Non random mutations : How life changes itself: the Read-Write (RW) genome

Non random mutations : How life changes itself: the Read-Write (RW) genome 2 3

https://reasonandscience.catsboard.com/t1476-non-random-mutations-how-life-changes-itself-the-read-write-rw-genome

Simon Conway Morris: Evolutionary Paleobiology at Cambridge, (Runes of Evolution, 38)
argues that adaptation is not an undirected, random walk through all possibilities. For example, when muscle tissue develops into organs that produce electricity, the process requires very precise amino acid replacements at specific sites, together with accelerated evolution of the new function, and Conway Morris concludes that:
“there is little doubt that these changes are very far from random”
He therefore argues that while the underlying principles of Darwinian evolution are correct, they do not provide a complete explanation of development, and a more comprehensive theory of evolution is required.

Paul Davies: the demon in the machine, page 78
A lot of E. coli suffered glucose deprivation. When the dust settled, this is what emerged. Mutations are not random: that part is correct. Bacteria have mutational hotspots – specific genes that mutate up to hundreds of thousands of times faster than average.

Starving bacteria, Rosenberg discovered, can switch from a high-fidelity repair process to a sloppy one. Doing so creates a trail of damage either side of the break, out as far as 60,000 bases or more: an island of selfinflicted
vandalism. Rosenberg then identified the genes for organizing and controlling this process. It turns out they are very ancient; evidently, deliberately botching DNA repair is a basic survival mechanism stretching back into the mists of biological history. By generating cohorts of mutants in this manner, the colony of bacteria improves its chances that at least one daughter cell will accidentally hit on the right solution. Natural selection does the rest. In effect, the stressed bacteria engineer their own high-speed evolution by generating genomic diversity on the fly.

And all available scientific evidence also indicates that evolution is an engineered process. In engineering and computer science, evolution never happens by accident. It’s always the result of a deliberate act. A program that can self-evolve is always considered an engineering marvel. 6

The macroscopic signals that a cell receives from its environment can influence which genes it expresses — and thus which proteins it contains at any given time — or even the rate of mutation of its DNA, which could lead to changes in the molecular structures of the proteins. 8

The genome has traditionally been treated as a Read-Only Memory (ROM) subject to change by copying errors and accidents. 7  I propose that we need to change that perspective and understand the genome as an intricately formatted Read-Write (RW) data storage system constantly subject to cellular modifications and inscriptions. Cells operate under changing conditions and are continually modifying themselves by genome inscriptions. These inscriptions occur over three distinct time-scales (cell reproduction, multicellular development and evolutionary change) and involve a variety of different processes at each time scale (forming nucleoprotein complexes, epigenetic formatting and changes in DNA sequence structure). Research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply accidents or damage to the DNA. This cell-active view of genome change applies to all scales of DNA sequence variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs). This conceptual change to active cell inscriptions controlling RW genome functions has profound implications for all areas of the life sciences.

Ever since the formulation of the neo-Darwinist Modern Synthesis evolutionary theoryin the 1930s and 1940s, it has been an article of faith that hereditary variation results from stochastic copying errors and unavoidable damage to the genome

In the past 60 years, since the structure of DNA was elucidated, molecular biologists have studied the basic mechanisms of long-term genome change. They have discovered a wide array of proofreading and damage repair biochemical systems that remove copying errors and correct DNA damage. At the same time, they have revealed an amazing and wholly unanticipated array of cellular and molecular systems that operate to generate genome variability, both temporary and structural. As we begin the second decade of the 21st century, accumulating empirical evidence has thus shifted the perspective on genome variation to that of an active inscription process changing the information passed on to future generations.

Mutation 1

It is clear that new gene alleles are accumulating in populations today, but there are two possible sources for these changes; mutations, and intentional changes introduced by genetic recombination. The theory of evolution attributes the continued production of genetic diversity to mutations, but evolutionists overlook the fact that the cell was intelligently designed. The cellular machinery was programmed to perform a level of self genetic engineering, and is editing genes systematically so that organisms can adapt to a wide variety of environmental conditions.

Evolutionists contend that mutation, acted upon by natural selection is the mechanism for evolutionary advancement. While this mechanism has the power to change the genome over time, most biological evolution is actually due to genetic recombination followed by natural selection. There are many examples put forward by evolutionary biologists that attempt to show how new genes have been introduced into the genome of an organism. However, in most documented cases it merely illustrates the built-in plasticity or variation within the original created kind. Merely shuffling of already existing genes becomes woefully inadequate if the observational science is followed.
Despite the few examples of beneficial genetic mutations it is unrealistic to assume that this information produced through changing already existing DNA would then be acted on again many more times by other related mutations to build radically different and complex structures than what was there previously. This is to say that mutations are not a reasonable means of producing cascading morphological change from one kind of animal to another but merely speciation.

Biophysicist Dr. Lee Spetner in his book, Not by Chance: Shattering the Modern Theory of Evolution, analyzed examples of mutational changes that evolutionists claimed were increases in information, and demonstrated that they were actually examples of loss of specificity, meaning loss of information.
“ In all the reading I've done in the life-sciences literature, I've never found a mutation that added information. … All point mutations that have been studied on the molecular level turn out to reduce the genetic information and not increase it." - Spetner ”
and
“ We see then that the mutation reduces the specificity of the ribosome protein and that means a loss of genetic information. ... Rather than saying the bacterium gained resistance to the antibiotic, it is more correct to say that is lost sensitivity to it. ... All point mutations that have been studied on the molecular level turn out to reduce the genetic information and not increase it.

Georgia Purdom, Ph.D. of molecular genetics, has stated,

“ Mutations only alter current genetic information; they have never, ever been observed to add genetic information; they can only change what is there. I have a lot of papers come across my desk of supposedly mutations that have added genetic information, and I've read them all, and I've looked at them all, and never, once have I seen one that has added genetic information; they just don't do that.

Nonrandom mutations 4

Mutations are supposed to be accidental, undirected events that are in no way adaptive. For example, if an animal species needs thick fur to survive in a cold climate, it will not respond by growing fur; rather, any animals who undergo random genetic changes that happen to result in thick fur will survive to produce more offspring. As Robert Gilson says, ‘The doctrine of random variation is just as unprovable as is the doctrine of the Virgin Birth, and just as sacrosanct to its adherents.’1

Attempts to justify the doctrine of random mutations usually refer to a series of experiments on the bacterium E. coli in the late 1940s and early 50s. These experiments found that when bacterial cells are suddenly subjected to a particular selection pressure (e.g. the addition of a lethal antibiotic), a small proportion of cells invariably survive because they contain a mutation that confers resistance to the antibiotic. Tests were then carried out which proved that the mutations were present in the surviving cells before the antibiotic was added to the culture, and that they were therefore truly spontaneous and nonadaptive. However, the original researchers recognized that this did not rule out the possibility of adaptive, nonrandom mutations.2

More recent experiments have shown that mutations can indeed occur in direct response to an environmental challenge – and have aroused great controversy.3 It has been found that bacteria which are unable to digest lactose, if given no other food, will after a few days develop new mutants that are able to handle it, the mutation rate being many orders of magnitude faster than the ‘spontaneous’, ‘random’ rate. Two independent mutations were needed, giving an ‘accidental’ explanation a probability of less than 1 in 10^18. Adaptive mutations also appear to occur in yeast cells and possibly fruit flies.4 The existence of adaptive mutations is now widely accepted, though the term ‘directed mutations’ is sometimes shunned. Although some of the biochemical mechanisms involved have been identified, there is no real understanding of what lies behind the phenomenon.

According to Eshel Ben-Jacob and his colleagues, ‘a picture of problem-solving bacteria capable of adapting their genome to problems posed by the environment is emerging’; ‘It seems as if the bacterial colony can not only compute better than the best parallel computers we have, but can also think and even be creative.’5 As James Shapiro has said, even the ‘simplest’ form of life – tiny, ‘brainless’ bacteria – ‘display biochemical, structural and behavioral complexities that outstrip scientific description’.6

The rapidity with which pests, from rats to insects, acquire resistance to poisons is also hard to account for on the basis of conventional evolutionary theory. Some 500 species of insects and mites have been able to defeat at least one pesticide by genetic changes that either defensively alter the insect’s physiology or produce special enzymes to attack and destroy the poison. 17 have shown themselves capable of resisting all chemicals deployed against them. As Robert Wesson says, ‘If it is true that mutations are much more frequent where they are needed than when they are virtually certain to be harmful, they cannot be held to be random.’7 Shapiro states that ‘All careful studies of mutagenesis find statistically significant nonrandom patterns of change ...’8

Molecular biologist Lynn Caporale points out that mutations seem to occur preferentially in certain parts of the genome while other DNA sequences tend to be conserved – which shows, she says, that evolution is not purely a game of chance. Although she believes that genomes can ‘steer’ mutations to ‘hot spots’ where they are more likely to increase fitness, and that the genome may be ‘in some way intelligent’, she does not believe that the actual mutations themselves are nonrandom in the sense of being somehow engineered by the organism in question to bring about the changes it needs.9 This is a good example of how Darwinists sometimes dress up their dogmas in ‘sexy’ and even mystical-sounding language.

the randomness of mutations has been called into question since the 1970s in experiments demonstrating that cells subject to non-lethal selection come up repeatedly with just the  right ‘adaptive’ or ‘directed’ mutations in specific genes that enable the cells to grow and multiply 5

1) http://creationwiki.org/Mutation
2) http://vcp.med.harvard.edu/papers/shapiro-read-write-genome.pdf
3) http://www.ncbi.nlm.nih.gov/pubmed/23876611
4) http://davidpratt.info/evod1.htm
5) http://www.i-sis.org.uk/Nonrandom_directed_mutations_confirmed.php
6) http://cosmicfingerprints.com/romans1/
7) http://www.ncbi.nlm.nih.gov/pubmed/23876611
8 ) http://www.nature.com.https.sci-hub.hk/articles/35011540

Nonrandom Mutations Scramble the Case for Common Descent 1

"Cowards die many times before their deaths; The valiant never taste of death but once." (Julius Caesar, 2.2.32–37)

New work by researchers from Great Britain reveals that mutation rates in the genome of E. coli are nonrandom and optimized to minimize their impact on survival. This optimization adds to the case for intelligent design. Moreover, it challenges a key assumption made by evolutionary biologists, namely that shared DNA sequences in the genome of related organisms serves as evidence for common descent and, consequently, biological evolution.

They say death and taxes are the only two things certain in life. But in biology, there is a third inevitability: mutations. Changes will happen in an organism’s genetic material and, as a result, the DNA sequences of the genome will be altered. 
Although evolutionary biologists regard mutations as the engine that drives the evolutionary process, more often than not, mutations are deleterious to the organism. These scientists have long thought that mutations occur in genomes randomly. Natural selection fixes into the population the few mutations that increase the organism’s fitness. But a recent study indicates that organisms can manage mutations, much in the same way an accountant structures finances to reduce the amount of taxes a client owes.
This newly recognized ability challenges one of the key assumptions evolutionary biologists employ when interpreting genomes’ shared features as evidence for common descent and, hence, biological evolution. On the other hand, this discovery can be rightly enlisted to further the case for intelligent design.

Nonrandom Mutations in E. coli


By analyzing and comparing the genomes of 30 E. coli strains, researchers from Great Britain discovered that the mutation frequency varies across this bacterium’s genome.¹ Some regions (hot spots) have a relatively high mutation rate; others (cold spots) display a relatively low rate of genetic change.
The researchers learned that hot and cold spot locations are not random. Hot spots occur in regions where mutations would do the least amount of damage. Meanwhile, cold spots show up in areas that harbor genes critical for E. coli’s survival. The hot and cold regions both typically encompass large stretches containing genes that are part of the same operon. These neighboring genes often encode proteins that participate in the same cellular processes.
Additionally, the researchers determined that cold spots tend to occur in highly expressed genes. Yet because transcription (which dictates, in part, the rate of gene expression) tends to cause mutations, it seems that hot spots should associate with highly expressed genes. This surprising result indicated to the investigators that there must be some mechanism that actively manages the mutation rate, compensating for the transcriptional process’s mutagenicity.
Thus, it appears that the mutation rates across genomes have been optimized to reduce the risk of harmful genetic changes. Although the nonrandom distribution of mutations in genomes is contrary to the most common understanding of evolutionary theory, it is not surprising to learn that mutation rates and the location of mutational hot and cold spots are optimized to protect E. coli from the loss of fitness. Biochemical systems are characteristically optimized. It is reasonable to think that, if mutation rates across the E. coli genome have been optimized to minimize damaging effects, then the rates are optimized similarly in other organisms’ genomes.
This result is consistent with research that demonstrates that substitution mutations and recombination are nonrandom and take place in hotspots. Other studies also show that other genome-altering processes (such as intron insertion and transposon insertion) are nonrandom, occurring in hot spots, as well.

Nonrandom Mutations and the Case for Design
As I discussed in my book The Cell’s Design, the characteristic features of life’s chemistry are the same as what we would recognize as evidence for a human designer’s work. So, by analogy, it is logical to conclude that a Mind was responsible for bringing life into existence. Systems, objects, devices, etc., designed by humans are often optimized. In fact, optimization connotes high quality and superior designs. As such, the optimization of mutation rates can be seen as further evidence for intelligent design in nature. The distribution of hot and cold spots across the genome and association of cold spots with genes critical for survival portrays an elegance and cleverness that bespeaks of a Creator’s handiwork.
Nonrandom mutation rates also raise questions about the validity of a key assumption made by evolutionary biologists when they interpret shared features of genomes as evidence for common descent.

The Challenge for Biological Evolution
Evolutionary biologists consider identical (or nearly identical) DNA sequence patterns found in the genomes of related organisms as evidence of descent from a shared ancestor. According to this line of reasoning, the shared patterns arose as a result of mutational events that occurred in the common ancestor’s genome. Presumably, as the varying evolutionary lineages diverged from the nexus point, they carried with them the altered sequences created by the primordial mutations. This interpretation rests on the underlying assumption that the mutations that generated the shared fingerprint are rare and random.
But, if the mutations are nonrandom—preferentially taking place in hot spots—then it could be asserted that the DNA sequence patterns were generated independently in the separate biological groups. That is, the shared DNA sequence patterns may not be the result of descent with modification from a common ancestor, but instead arose separately. In other words, shared DNA sequences are not necessarily evidence for common descent and biological evolution.
Death and taxes may be a given, but the case for biological evolution is far from certain.

1) http://www.reasons.org/articles/nonrandom-mutations-scramble-the-case-for-common-descent

James Shapiro’s talk, clearly one of the most interesting of the conference, highlighted this difficulty in its most fundamental form. Shapiro presented fascinating evidence showing, contra neo-Darwinism, the non-random nature of many mutational processes – processes that allow organisms to respond to various environmental challenges or stresses. The evidence he presented suggests that many organisms possess a kind of pre-programmed adaptive capacity – a capacity that Shapiro has elsewhere described as operating under “algorithmic control.” Yet, neither Shapiro, nor anyone else at the conference, attempted to explain how the information inherent in such algorithmic control or pre-programmed capacity might have originated.

http://www.cnsnews.com/commentary/david-klinghoffer/scientists-confirm-darwinism-broken

Evolution - A View from the 21st Century
James A. Shapiro

Natural genetic engineering represents the ability of living cells to manipulate and restructure the DNA molecules that make up their genomes.

To date, all studies of genetically modified organisms have required an intact cell structure for the introduction of new genetic information by DNA or nuclear transplantation. So there is no unequivocal empirical basis for believing the frequent assertion that DNA contains all necessary hereditary information.

We still do not adequately understand the role that preexisting cell structures and organelles play in templating the formation of their descendants in progeny cells. In mammalian reproduction, for example, we know that both the sperm and the maternal environment contribute non-DNA factors to the fertilized egg and developing embryo. Simple reflection makes it obvious that a properly structured egg is essential to hereditary transmission in all “higher” organisms. Modifications of cell structure have been critical events at some of the most important stages of evolutionary innovation, and purely DNA-based explanations are insufficient to describe them in a scientifically comprehensive way. In ciliate protozoa, in the mid-20th Century, Tracy Sonneborn did pioneering work on genome-independent heredity of the cell cortex

For over six decades, however, an increasingly prevalent alternative view has gained prominence. The alternative view has its basis in cytogenetic and molecular evidence. This distinct perspective treats the genome as a read-write (RW) memory system subject to nonrandom change by dedicated cell functions

We can distinguish at least seven distinct but interrelated genomic functions essential for survival, reproduction, and evolution:

1. DNA condensation and packaging in chromatin
2. Correctly positioning DNA-chromatin complexes through the cell cycle
3. DNA replication once per cell cycle
4. Proofreading and repair
5. Ensuring accurate transmission of replicated genomes at cell division
6. Making stored data accessible to the transcription apparatus at the right time and place
7. Genome restructuring when appropriate

In all organisms, functions 1 through 6 are critical for normal reproduction, and (as you will see later) quite a few organisms also require function 7 during their normal life cycles. We humans, for instance, could not survive if our lymphocytes (immune system cells) were incapable of restructuring certain regions of their genomes to generate the essential diversity of antibodies needed for adaptive immunity. In addition, function 7 is essential for evolutionary change. This part of the book devotes considerable attention to discussing the numerous molecular modalities of genome restructuring discovered since the double helix structure of DNA was described in 1953.

From an evolutionary point of view, the main question to ask is how transcriptional regulatory circuits arise in the first place. How are similar binding sites amplified and distributed to multiple locations throughout the genome? How do higher-order circuit elements, enhancers, and more-complex cis-regulatory modules (CRMs) form and then disperse through the genome? These questions are distinct from those that evolutionists ask about the origins and diversification of coding sequences. We need to keep in mind that genomes contain many different kinds of information and that the entire cellular DNA has to evolve in a way that produces functional and adaptive expression systems. A little thought will make it clear how difficult it is to maintain the traditional idea that each individual component of these elaborate circuits evolves by making its own independent random walk through the enormous space of genome sequence possibilities. As you will see, there are alternative ways, based on established molecular processes, to think about the efficient evolution of genomic circuits based on rapid distribution of transcriptional regulatory sequence motifs.

Genome Compaction, Chromatin Formatting, and Epigenetic Regulation

For a few decades in the late 20th Century, it was possible to think that transcriptional regulatory circuits are sufficiently complex and sensitive to provide an adequate account of how cells regulate coding sequence access. However, two separate lines of thinking and experimentation taught us about additional layers of higher-order control on genome expression. Although originally independent, the two approaches converged at the molecular level in a surprising and satisfying way. This multilayered view of regulation enriches our ability to understand different aspects of genome function. It also turns out that it helps us account for the timing of evolutionary change in unexpected ways. The first line of thought had its origins in the problems posed by multicellular development and cellular differentiation. How do cells become different from each other? How do tissues composed of specialized cell types form? What principles drive tissue formation and morphogenesis down well-defined paths during embryonic development? Without any detailed knowledge of molecular mechanisms, but well versed in developmental genetics, Conrad Waddington theorized about an “epigenetic landscape” that “canalized” genome function during development.

Although described metaphorically in terms of surface grooves guiding marbles rolling down a hillside, this hypothetical concept has had lasting influence on researchers and has finally found a concrete molecular explanation. The term epigenetic means “beyond (or added to) genetics.” It refers to a mode of heredity independent of the basic DNA sequence or “genetic” constitution. This idea is useful in understanding multicellular development. It describes how certain groups of cells—say, in a particular tissue or organ—can share inherited characteristics while retaining the same genome as cells with distinct inherited characteristics in a different tissue or organ. Besides such theorizing about cell differentiation, several phenomena provided independent evidence for an additional mode of inheritance. Perhaps the most instructive of these cases is genetic imprinting, which in animals and flowering plants means that the expression of a genetic locus depends on whether it is inherited from the male or female parent. Certain genetic loci are expressed only from the copy inherited from the father and other loci only when inherited from the mother. In the mealy bug, where the term imprinting was first applied, the expression of a whole set of chromosomes inherited from the father is silenced in males but not in females. Somehow, during the formation of the sperm and egg cells, different genetic loci or even whole chromosomes are marked, or imprinted, for silencing in the next generation.

Although the imprinting of a particular locus changes as it passes through male or female gametes, the underlying genetic information does not change. Because the imprint remains throughout multicellular development, the imprinted state is heritable through numerous mitotic cell divisions. In the mealy bug example, and in many vertebrate and plant examples, broader regions of the genome encompassing multiple genetic loci or whole chromosomes can be imprinted. Thus, epigenetic inheritance represents a high-level control (or set of controls) that can extend to entire haploid genomes. Epigenetic inheritance can extend beyond the development of a single individual to encompass several, or even many, generations. For example, the transgenerational epigenetic changes in maize plants called paramutations involve no alteration of DNA sequence but are stably transmitted through sexual reproduction for many generations. Similar changes are found in animals. In rodents, certain environmental stimuli, which include chemicals that disrupt endocrine signaling in sexual development, induce transgenerational changes in the offspring that are inherited by their descendants. Such heritable changes have been ascribed to alteration of epigenetic modifications.

Comparable environmentally induced transgenerational changes have also been documented in plants. It has become evident that the epigenetic mode of inheritance exists in tandem with inheritance based exclusively on DNA sequences. For a small but growing number of scientists, the epigenome (the constellation of all epigenetic modifications in the nucleus) constitutes a primary interface between environmental factors and the genome. As we turn our attention to the molecular nature of epigenetic modifications, you will see how this interface operates. Later, you will learn how epigenetic controls connect genome restructuring functions to organismal life histories. The second line of research leading to our current understanding of epigenetics was experimentation in diverse fields on the relationship between DNA packaging into chromatin and replication and transcription. From early and mid-20th Century cytogenetics, it had been known that different chromosome regions stained distinctly and formed different types of chromatin (literally, “colored material”). Euchromatin (“true” chromatin) stained lightly and appeared to be the active region of the genome. Heterochromatin (“different” chromatin) stained darkly and was associated with silent regions of the genome (for example, the silenced paternal chromosomes in male mealy bugs). Genetic manipulations that placed an active genetic locus next to heterochromatic regions, such as centromeres, resulted in silencing of the previously active locus. This “position effect” indicated that heterochromatic silencing could spread relatively long distances in the genome. Position effect phenomena further indicated that location in the genome was an important factor in controlling expression. Many experiments have verified the importance of “genome context” in the expression of individual genetic loci.

In the late 20th and early 21st Centuries, the correlation between chromatin structure and functional expression was placed on a defined molecular basis. The packaging of DNA within the eukaryotic cell depends at the most basic nucleosome level on winding the negatively charged double helix around positively charged proteins called histones. A special sequence code helps position the histones along the DNA to form regularly spaced nucleosomes. There are two general differences between DNA and histones in euchromatin and heterochromatin: • Heterochromatic DNA is more heavily modified by methyl groups attached to the cytosine (C) bases in its sequence. • The histones in euchromatin and heterochromatin carry different chemical modifications (methyl, acetyl, and other chemical groups attached to particular amino acids in the histone “tails” that stick out from the nucleosomes). The histone modifications constitute what has come to be called a histone code; it allows molecular biologists to distinguish the chromatin state of associated DNA sequences. By examining  DNA methylation and histone modifications in active, silenced, and imprinted regions of the genome, a catalog is taking shape that allows us to identify the chromatin configurations associated with each epigenetic state of the genome. We already know from studies in yeast that the simple division into euchromatin and heterochromatin is too simple; chromatin configurations are specialized for different genomic functions.  Cells possess enzymes that either attach or remove methyl and acetyl groups from cytosines in DNA and exposed amino acid tails in histones. Thus, the formation or modification of chromatin structure is an active process with major consequences for the functional state of the underlying DNA. Such active chromatin reformatting is regulated by cell signaling circuits. It plays a major role in cell differentiation as cells become more specialized, silence large unused regions of their genomes by incorporation into silent heterochromatin, and open other regions encoding protein and RNA molecules needed for differentiated cell function. 


The ability of cells to target chromatin formatting within the genome is aided by the recently discovered role of micro- and other noncoding RNA molecules (ncRNAs). Some of these ncRNAs form a complex with specialized RNA binding proteins linked to the enzymatic machinery for chromatin reformatting and specifically alter chromatin in the regions that have sequences complementary to the ncRNA. You will see later how this RNA-targeted chromatin modifying/epigenetic regulation plays a critical role in the control of genome restructuring in response to episodes of cell stress or genome shock. Barbara McClintock used this phrase in speaking to explain a challenge or stress event that provoked a cell to activate the molecular systems that restructure genomes. The indexing of the genome into extended chromatin domains that may encompass dozens of genetic loci and hundreds of thousands of base pairs is itself subject to additional formatting. We have learned about the existence of various classes of insulator sequences, which serve as boundaries between different types of chromatin . They also separate transcriptional formatting signals, such as promoters and enhancers. Some insulators nucleate insulator bodies that attach chromosomes to the nuclear envelope and thereby create a barrier to extension of chromatin domains. Other insulators work by directing RNA PolIII transcription of SINE or tRNA molecules and thus moving their chromosome site into one of many specialized transcription factories within the functionally compartmentalized nucleus. Certain sequences format the initiation of silent chromatin domains. In general, these are repetitive DNA sequences recognized by ncRNAs. These silent chromatin formatting sequences will become important when we discuss the impact that genome restructuring has
on the expression of stored information.

Genome Formatting for Replication, Localization, and Transmission to Daughter Cells

To function effectively as a storage medium in proliferating cells, replicated DNA molecules must pass reliably to progeny cells at division. We have already discussed the role of checkpoint surveillance routines in ensuring the accuracy of this process in eukaryotic cells. As is the case for transcriptional regulation, DNA molecules must be formatted by the appropriate signals for a complete replication process, for proper localization during the cell cycle, and for accurate transmission at division. Several different functional types of formatting signals are involved in integrating these biochemical and biomechanical events into the cell cycle:
• Sites for initiating DNA replication. In prokaryotes these are called origins of replication, or ori sites. For the basic genomic components, there is generally one ori per molecule. Ori sites tend to have a composite organization that includes multiple recognition sequences related to the control circuitry that ensures there is only one initiation event per cell division cycle. In eukaryotes, these initiation sites are called autonomous replication sequences (ars) and exist at multiple locations in each of the chromosomes. The ars sites are less defined in eukaryotes than Ori sites in prokaryotes, although  recent work has begun to discern characteristic motifs. They interact with an origin of replication complex (ORC) multiprotein apparatus that is connected to the cell cycle control circuitry so that each ars sequence can only initiate replication once per S phase of each cell cycle.
• Sites for completing DNA replication. In prokaryotes, these assume a variety of forms. Many of the prokaryotic DNA molecules are circular in structure and contain special terminus regions that have signals for biochemical processes that allow the replicated molecules to form completed duplexes and separate from each other if they have become interlocked or joined into a single double circle. Some prokaryotes have linear DNA molecules with closed hairpin ends connecting the two strands (also found in some viruses). The hairpin ends contain signals that facilitate the “resolution” of daughter molecules by a special recombination event as soon as the hairpin has been replicated. In eukaryotes, the chromosomal DNA molecules are linear with open ends, which poses two problems for maintenance and replication:
i. The ends must be prevented from joining, in the same way that ends do for some forms of double-strand (DS)
break repair.
ii. The replication apparatus can copy only one DNA strand completely, leaving the other strand incomplete. These two problems are solved by constructing a special telomere (literally, “end body”) structure at each extremity of the chromosomal DNA molecule. The telomere contains a number of different signals that facilitate the addition of extra DNA sequences to the end after replication (usually involving the enzyme telomerase but sometimes employing other mechanisms). They also format a special telomeric chromatin structure that protects against end-to-end joining by DNA repair functions.
• Sites for ensuring transmission at cell division. In prokaryotes, these generally are labeled partition (par) sites. The par sites ensure separation of replicated DNA molecules and movement to the cell poles, powered by an actin-related motor protein, so that the two copies end up in separate cells after division in the middle of the cell. In eukaryotes, chromosome separation is formatted by the centromere (literally, “central body”) or cen sequence. In most eukaryotes, centromeres are complex structures containing many tandemly repeated DNA sequence elements. These format a special centromeric heterochromatin structure that undergirds assembly
of the kinetochore structure, which in turn attaches to the microtubules of the spindle apparatus. This ensures separation

More evidence that mutations are not random

"At first glance, what we found seemed to contradict the established theory that initial mutations are entirely random and that only natural selection determines which mutations are observed in organisms," said Detlef Weigel, scientific director of the Max Planck Institute and senior author of the paper. study.

Instead of randomness, they found stretches of the genome with low mutation rates. In these patches, they were surprised to find an exaggerated representation of essential genes, such as those involved in cell growth and gene expression.

These are the really important regions of the genome,” Monroe said. “The areas that are biologically most important are the ones that are protected from mutations.”

The findings add a surprising twist to Charles Darwin's theory of evolution by natural selection because it reveals that the plant evolved to protect [Hello? There is? Teleology???] its mutation genes to ensure survival.

“The plant has developed a way to protect its most important places from mutation,” Weigel said.

Mutation bias reflects natural selection in Arabidopsis thaliana
https://www.nature.com/articles/s41586-021-04269-6

James A. Shapiro (2019): Today, we know that many life-history events lead to rapid and nonrandom evolutionary change mediated by specific cellular functions. There are many ways that genomes, viruses, cells, and organisms interact to generate evolutionary variation. These include cell mergers and activation of natural genetic engineering by stress, infection, and interspecific hybridization. 

James A. Shapiro : No genome is an island: toward a 21st century agenda for evolution  2019

Genetic changes that crop up in an organism's DNA may not be completely random, new research suggests. That would upend one of the key assumptions of the theory of evolution.

Researchers studying the genetic mutations in a common roadside weed, thale cress (Arabidopsis thaliana), have discovered that the plant can shield the most "essential" genes in its DNA from the changes, while leaving other sections of its genome to build up more alterations.

"I was totally surprised by the non-random mutations we discovered," lead author Grey Monroe, a plant scientist at the University of California, Davis, told Live Science. "Ever since high-school biology, I have been told that mutations are random."

Random mutations are an important part of the theory of evolution by natural selection, in which mutations give rise to adaptations that are passed on to offspring and alter their chances of survival. Scientists have assumed that these mutations were random and that the first step in evolution by natural selection was, therefore, also random. But this may not be entirely true, the new study suggests.

"The idea of random mutation has been around for over a hundred years in biology and is something you hear so often as a student that it is easy to take it for granted," Monroe said. "Even as a practicing geneticist and evolutionary biologist, I had never seriously questioned the idea."

The new finding does not disprove or discredit the theory of evolution, and the researchers said randomness still plays a big role in mutations. But the study does show that these genetic alterations are more complex than scientists previously believed.

DNA errors
There are plenty of chances for genetic mutations and even errors to occur during the life of an organism.

"DNA is a fragile molecule; on average, the DNA in a single cell is damaged between 1,000 and 1 million times every day," Monroe said. "DNA also has to be copied each time a cell divides, which can introduce copying errors."

Luckily for humans and all other organisms, our cells can counteract a lot of this damage. "Our cells are working constantly to correct DNA and have evolved complex molecular machines, DNA repair proteins, to search for mistakes and make repairs," Monroe said.

However, DNA repair proteins are not a foolproof solution and cannot fix all mistakes. "If damage or copying errors are not repaired, they cause a mutation, a change in the DNA sequence," Monroe said.

There are two main types of mutations: somatic mutations, which cannot be passed on to offspring, and germline mutations, in which offspring can inherit the DNA error from a mutated gene in a parent. Germline mutations are what fuel evolution by natural selection and become more or less common in a population based on how they affect the carrier's ability to survive.

Not all mutations have the potential to alter an organism's chances of survival. Mutations cause major changes to an organism only when they occur in genes — sections of DNA that code for a particular protein. Most of the human genome is made of non-gene DNA, Monroe said.

Non-random pattern
In the new study, researchers decided to test the randomness of mutations by investigating whether mutations were happening evenly between gene and non-gene regions of DNA in the genomes of thale cress.

Thale cress is a "great model organism" for studying mutations because its genome has only around 120 million base pairs (for comparison, the human genome has 3 billion base pairs), which makes it easier to sequence the plant's DNA. It also has a very short life span, which means that mutations can rapidly accumulate across multiple generations, Monroe said.

Over three years, the researchers grew hundreds of plants in laboratory conditions for multiple generations. In total, the researchers sequenced 1,700 genomes and found more than 1 million mutations. But when they analyzed these mutations, they found that the parts of the genomes containing genes had much lower rates of mutation than non-gene regions.

Thale cress is a "model organism" for studying genetic mutations because of its small genome and short lifespan.

Thale cress (Arabidopsis thaliana) is a "model organism" for studying genetic mutations because of its small genome and short lifespan. (Image credit: Pádraic Flood)
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"We think it is likely that other organisms could also have non-random genetic mutations," Monroe said. "We have actually been following up with our study by investigating this question in other species and are finding results that suggest non-random mutation is not unique to Arabidopsis."

However, the researchers suspect that the level of non-randomness among different species may not be the same.

Protecting essential genes
The non-random pattern in mutations between gene and non-gene regions of DNA suggests that there is a defensive mechanism in place to prevent potentially disastrous mutations.

"In genes coding for proteins essential for survival and reproduction, mutations are most likely to have harmful effects, potentially causing disease and even death," Monroe said. "Our results show that genes, and essential genes in particular, experience a lower mutation rate than non-gene regions in Arabidopsis. The result is that offspring have a lower chance of inheriting a harmful mutation."

Researchers found that to protect themselves, essential genes send out special signals to DNA repair proteins. This signaling is not done by the DNA itself but by histones, specialized proteins DNA wraps around to make up chromosomes.

"Based on the result of our study, we found that gene regions, especially for the most biologically essential genes, are wrapped around histones with particular chemical marks," Monroe said. "We think these chemical marks are acting as molecular signals to promote DNA repair in these regions."

The idea of histones having unique chemical markers is not new, Monroe said. Previous studies into mutations in cancer patients have also found that these chemical markers can affect whether DNA repair proteins fix mutations properly, he added.

However, this is the first time these chemical markers have been shown to influence genome-wide mutation patterns and, as a result, evolution by natural selection.

Potential implications
The researchers hope their findings could eventually be used to make improvements in human medicine.

"Mutations affect human health in so many ways, being a cause of cancer, genetic disease and aging," Monroe said. Being able to protect certain regions of the genome from mutations could help prevent or treat these problems, he added.

However, more research into animal genomes is needed before researchers can tell if the same non-random mutations occur in humans. "Our discoveries were made in plants and do not give rise to new treatments," Monroe said, "but they change our fundamental understanding of mutation and inspire many new research directions."

Selection is a result of built-in mechanisms by organisms to adapt to the environment. 

Evidence in recent years has demonstrated that mutations can be far from just random but actually orchestrated by cells to adapt to environmental conditions. As such, it is a purposefully designed, pre-programmed process under the cell's control and regulation in order to react to environmental conditions and adapt to them. This goes diametrically against the orthodox evolutionary view that mutations are mere random accidents.

Spetner, Lee (2014): In my book Not By Chance! I introduced a hypothesis suggesting that much of the evolution we actually observe is the result of organisms’ built-in capability to respond adaptively to environmental inputs. I called it the nonrandom evolutionary hypothesis (NREH). This kind of evolution relies on events that are epigenetic in the broad sense. The type of evolution I have suggested is driven by nonrandom epigenetic change triggered by environmental inputs. I have suggested that an environmental change can cause the genome of an individual to be altered to effect an adaptive response to the change, and this altered form of the genome can be inherited. It is generally recognized that environmental inputs can stimulate epigenetic events, but it is not so generally recognized that a significant fraction of these are adaptive to the environment that did the stimulation. Animals and plants have the built-in ability to respond adaptively to environmental stimuli. This capability enables these plants and animals to adapt quickly to a changing environment. The ability to respond requires that an organism be able to perceive a change in the environment and have a mechanism whereby that perception leads to the activation of a latent gene or other genetic resources, which in turn leads to a phenotypic change that will grant the organism an advantage in the new environment. 

In the last several decades there were already some biologists who felt that neo-Darwinian theory could not account for large-scale evolution (Ho and Saunders 1979, Shapiro 1992, 2009, Johnston and Gottlieb 1990). Noble (2013) claims the central assumptions of neo-Darwinism “have been disproved.” I showed (Spetner 1997) that 

(1) speciation by the neo-Darwinian process is so highly improbable that it should be considered impossible, and 
(2) when random mutations were shown to produce some microevolution, they were not the kind of mutations that could lead to Common Descent even if they were to operate over an unlimited span of time. 

Random point mutations, which neo-Darwinian evolution holds are the source of novelty in evolution, have not been shown to add any information to the genome. Usually, they have been seen to have lost information. I have stated (Spetner 1997) that no random point mutation has been observed that adds information to the genome, and the statement still holds. Some biologists are now beginning to realize that the genetic changes required for evolution have to be non-random. Large nonrandom genetic changes are indeed known to occur, and these changes are under cellular control. An environmental change can be a long-term challenge, and the organism can respond through a heritable change that will serve to adapt it and its progeny to the new environment. The organism can do this through an inherent, built-in capability to alter its genome to enable it to respond to the change. The cell may have other tricks it can do as well to accomplish the same purpose. This capability has some similarity to its ability to exercise its short-term control. James Shapiro has suggested that cells have the capability of doing their own genetic engineering. This capability is built into the cell, which enables organisms to alter their genome to adapt to a changing environment. Organisms thus have the capability to adapt quickly to a new environment. The genetic rearrangements that will reveal the adaptive genes are known to be triggered by inputs from the environment.  41

James Shapiro (2011): Stated in terms of an electronic metaphor, the view of traditional genetics and conventional evolutionary theory is that the genome is a read-only memory (ROM) system subject to change by stochastic damage and copying errors. For over six decades, however, an increasingly prevalent alternative view has gained prominence. The alternative view has its basis in cytogenetic and molecular evidence. This distinct perspective treats the genome as a read-write (RW) memory system subject to nonrandom change by dedicated cell functions. The radical difference between the ROM and RW views of genomic information storage is basic to a 21st Century understanding of all aspects of genome action in living cells. 23

We can distinguish at least seven distinct but interrelated genomic functions essential for survival, reproduction, and evolution: 

1. DNA condensation and packaging in chromatin 
2. Correctly positioning DNA-chromatin complexes through the cell cycle 
3. DNA replication once per cell cycle 
4. Proofreading and repair  
5. Ensuring accurate transmission of replicated genomes at cell division 
6. Making stored data accessible to the transcription apparatus at the right time and place 
7. Genome restructuring when appropriate 

In all organisms, functions 1 through 6 are critical for normal reproduction, and quite a few organisms also require function 7 during their normal life cycles. We humans, for instance, could not survive if our lymphocytes (immune system cells) were incapable of restructuring certain regions of their genomes to generate the essential diversity of antibodies needed for adaptive immunity. In addition, function 7 is essential for evolutionary change. 23

On a side note: One of the examples of objects that have the imprint of design is: Creating a specified complex object that performs multiple necessary/essential specific functions simultaneously ( Like a swiss multi-tool army knife) Machines, tools, etc. that perform functions/reactions with multiple possible meaningful, significant outcomes and purposes/ functional products. They can operate forward and reverse, and perform/incorporate interdependent manufacturing processes ( one-pot reactions) to achieve a specific functional outcome. Dna, mentioned above incorporating 7 life-essential functions simultaneously, fits perfectly that description, and is, therefore, one of the many reasons why DNA points to intelligent design.  

James Shapiro (2011): Discoveries in cytogenetics, molecular biology, and genomics have revealed that genome change is an active cell-mediated physiological process. This is distinctly at variance with the pre-DNA assumption that genetic changes arise accidentally and sporadically. The discovery that DNA changes arise as the result of regulated cell biochemistry means that the genome is best modelled as a read–write (RW) data storage system rather than a read-only memory (ROM). Cells have a broad variety of natural genetic engineering (NGE) functions for transporting, diversifying and reorganizing DNA sequences in ways that generate many classes of genomic novelties; natural genetic engineering functions are regulated and subject to activation by a range of challenging life history events; cells can target the action of natural genetic engineering functions to particular genome locations by a range of well-established molecular interactions, including protein binding with regulatory factors and linkage to transcription; and genome changes in cancer can usefully be considered as consequences of the loss of homeostatic control over natural genetic engineering functions.40

James Shapiro (2013): It is essential for scientists to keep in mind the astonishing reliability and complexity of living cells. Even the smallest cells contain millions of different molecules combined into an integrated set of densely packed and continuously changing macromolecular structures. Depending upon the energy source and other circumstances, these indescribably complex entities can reproduce themselves with great reliability at times as short as 10–20 minutes. Each reproductive cell cycle involves literally hundreds of millions of biochemical and biomechanical events. We must recognize that cells possess a cybernetic capacity beyond our ability to imitate. Therefore, it should not surprise us when we discover extremely dense and interconnected control architectures at all levels. Simplifying assumptions about cell informatics can be more misleading than helpful in understanding the basic principles of biological function. Two dangerous oversimplifications have been (i) to consider the genome as a mere physical carrier of hypothetical units called “genes” that determine particular cell or organismal traits, and (ii) to think of the genome as a digitally encoded Read-Only Turing tape that feeds instructions to the rest of the cell about individual characters. As we are learning from the ENCODE project data, the vast majority of genomic DNA, including many so-called “non-coding” (nc) segments, participate in biologically specific molecular interactions. Moreover, the term “gene” is a theoretical construct whose functional properties and physical structure have never been possible to define rigorously. It is telling that genome sequence annotators used to call protein-coding regions (chiefly in prokaryotic DNA) “genes,” but now use the more neutral terms CDS, for “coding sequence.” The Turing tape idea falls short, as we will see, because it does not take into account direct physical participation of the genome in reproductive and regulatory interactions. The concept of a Read-Only Turing genome also fails to recognize the essential Write capability of a universal Turing machine, which fits remarkably well with the ability of cells to make temporary or permanent inscriptions in DNA  42

Ryan M. Hull (2017): The assertion that adaptation occurs purely through natural selection of random mutations is deeply embedded in our understanding of evolution. However, we have demonstrated that a controllable mechanism exists in yeast for increasing the mutation rate in response to at least 1 environmental stimulus and that this mechanism shows remarkable allele selectivity. Cells have a remarkable and unexpected ability to alter their own genome in response to the environment.Evidence for adaptation through genome-wide nonrandom mutation is substantial.45

More recent scientific investigations have further bolstered this finding. A more recent scientific news article reported:

Science Daily (2022): Mutations occur when DNA is damaged and left unrepaired, creating a new variation. The scientists wanted to know if mutation was purely random or something deeper. What they found was unexpected. Mutations are very non-random and it's non-random in a way that benefits the plant. It's a totally new way of thinking about mutation. Arabidopsis thaliana, or thale cress, is a small, flowering weed considered the "lab rat among plants" because of its relatively small genome comprising around 120 million base pairs. Humans, by comparison, have roughly 3 billion base pairs. It's a model organism for genetics. Lab-grown plants yield many variations.  Work began at Max Planck Institute where researchers grew specimens in a protected lab environment, which allowed plants with defects that may not have survived in nature be able to survive in a controlled space. Sequencing of those hundreds of Arabidopsis thaliana plants revealed more than 1 million mutations. Within those mutations a nonrandom pattern was revealed, counter to what was expected. At first glance, what we found seemed to contradict established theory that initial mutations are entirely random and that only natural selection determines which mutations are observed in organisms. Instead of randomness they found patches of the genome with low mutation rates. In those patches, they were surprised to discover an over-representation of essential genes, such as those involved in cell growth and gene expression. These are the really important regions of the genome. The areas that are the most biologically important are the ones being protected from mutation. The areas are also sensitive to the harmful effects of new mutations. DNA damage repair seems therefore to be particularly effective in these regions. The way DNA was wrapped around different types of proteins was a good predictor of whether a gene would mutate or not. It means we can predict which genes are more likely to mutate than others and it gives us a good idea of what's going on. The findings add a surprising twist to Charles Darwin's theory of evolution by natural selection because it reveals that the plant has evolved to protect its genes from mutation to ensure survival. The plant has evolved a way to protect its most important places from mutation. 22

J. Grey Monroe (2022): The random occurrence of mutations with respect to their consequences is an axiom upon which much of biology and evolutionary theory rests. This simple proposition has had profound effects on models of evolution developed since the modern synthesis, shaping how biologists have thought about and studied genetic diversity over the past century. From this view, for example, the common observation that genetic variants are found less often in functionally constrained regions of the genome is believed to be due solely to selection after random mutation. Yet, emerging discoveries in genome biology inspire a reconsideration of classical views. It is now known that nucleotide composition, epigenomic features and bias in DNA repair can influence the likelihood that mutations occur at different places across the genome. At the same time, we have learned that specific gene regions and broad classes of genes, including constitutively expressed and essential housekeeping genes, can exist in distinct epigenomic states. This could in turn provide opportunities for adaptive mutation biases to evolve by coupling DNA repair with features enriched in constrained loci. Indeed, evidence that DNA repair is targeted to genic regions and active genes has been found. 

While it will be important to test the degree and extent of mutation bias beyond Arabidopsis, the adaptive mutation bias described here provides an alternative explanation for many previous observations in eukaryotes. Our discovery yields a new account of the forces driving patterns of natural variation, challenging a long-standing paradigm regarding the randomness of mutation.44

Adaptation and is an engineered process, which does not happen by accident. The Cell receives macroscopic signals from the environment and responds by adaptive, nonrandom mutations. The capacity of Mammals and other multicellular organisms to adapt to changing environmental conditions is extraordinary.  In order to effectively produce and secrete mature proteins, cellular mechanisms for monitoring the environment are essential. Exposure of cells to various environmental causes accumulation of unfolded proteins and results in the activation of a well-orchestrated set of pathways during a phenomenon known as the unfolded protein response (UPR). Cells have powerful quality control networks consisting of chaperones and proteases that cooperate to monitor the folding states of proteins and to remove misfolded conformers through either refolding or degradation. Free-living organisms, which are more directly exposed to environmental fluctuations, must often survive even harsher folding stresses. These stresses not only disrupt the folding of newly synthesized proteins but can also cause misfolding of already folded proteins.  In living organisms, robustness is provided by homeostatic mechanisms. At least five epigenetic mechanisms are responsible for these life-essential processes :

- heat shock factors (HSFs)
- The unfolded protein response (UPR)
- nonhomologous end-joining and homologous recombination
- The DNA Damage Response
- The Response to Oxidative Stress

The cell modulates the signalling pathways at transcriptional, post-transcriptional, and post-translational levels. Complex signaling pathways contribute to the maintenance of systemic homeostasis. Homeostasis is the mechanistic fundament of living organisms.

Homeostasis, from the Greek words for "same" and "steady," refers to any process that living things use to actively maintain fairly stable conditions necessary for survival. It is also synonymous with robustness and adaptability.

This essential characteristic of living cells, homeostasis, is the ability to maintain a steady and more-or-less constant chemical balance in a changing environment. Cell survival requires appropriate proportions of molecular oxygen and various antioxidants. Reactive products of oxygen, calles Reactive Oxygen Species ( ROS) are amongst the most potent and omnipresent threats faced by cells. Cells, damaged by ROS, irreversibly infected, functionless and/or potentially oncogenic cells are destined for persistent inactivation or elimination, respectively. If mechanisms that do not trigger controlled and programmed Cell death ( apoptosis) are not present at day 1, the organisms cannot survive and dies. Simply put, the principle is that all of a multicellular organism's cells are prepared to suicide when needed for the benefit of the organism as a whole. They eliminate themselves in a very carefully programmed way so as to minimize damage to the larger organism.  On average, in human adults, it’s about 50-70 BILLION cells that die per day. We shed 30,000 to 50,000 skin cells every minute.

1. The control of metabolism is a fundamental requirement for all life, with perturbations of metabolic homeostasis underpinning numerous disease-associated pathologies.
2. Any incomplete Metabolic network without the control mechanisms in place to get homeostasis would mean disease and cell death.
3. A minimal metabolic network and control mechanisms had to be in place from the beginning, which means, and gradualistic explanation of the origin of biological Cells, and life is unrealistic. 
Life is an all-or-nothing business and points to a creative act of God.

The following molecules must stay in a finely tuned order and balance for life to survive:
- Halogens like chlorine, fluoride, iodine, and bromine.  The body needs to maintain a delicate balance between all these elements.
- Molybdenum (Mo) and iron (Fe) are essential micronutrients required for crucial enzyme activities and mutually impact their homeostasis, which means, they are interdependent on each other to maintain homeostatic levels. 
- Potassium plays a key role in maintaining cell function, and it is important in maintaining fluid and electrolyte balance. Potassium-40 is probably the most dangerous light radioactive isotope, yet the one most essential to life. Its abundance must be balanced on a razor’s edge.
- The ability of cells to maintain a large gradient of calcium across their outer membrane is universal. All biological cells have a low cytosolic (liquid found inside Cells ) calcium concentration, can and must keep this even when the free calcium outside is up to 20,000 times higher concentrated! 
- Nutrient uptake and homeostasis must be adjusted to the needs of the organisms according to developmental stages and environmental conditions.
- Magnesium is the second most abundant cellular cation after potassium. The concentrations are essential to regulate numerous cellular functions and enzymes
- Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport 
- Phosphate, as a cellular energy currency, essentially drives most biochemical reactions defining living organisms, and thus its homeostasis must be tightly regulated. 
- Zinc (Zn) is an essential heavy metal that is incorporated into a number of human Zn metalloproteins. Zn plays important roles in nucleic acid metabolism, cell replication, and tissue repair and growth. Zn contributes to intracellular metal homeostasis. 
- Selenium homeostasis and antioxidant selenoproteins in the brain: lack of finetuned balance has implications for disorders in the central nervous system
- Copper ion homeostasis is maintained through regulated expression of genes involved in copper ion uptake. 

In the early 1960s, Ernest Nagel and Carl Hempel showed that self-regulated systems are teleological.

In his book: THE TINKERER’S ACCOMPLICE, How Design Emerges from Life Itself  J. S. TURNER, writes on page 12 :
Although I touch upon ID obliquely from time to time, I do so not because I endorse it, but because it is mostly unavoidable. ID theory is essentially warmed-over natural theology, but there is, at its core, a serious point that deserves serious attention. ID theory would like us to believe that some overarching intelligence guides the evolutionary process: to say the least, that is unlikely. Nevertheless, how design arises remains a very real problem in biology.  My thesis is quite simple: organisms are designed not so much because natural selection of particular genes has made them that way, but because agents of homeostasis build them that way. These agents’ modus operandi is to construct environments upon which the precarious and dynamic stability that is homeostasis can be imposed, and design is the result.62

Comment: Turner does not identify these agents, but Wiki describes agents as CONSCIOUS beings, which act with specific goals in mind. In the case of life, this agent made it possible for biological cells to actively maintain fairly stable levels of various metabolites and molecules, necessary for survival. We are once more, upon careful examination of the evidence in nature, justified to infer an intelligent designer as the most case-adequate explanation of the origin of homeostasis and the ability of adaptation, commonly called evolution, of all living organisms.

Gerd B. Muller et.al.,(2015):  Developmental, or phenotypic, plasticity is the capacity of an organism to change its phenotype in response to the environment. Plasticity is ubiquitous across all levels of biological organization. While the evolution of plasticity has been studied for decades, there is renewed interest in plasticity as a cause, and not just a consequence, of phenotypic evolution. For example, plasticity facilitates colonization of novel environments, affects population connectivity and gene flow, contributes to temporal and spatial variation in selection and may increase the chance of adaptive peak shifts, radiations and speciation events. Particularly contentious is the contribution of plasticity to evolution through phenotypic and genetic accommodation. Phenotypic accommodation refers to the mutual and often functional adjustment of parts of an organism during development that typically does not involve genetic mutation. Genetic accommodation may provide a mechanism for rapid adaptation to novel environments. 

too much causal significance is afforded to genes and selection, and not enough to the developmental processes that create novel variants, contribute to heredity, generate adaptive fit

Gerd B. Muller: The extended evolutionary synthesis: its structure, assumptions and predictions 9 July 2015