In 2008, evolutionary biologist Leonid Kruglyak said something profound on the subject of missing heritability, “It's a possibility that there's something we just don't fundamentally understand, that it's so different from what we're thinking about that we're not thinking about it yet.”

When you study genetics, you run into the phrase “genetic architecture.” It's in almost every article on genetics, sometimes several times in a single article. What you don't run into is the phrase “genetic architect.” This is because we assume there's no need to mention it. We assume there is one genetic architect – one force, or process, which is responsible for all genetic architecture. We refer to it as the Modern Evolutionary Synthesis (natural selection combined with Mendelian genetics). We learn about this architect in school. We learn that we get our genes through the mechanisms of inheritance and random mutation. When random mutations are advantageous to our survival, they get passed on and our species evolves. This process is the one and only genetic architect and is supposed to explain everything that happens on the genetic level – but it doesn't.

Recent discoveries in epigenetics are helping us to understand more about DNA than we did in the past. There are mechanisms being discovered that are providing answers to some of our questions. For example, epistasis, how genes interact to produce effects, is an epigenetic mechanism that explains why some genes are inherited but not expressed. We know how these mechanisms work, but we don't know what causes them. The assumption is that they're all either hereditary or caused by something random. Some of these mechanisms have been found to be hereditary for a few generations and some which aren't hereditary, like somatic epitypes, have been found to be caused by things such as diet or exposure to certain elements in the environment. Some of what we've found is in line with what we think we know, but for the most part the heredity and randomness that we expect to be there isn't there.

Many genetic disorders have reached epidemic proportions. Among them are obesity, heart disease, and cancer. The heritability of these disorders is missing (obesity has the highest heritability, while some cancers have heritability as low as 1%). They're too widespread to be the result of random mutations. Unhealthy lifestyle does contribute and many cancers are caused by pollution, radiation, and infection, but these diseases and disorders existed long before our current unhealthy way of living pollution-causing industries. There is evidence that obesity and heart disease existed in prehistoric times. There are written records of cancer from as early as 1600 BC.

Where does the predisposition to having these disorders come from? Some people carry the gene variants (single nucleotide polymorphisms) that are associated with these disorders, but the phenotype never gets expressed, something known as incomplete penetrance. So these people acquire genes with mutations, but their genes don't have a predisposition to expressing the phenotype of the disease. What accounts for the predisposition to what phenotypes are expressed? Heredity may account for a small percentage, but what accounts for the rest (the majority)?

If you look a little more deeply into obesity, you'll find that people with the predisposition for obesity have a predisposition for other disorders as well. These include PCOS (polycystic ovary syndrome), hypothyroidism, endometriosis, diabetes, macromastia, and hyperestrogenism. Basically, it's a predisposition to endocrine system problems. You could say that the predisposition is toward having problems with the glands (hormones), but that different people express different endotypes.

If you find out what causes the predisposition, then you're in a position where you can stop the disorder before it happens. Heredity and random mutation don't provide us with the causes. They are a part of the reason these disorders exist, but their part is not as all-determining as we have been taught to believe. In 2002, I began discovering genetic predispositions for groups of phenotypes (disease phenotypes as well as physical phenotypes) and I've steadily been making discoveries for over sixteen years. In 2017, I discovered what causes the predispositions.

The cause is not heredity, it isn't random mutation, and it doesn't lead to evolution. In other words, it isn't the genetic architect that was discovered in the 1800s. What I've been in the process of discovering since 2002 is another genetic architect.

Without the predisposition for a genetic disorder, it doesn't matter if anyone in your family has it or not. With a predisposition, there is nothing that can prevent the disorder, or a related disorder, from occurring. Gene editing might be effective in helping an individual from having one particular disorder, but it won't prevent a related disorder from occurring. Gene editing doesn't work on the level of epistasis, which is just as important, if not more so, as individual genes. All that will happen with gene editing, in its current stage of development, is that the person who gets their genes edited will have to continue getting their genes edited for their entire life, the same way people who get their conditions treated have to continue treatments for their entire life. There are also disorders which we haven't been able to successfully treat – narcissistic personality disorder, sociopathy, and borderline personality disorder, for example. The knowledge I'm going to share is going to lead to a new kind of gene editing, one that will edit genetic predispositions. This will be something better than lifelong treatment and lifelong editing of single genes.

In the article Identification of Single Nucleotide Polymorphisms in the PZ1CDKN1A Gene and Correlations with Longevity in the Italian Population, it states, “centenarians likely lack numerous gene variants that are associated with age-related diseases and they may be more likely to carry protective variants as well.” The age-related diseases are cardiovascular disease, Alzheimer's, diabetes mellitus, and cancer. Cardiovascular disease is part of three of the predispositions I've discovered. Alzheimer's is part of twenty seven. Diabetes is part of nine. Cancer is part of twelve. What is important about the statement in the article is that it's saying that centenarians likely lack certain predispositions, but that they also are more likely to have certain beneficial predispositions.

The Other Architect is all genetic predispositions, as well as all the things which cause them. It isn't a negative force or mechanism. There are positive genetic predispositions. Heightened physical and mental abilities, as well as heightened resistance to diseases caused by viruses. Negative predispositions can be prevented by blocking what causes them. We can also re-create the causes of the positive predispositions (keep in mind, I'll be discussing the causes of the predispositions in the seventh and eight articles).

We're connected to something on this planet that affects us genetically, something that creates genetic architecture. We won't be able to survive on another planet if we don't take this something with us, and we'll never fully understand life until we understand this something. For years, we collectively believed in the existence of just one genetic architect. Now we are finding out that there is another. Neither of them encompasses the other. Their relationship is complementary. They both work together to produce all of the genetic architecture that exists on this planet. One of them tells us about fitness, survival, and evolution. The other one tells us about something just as powerful which we'll now be able to explore collectively.

I call this something the Other Architect. It involves forces and mechanisms, just as the architect we've been focusing all our research on has. I name these forces in the sixth, seventh, and eighth articles.

“One of life's most fulfilling moments occurs in that split second when the familiar is suddenly transformed into the dazzling aura of the profoundly new... These breakthroughs are too infrequent, more uncommon than common, and we are mired most of the time in the mundane and trivial. The shocker: what seems mundane and trivial is the very stuff that discovery is made of. The only difference is our perspective, our readiness to put the pieces together in an entirely new way to see patterns where only shadows appeared a moment before.”

—from Thinking in Future Tense by Edward B. Lindaman

The genetic predispositions (epistases) presented in the last two articles, as well as those presented in this article and those that will be presented in the next article, can be found in every human population, regardless of the continent. Further investigation of these genetic predispositions will help us to understand why people who have high genetic difference can be so similar at the same time. It will also help us understand why people who have low genetic difference can be so different.

What explains this is epistatic distance. People with low epistatic distance have the same genes expressed and the same genes silenced. The way their genes interact with, and influence, each other is also similar. They might share few genes (have high genetic distance) or they might share many genes (have low genetic distance). Either way their phenotypes (physical phenotypes and disease phenotypes) will be similar (sometimes extremely similar).

People with high epistatic distance will have different genes expressed and different genes silenced. The way their genes interact with, and influence, each other will be different. Whether they have high genetic distance or low genetic distance, their phenotypes will be different.

Basically, some individuals have high genetic distance, but low epistatic distance; some individuals have low genetic distance, but high epistatic distance; some individuals have high genetic distance and high epistatic distance; and some people, including most people who are related, have low genetic distance and low epistatic distance.

The non-heritable causes of human disease have traditionally been ascribed to environmental factors. With few exceptions, however, such as smoking for lung cancer or alcohol for liver cirrhosis, specific identification of most of these factors has proven elusive for common multifactorial diseases and methodological breakthroughs likely to change this are nowhere in sight.

—“Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime”

Though composing a very small fraction of the genome, mutations in the exome are thought to harbor 85% of mutations that have a large effect on disease.

—Wikipedia “Exome”

Approximately 90% of the maize genome is made up of TEs, as is 44% of the human genome.

—Wikipedia “Transposable Element”.

The effects of miRNA dysregulation on gene expression also seem to be important in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder, Parkinson's disease (neurodegenerative), Alzheimer's disease (neurodegenerative) and autism spectrum disorders.

—Wikipedia “Regulation of Gene Expression”

Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation.

Altered expressions of microRNAs also silence or activate many genes in progression to cancer. Altered microRNA expression occurs through hyper/hypomethylation of CpG sites in CpG islands in promoters controlling transcription of the microRNAs.

—Wikipedia “DNA Methylation”

The p53 protein functions as a transcription factor with a crucial role in orchestrating the cellular stress response. In addition to its crucial role in cancer, p53 has been implicated in other diseases including diabetes, cell death after ischemia, and various neurodegenerative diseases such as Huntington, Parkinson, and Alzheimer. Studies have suggested that p53 expression is subject to regulation by non-coding RNA.

—Wikipedia “Non-coding RNA”

The Other Architect is made up of all the mechanisms which regulate gene expression and everything which activates and directs these mechanisms.

What initiates these mechanisms is neither hereditary or random. There are some random environmental factors (diet, stress, chemicals, etc.) which affect us genetically, but these are not part of the Other Architect. The Other Architect does its work at very specific times and its work has specific patterns. The Other Architect is its own environment, and very specific events in that environment cause specific genetic interaction networks (genetic predispositions) to form. The formations of these genetic interaction networks occur at two very specific times.

Identification of genetic variants “sensitive” to specific external signals will open new opportunities for studying the role of genetic and non-genetic factors in complex traits.

—“Joint Influence of Small-Effect Genetic Variants on Human Longevity”

Maternal effects work to alter the phenotypes of the offspring through pathways other than DNA.

—Wikipedia “Maternal Effect”

Genetic recombination (also known as genetic reshuffling) is the production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be passed on from the parents to the offspring. Most recombination is naturally occurring.

In eukaryotes, recombination during meiosis is facilitated by chromosomal crossover. The crossover process leads to offspring having different combinations of genes from those of their parents, and can occasionally produce new chimeric alleles. The shuffling of genes brought about by genetic recombination produces increased genetic variation, It also allows sexually reproducing organisms to avoid Muller's ratchet, in which the genomes of an asexual population accumulate genetic deletions in an irreversible manner.

In gene conversion, a section of genetic material is copied from one chromosome to another, without the donating chromosome being changed. Gene conversion occurs at high frequency at the actual site of the recombination event during meiosis. It is a process by which a DNA sequence is copied from one DNA helix (which remains unchanged) to another DNA helix, whose sequence is altered.

During both mitosis and meiosis, DNA damages caused by a variety of exogenous agents (e.g. UV light, X-rays, chemical cross-linking agents) can be repaired by homologous recombinational repair (HRR). These findings suggest that DNA damages arising from natural processes, such as exposure to reactive oxygen species that are byproducts of normal metabolism, are also repaired by HRR. In humans and rodents, deficiencies in the gene products necessary for HRR during meiosis cause infertility. In humans, deficiencies in gene products necessary for HRR, such as BRCA1 and BRCA2, increase the risk of cancer.

In mammals, females most often have higher rates of recombination.

Wikipedia “Genetic Recombination”

The Other Architect directs regulatory mechanisms and genetic interaction networks (gene expression). Understanding exactly how it does this is going to open things up for us that have been closed up to now. When regulatory mechanisms break down, everything else starts breaking down. Not knowing anything about what actuates and directs these mechanisms has left us powerless to do anything when they start breaking down. This is one of the things that is going to change soon. Not only are we going to figure out exactly what drives what regulatory mechanism to perform its function, we'll also discover exactly what causes each of them to break down. At the present time, we have limited knowledge on the subject because our methods are limited. Studying the Other Architect will provide us with new methods (as well as a new methodological framework), and the discoveries we make with these new methods will increase our knowledge.

Epigenetic studies performed in samples collected at birth have the potential to reveal neonatal predictors of mental disorders before manifestation of their clinical symptoms.

We observed hypomethylation of EFHD1 to be associated with mental disorder.

Several genes in our study function in pathways involved in neurodevelopment and neurogenesis, which supports previous studies that suggested that mental disorders have an early neurodevelopmental component and methylomic abnormalities may be responsible for these effects. Our data suggest that altered DNA methylation measured at birth may be a useful approach to identify genes that contribute to the pathophysiology of mental disorders.

—“Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome”

Changes in histone modifications have been linked to genome instability, chromosome segregation defects and cancer.

It now seems clear that aberrant histone modification profiles are intimately linked to cancer. Crucially, however, unlike DNA mutations, changes in the epigenome associated with cancer are potentially reversible.

—“Regulation of chromatin by histone modifications”

Researchers have captured video showing how pieces of DNA once thought to be useless can act as on-off switches for genes.

These pieces of DNA are part of over 90 percent of the genetic material that are not genes. Researchers now know that this "junk DNA" contains most of the information that can turn on or off genes. But how these segments of DNA, called enhancers, find and activate a target gene in the crowded environment of a cell's nucleus is not well understood.

Analyses of how enhancers activate genes can aid in the understanding of normal development, when even small genetic missteps can result in birth defects. The timing of gene activation also is important in the development of many diseases including cancer.

"The key to curing such conditions is our ability to elucidate underlying mechanisms," said Thomas Gregor, an associate professor of physics at the Lewis-Sigler Institute for Integrative Genomics. "The goal is to use these rules to regulate and re-engineer the programs underlying development and disease processes." [This is exactly what the research I a proposing is going to do.]

As their name suggests, enhancers switch on the expression of other genes. In the mammalian genome, there are an estimated 200,000 to 1 million enhancers, and many are located far away on the DNA strand from the gene they regulate, raising the question of how the regulatory segments can locate and connect with their target genes.

The enhancers stay connected to the gene the entire time it is active. When the enhancer disconnects, gene activity stops.

Given that there can be numerous genes between the enhancer and its target, it is remarkable that enhancers can reach the exact target at the right time for that gene to become active, the researchers said.

—“Imaging in living cells reveals how 'junk DNA' switches on a gene”

Waterland showed that a mother mouse’s diet during pregnancy influences the colors of her pups’ coats via the methylation of a particular gene. “That was the first time that had ever been shown,” says Waterland. “A transient nutritional stimulus during a critical period of development could form a permanent phenotypic change by an epigenetic mechanism.”

Loci that possess this type of individual-specific epigenetic marking that occurs early in development, is present in all tissues, and lasts for a lifetime are called metastable epialleles. (Epigenetic marks are more commonly thought of as specific to certain cell types.)

The researchers began probing the human genome to identify more metastable epialleles. In 2015, they pinned down a tumor suppressor, VTRNA2-1, the methylation of which is tied to season of conception; a year later, they showed the same for POMC, a gene whose methylation patterns are related to an individual’s body mass index.

Along the way, they’ve come across numerous other sites in the human genome that appear to be metastable epialleles. In the group’s most recent study, published this past summer in Science Advances, the researchers identified 687 candidate metastable epialleles—and that’s still likely an incomplete list. In unpublished work, they carried out an unbiased screen of methylomes from 10 individuals and found a “treasure trove” of metastable epialleles, says Waterland.

—In Their Earliest Days, Embryos Record Their Environments

Metastable epialleles refer to loci with variable methylation states among individuals without underlying genetic differences. Although these loci have generally been assumed to be vulnerable to environmental influence, a new study reports their remarkable metastable epigenetic robustness toward a range of physiological, chemical and dietary disruptions in mammals.

—Metastable epialleles are stable in their instability

Observations of the variety of histone modifications, their site-specific effects, and the coordinated or antagonistic actions among different modifications lead to a very interesting question: Are there particular histone modification patterns for which we can decipher specific biological meanings in certain contexts? In fact, the original “histone code” hypothesis derived from investigations of limited loci suggest such a scenario; that is, certain combinations of histone modifications may be “translated” in a way mimicking the “genetic code”. However, recent global profiling aided by deep sequencing–based methods gradually revealed the whole iceberg. It seems it is more complicated than a simple code. Alternative hypotheses, including “histone web” or “histone language,” have been proposed from current large data collections. [It's the Other Architect.]

Compared with a less complex combination of silent marks for silent genes, active genes may be associated with many more active marks and thus have a very complex combination of patterns. Theoretically, any two or multiple active marks can form a combinatorial pattern or “code” and the number of potential combinations out of 39 marks is huge. In reality, however, limited combinations (little over 4000 combinatorial patterns) are detected. Limited combinatorial patterns suggest the co-existence of multiple active marks. Indeed, a common module (or backbone) consisting of 17 modifications across more than 3000 promoters exists in the human genome. The 17 modifications include H2BK5ac, H2BK12ac, H2BK20ac, H2BK120ac, H2A.Z, H3K4ac, H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me1, H3K18ac, H3K27ac, H3K36ac, H4K5ac, H4K8ac, and H4K91ac, presenting in 821 different patterns. Adding more active marks to this module, associated genes seem to have increased expression. The existence of this module suggests that multiple active marks, largely histone acetylation marks, work in a concerted fashion to robustly facilitate gene expression upon external signal stimulation.

The most difficult aspect of understanding histone patterns is that there are multiple layers engaging in crosstalk with one another: histone acetylation, histone methylation, and phosphorylation. One modification affects another kind of modification, thus effecting particular patterns. Making it more complex, crosstalk between histone modifications and another epigenetic modification, DNA methylation, has been reported frequently. Thus, more systematic and comprehensive models including as many epigenetic layers as possible should be in the scope of researchers for future investigations. [The interaction networks of the Other Architect.]

—Histone Modification Patterns and Their Responses to Environment

Today, there are lines of evidence which demonstrate the importance of DNA methylation and histone acetylation in transcription. However, the mechanisms that cause changes in the histone acetylation and methylation of CpG sites are not completely identified. [It is the Other Architect. The exact causes can be pinpointed.]

Identifying events that cause inactivation of genes is critical and very important for understanding the mechanisms that lead to cancer; thus, the correct perception of these events ultimately can be helpful in cancer prevention and treatment. [These events are Other Architect events. I can have them pinpointed in a year with a good team.]

Change in methylation pattern may lead to congenital defects. For example, downregulation of some genes affects the growth rate and changes in the DNMT3b catalytic domain results in immunodeficiency. [I can pinpoint the exact cause of this.]

—DNA Methylation Pattern as Important Epigenetic Criterion in Cancer

Environmental chemical exposure, inherited genetic polymorphisms, and changes in diet lead to fluctuation in patterns of DNA methylation. Diet-acquired methyl groups are transferred to DNA by methionine and folate pathways. Serious clinical consequences including atherosclerosis, cancer, and neural tube defects may occur due to alterations in DNA methylation by consuming a diet with low methionine, folate, or selenium. Such nutrient imbalance in the diet causes genetic instability (leading to chromosome rearrangement) and hypomethylation (leading to unfit gene expression).

—Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets

Gene expression data demonstrated increased activity of HAT and decreased level of HDAC activity in patients with Asthma. Patients with chronic obstructive pulmonary disease showed there is an overall decrease in HDAC activity with unchanged levels of HAT activity. [I can pinpoint the exact causes.]

The overexpression and increased activity of HDACs has been shown to be characteristic of tumorigenesis and metastasis, suggesting an important regulatory role of histone deacetylation on oncogene expression. [This can be pinpointed as well.]

—Wikipedia "Histone acetylation and deacetylation"

Most experiments and studies focus on the negative processes of the two genetic architects. Genetic disorders are seen as a problem to solve and everyone is trying to solve the problem with knowledge of only one of the two architects. By doing things in this way, they'll never solve the problem they all want to solve.

newmechanisms@gmail.com