Now, three species, A, B, and C. If B and C bump each other, they may make a hybrid. This can be species D. The reproductive barrier only works absolutely against the original parental species, but there is no guarantee for sibling species. This permits some branching points of species, families, and classes must be a complex mesh pattern of crisscrossing due to hybrids, rather than a simple bifurcation. The current genome data of Homo Sapiens suggests this view.

10.  How has diversity in life on Earth increased?

Natural selection consumes the number of variations. From a big pool of variations to a small group of less diverse survivors. From high diversity to low diversity. But the reality looks opposite. The diversity in nature has increased tremendously, except during periods of mass extinction and after human modernization. The diversity in nature is highly layered, like floors in a high-rise building. The people on different floors don’t meet, even though everyone occupies the same space in the two-dimensional view. Each species lives on its own floor. Their own floor is discovered when they emerge as a new species. Imagine water and water leaks in the building. Water is supplied (i.e. rain falling) on the roof. Then, each floor has water leaks from the ceiling. If one floor takes or pools them all, no one on the downstairs can survive. New floors are introduced as long as every floor has access to water. If a floor runs out, it disappears.

The conditions required for seeing Darwinian Natural Selection (population-based genetic selection) are 1. A closed population, 2. Consistent and uniform selection of all individuals in a population. 3. High threshold of die or live selection to create a bottleneck.   

A.       Domestication (multigenic-diploid organisms)

B.       Antibiotic resistance (monogenic dominant-haploid organisms)

C.      Laboratory experiments of haploids (e.g. bacteria) in a constant-shaking liquid culture system (monogenic dominant-haploid organisms)

D.      Closed conditions in nature with unique threshold compartments (monogenic dominant or recessive – diploid organisms)

The fossil record shows gradual changes. However, punctuated stasis is also well recognized. Phylogenetic trees created based on anatomical patterns have been revised through DNA sequence comparisons. Interestingly, in the sequence comparison data, ‘punctuated stasis’ is not observed but smooth, constant changes. This appears to the further support of gradual evolution. Where does this discrepancy come from?

Because the current data is a micro-sequence comparison. As a consequence, chromosomal rearrangement and karyotype changes are completely overlooked.

Although the changes appear gradual over time, the changing process can be stepwise, like staircases or gear notches, rather than a continuous slope or smooth tire. Each step is distinct and irreversible as a unique species, not a smooth continuum that can swing back.

The whole-genome data from various species indicate that the primary difference between two closely related species is chromosomal structures, including inversions and translocations. Currently, this is explained as a consequence. Can we think of this as the causative?

What is the fundamental branching point between Darwinian and my unorthodox view? Darwin viewed the world of life as a competitive arena. Struggle for existence and survival. My view is that an environment provides sufficiency for life to emerge, but not a 100% guarantee for its survival. Survival is always permitted but not guaranteed. The environmental sufficiency limits where a species can live. Species is a group of individuals with exchangeable genetic information which defines the developmental process and the range of epigenetic variation. This builds commonality and the range of phenotypic variation with epigenetics. Some genetic changes can alter cosmetic or physiological phenotypes, but it is not possible to alter the development process within a species. A new species comes into the world because it finds the previously unoccupied niche. In other words, any change in a new small group permits to survive in the previous uninhabited condition, it continues.  Survival is the norm, but not winning in competitions. Most deaths have nothing to do with genetics but age, nutrients and accidents.  No way to achieve population-based genetic selection and adaptation.

The impact of Darwin’s idea of evolution encompasses philosophy, biology, population genetics, geology, paleontology, genetics, developmental biology, chromosomal biology, comparative genomics, ecology, economics, sociology, anthropology, psychology, and more. However, it is worth rethinking where the idea originated from, using modern scientific data, with fresh perspectives, squinting eyes, and some imagination.

Population-based genetic selection and adaptation are rare.  Only if the phenotypic trait is monogenic and likely dominant does it have a chance to occur. Because of a lack of population-based adaptation, a species becomes extinct.  When the environment which provides sufficiency for survival disappears, the species has no chance to live. Then, extinct without adaptation.

Human society is creating a condition of population-based wealth selection. In modern Western society, wealth behaves like a hereditary trait. Wealth provides phenotypic variation. Wealth is inherited. Weath provides fitness in competitions. Wealth-based phenotype is dominant.  Exclusive and competitive with a shared goal.  The competition begins.  To survive and continue in this less diversified goal-oriented competition, one needs to be better among all survivors.

This similarity to Darwin’s idea is not surprising. Darwin lived in the era of the emergence of capitalism, industrialization and imperialism. He observed dynamic social changes that are highly competitive, selective and wealth-dependent. Darwin’s proposal is variation, heredity and natural selection. Wealth controls phenotypic variation, heritability, and creates a survival advantage based on wealth in human societal competitions. I believe that Darwin drew inspiration from the human society of that time. He must build his idea based on careful observation of human society, domestication, and the Galapagos Islands.

I do not think my view is totally off the mark. Now is the time for rethinking. Because the concept of natural selection has served us long enough, and we have learned a lot more since then.  We can see that an actual elephant is in the room, not a monster.