Thursday, March 2, 2017

'Crucial Regulatory Segments' In 98 Percent of DNA Control Thousands of Genes

The mysterious majority -- as much as 98 percent -- of our DNA do not code for proteins. Much of this part of our genome was thought to be nonfunctional evolutionary leftovers that are just along for the ride. However, hidden among this noncoding DNA are many crucial regulatory elements that control the activity of thousands of genes. What is more, these elements play a major role in our health with their potential to trigger diseases such as cancer, heart disease, and even autism.

After the 2003 completion of the Human Genome Project -- which sequenced all 3 billion "letters", or base pairs, in the human genome -- many thought that our DNA would become an open book. But a perplexing problem quickly emerged: although scientists could transcribe the book, they could only interpret a small percentage of it.

Biologists have suspected for years that some kind of epigenetic inheritance occurs at the cellular level. The different kinds of cells in our bodies provide an example. Skin cells and brain cells have different forms and functions, despite having exactly the same DNA.

As part of a major ongoing effort to fully map and annotate the functional sequences of the human genome, including this silent majority, the National Institutes of Health (NIH) announced new grant funding for a nationwide project to set up five "characterization centers," including two at UC San Francisco, to study how these regulatory elements influence gene expression and, consequently, cell behavior.

The project's aim is for scientists to use the latest technology, such as genome editing, to gain insights into human biology that could one day lead to treatments for complex genetic diseases.

No Such Thing As Junk DNA

The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as “junk” but it turns out that so-called junk DNA plays critical roles in controlling how cells, organs and other tissues behave. The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health and consciousness because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.

As scientists delved into the "junk"" -- parts of the DNA that are not actual genes containing instructions for proteins -- they discovered a complex system that controls genes. At least 80 percent of this DNA is active and needed. Another 15-17 percent has higher functions scientists are still decoding.

Recent findings in the journal Science may have big implications for how medical experts use the genomes of patients to interpret and diagnose diseases, researchers said.

The genetic code uses a 64-letter alphabet called codons. Some codons, which they called duons, can have two meanings. One describes how proteins are made, and the other instructs the cell on how genes are controlled.

The newfound genetic code within deoxyribonucleic acid, the hereditary material that exists in nearly every cell of the body, was written right on top of the DNA code scientists had already cracked.

Importance of Genomic Grammar

After the shortfalls of the Human Genome Project became clear, the Encyclopedia of DNA Elements (ENCODE) Project was launched in September 2003 by the National Human Genome Research Institute (NHGRI). The goal of ENCODE is to find all the functional regions of the human genome, whether they form genes or not.

The Human Genome Project mapped the letters of the human genome, but it didn't tell us anything about the grammar: where the punctuation is, where the starts and ends are.

"The Human Genome Project mapped the letters of the human genome, but it didn't tell us anything about the grammar: where the punctuation is, where the starts and ends are," said NIH Program Director Elise Feingold, PhD. "That's what ENCODE is trying to do."

The initiative revealed that millions of these noncoding letter sequences perform essential regulatory actions, like turning genes on or off in different types of cells. However, while scientists have established that these regulatory sequences have important functions, they do not know what function each sequence performs, nor do they know which gene each one affects. That is because the sequences are often located far from their target genes -- in some cases millions of letters away. What's more, many of the sequences have different effects in different types of cells.

DNA Responds To Frequency

For more than 50 years we have assumed that changes affecting the genetic code solely impact how proteins are made, however many DNA changes that appear to alter protein sequences are actually causing disease by disrupting gene control programs or even both mechanisms simultaneously. This process appears to be largely controlled by specific frequencies affecting genes.

The Russian biophysicist and molecular biologist Pjotr Garjajev and his colleagues explored the vibrational behavior of the DNA. The bottom line was: “Living chromosomes function just like solitonic/holographic computers using the endogenous DNA laser radiation.” This means that they managed for example to modulate certain frequency patterns onto a laser ray and with it influenced the DNA frequency and thus the genetic information itself. Since the basic structure of DNA-alkaline pairs and of language (as explained earlier) are of the same structure, no DNA decoding is necessary.

This finally and scientifically explains why affirmations, autogenous training, hypnosis and the like can have such strong effects on humans and their bodies.
It is entirely normal and natural for our DNA to react to frequency. While western researchers cut single genes from the DNA strands and insert them elsewhere, the Russians enthusiastically worked on devices that can influence the cellular metabolism through suitable modulated radio and light frequencies and thus repair genetic defects.

Garjajev’s research group succeeded in proving that with this method chromosomes damaged by x-rays for example can be repaired. They even captured information patterns of a particular DNA and transmitted it onto another, thus reprogramming cells to another genome. So they successfully transformed, for example, frog embryos to salamander embryos simply by transmitting the DNA information patterns! This way the entire information was transmitted without any of the side effects or disharmonies encountered when cutting out and re-introducing single genes from the DNA. This represents an unbelievable, world-transforming revolution and sensation! All this by simply applying vibration instead of the archaic cutting-out procedure! This experiment points to the immense power of wave genetics, which obviously has a greater influence on the formation of organisms than the biochemical processes of alkaline sequences.

Epigenetic Switch

Genes are only part of our health story, explains Jeffrey S. Bland, PhD, FACN, FACB, author of the book, Genetic Nutritioneering: How You Can Modify Inherited Traits and Live a Longer, Healthier Life. The propensity for certain health conditions that you inherit from your family is not, by a long shot, the sole determinant of whether or not most folks will get sick. Your lifestyle choices have a significant impact, especially when it comes to chronic illnesses such as heart disease.

In the fields of infant nutrition, diabetes, obesity, and the metabolic syndrome, the term "metabolic programming" has been coined to give a name to the observation that environmental experiences early in life may be "genomically" remembered and give rise to health outcomes manifesting later in life. Epigenetics emerges as an important mechanism underlying this phenomenon.

Epigenetics is the phenomena whereby genetically identical cells express their genes differently, resulting in different physical traits. Researchers from the Boston University Cancer Center published two articles about this in Anticancer Research and Epigenomics.

"If we believe that everything in nature occurs in an organized fashion, then it is logical to assume that cancer development cannot be as disorganized as it may seem," said Sibaji Sarkar, PhD, instructor of medicine at BUSM and the articles corresponding author. "There should be a general mechanism that initiates cancer progression from predisposed progenitor cells, which likely involves epigenetic changes."

Increasingly, biologists are finding that non-genetic variation acquired during the life of an organism can sometimes be passed on to offspring--a phenomenon known as epigenetic inheritance.

The majority of epigenetic changes occur at specific times in an individual's life, from their time in the womb, to the development as newborns, then in puberty, and again in old age.

Environmental factors that influence epigenetic patterns -- e.g., diet, epigenetic disruptors in the environment such as chemicals, etc. - may also have long term, multigenerational effects.

Cellular Barcodes Reveal Regulatory Function

New technology has made identifying the function and targets of regulatory sequences much easier. Scientists can now manipulate cells to obtain more information about their DNA, and, thanks to high-throughput screening, they can do so in large batches, testing thousands of sequences in one experiment instead of one by one.

"It used to be extremely difficult to test for function in the noncoding part of the genome," said Ahituv, a professor in the Department of Bioengineering and Therapeutic Sciences. "With a gene, it's easier to assess the effect because there is a change in the corresponding protein. But with regulatory sequences, you don't know what a change in DNA can lead to, so it's hard to predict the functional output."

Ahituv and Shen are both using innovative techniques to study enhancers, which play a fundamental role in gene expression. Every cell in the human body contains the same DNA. What determines whether a cell is a skin cell or a brain cell or a heart cell is which genes are turned on and off. Enhancers are the secret switches that turn on cell-type specific genes.

Deleting Sequences to Understand Their Role

Shen, an assistant professor in the Department of Neurology and the Institute for Human Genetics, is taking a different approach to characterize the function of regulatory sequences. In collaboration with her former mentor at the Ludwig Institute for Cancer Research and UC San Diego, Bing Ren, PhD, she developed a high-throughput CRISPR-Cas9 screening method to test the function of noncoding sequences. Now, Shen and Ren are using this approach to identify not only which sequences have regulatory functions, but also which genes they affect.

Shen will use CRISPR to edit tens of thousands of regulatory sequences in a large pool of cells and track the effects of the edits on a set of 60 pairs of genes that commonly co-express.

For this work, each cell will be programmed to reflect two fluorescent colors -- one for each gene -- when a pair of genes is turned on. If the light in a cell goes out, the scientists will know that its target gene has been affected by one of the CRISPR-based sequence edits. The final step is to sequence each cell's DNA to determine which regulatory sequence edit caused the change in gene expression.

By monitoring the colors of co-expressed genes, Shen will reveal the complex relationship between numerous functional sequences and multiple genes, which was beyond the scope of traditional sequencing techniques.

"Until the recent development of CRISPR, it was not possible to genetically manipulate non-coding sequences in a large scale," said Shen. "Now, CRISPR can be scaled up so that we can screen thousands of regulatory sequences in one experiment. This approach will tell us not only which sequences are functional in a cell, but also which gene they regulate."

Can Our DNA Treat Disease?

By cataloging the functions of thousands of regulatory sequences, Shen and Ahituv hope to develop rules about how to predict and interpret other sequences' functions. This would not only help illuminate the rest of the unknown genome, it could also reveal new treatment targets for complex genetic diseases.

"A lot of human diseases have been found to be associated with regulatory sequences," Ahituv said. "For example, in genome-wide association studies for common diseases, such as diabetes, cancer and autism, 90 percent of the disease-associated DNA variants are in the noncoding DNA. So it's not a gene that's changed, but what regulates it."

As the price for sequencing a person's genome has dropped significantly, there is talk about using precision medicine to cure many serious diseases. However, the hurdle of how to interpret mutations in noncoding DNA remains.

"If we can characterize the function and identify the gene targets of these regulatory sequences, we can start to reveal how their mutations contribute to diseases," Shen said. "Eventually, we may even be able to treat complex diseases by correcting regulatory mutations."

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