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Dark matter secrets of the human genome

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Dark matter secrets of the human genome
Dark matter secrets of the human genome. Only two percent of our genome consists of protein-coding sequences. Scientists are understanding the function of the rest of the human genome and investigating its role in diseases.

Dark matter secrets of the human genome

In this article, we’re going to read about the dark matter secrets of the human genome. Twenty years ago, a massive scientific effort showed that the human genome contains 20,000 protein-coding genes, but they make up only 2% of our DNA. The rest of the genome was considered useless or redundant DNA, but we now realize it plays an important role.

When it was announced in April 2003 that the 13-year effort to sequence the entire book of life encoded within the human genome was complete, there were high expectations. There was hope that the $3 billion Human Genome Project would lead to cures for chronic diseases and provide insights into everything in our lives that is determined by genetics.

But even as press conferences were being held to announce this achievement, this guide to human life surprised scientists.

At the time, the prevailing belief was that most of the human genome consisted of instructions for building proteins, the building blocks of living organisms, which play various roles within and between our cells, writes the BBC.

With more than 200 different types of cells in the human body, it seemed logical that each would have its own set of genes to perform its essential functions. The emergence of unique sets of proteins was thought to be critical to the evolution of our species and our cognitive powers.

Instead, it turns out that less than two percent of the three billion letters in the human genome are devoted to proteins. Only about 20,000 distinct protein-coding genes were found in the long string of molecules known as base pairs that make up our DNA sequences.

Geneticists were surprised to find that the number of protein-making genes in humans is similar to that of some of the simplest organisms on Earth. Suddenly, the world of science was faced with the unpleasant reality that perhaps most of our understanding of what makes us human has been wrong.

Humans have a total of about 19,000 protein-making genes, while worms have about 20,000, and fruit flies have about 13,000 protein-making genes.

“I remember that unbelievable shock,” says Samir Onezin, a molecular biologist and CEO of Haya Therapeutics, which is trying to use insights from studying human genetics to develop new treatments for cardiovascular disease, cancer, and other chronic diseases“At that moment, people began to think that maybe our understanding of biology was wrong.”

The remaining 98 percent of our DNA is known as “dark matter” or the “dark genome.” At first, some geneticists proposed that the dark genome was the junk DNA or garbage dump of human evolution and the remnants of defective genes that had long since lost their significance.

Although it was obvious to others that the dark genome was vital to our understanding of being human. “Evolution has absolutely no tolerance for junk,” says Kari Stefansson, CEO of the Icelandic company that decodes genetics, which has sequenced more of the entire human genome than any other institution in the world. “There must be an evolutionary reason to maintain this genome size.”

Read More: Scientists discovered the secret of DNA’s X shape

Dark matter secrets of the human genome

Now, two decades later, we have our first insights into the role of the dark genome. It seems that the main function of the dark genome is to regulate the decoding process or the expression of protein-making genes. This part of the genome helps control how our genes behave in response to all the environmental pressures our bodies face throughout our lives, from diet and stress to pollution, exercise, and sleep.

Dark matter secrets of the human genome

Onezin sees proteins as the hardware components of life, while the dark genome is software that processes and responds to external information. As a result, the more we learn about the dark genome, the more we understand the complexity of humans and how we become human. “If we think of ourselves as a species, we see that we are adaptive to the environment at every level,” says Onezin. This adaptation is information processing. “When you go back to the question of what makes us different from a fly or a worm, we find that the answers lie in the dark genome.”

Dark matter secrets of the human genome

When scientists first began poring over the Book of Life in the mid-2000s, one of the biggest challenges was that the non-protein-coding regions of the human genome appeared to be full of repetitive DNA sequences called transposons. These repetitive sequences are so abundant that they make up almost half of the entire genome of all living mammals. “Even reconstructing the first human genome was more difficult with these repetitive sequences,” says Jeff Boke, who directs the Dark Matter Project at New York University’s Langone Medical Center. “If the sequence is unique, it’s easier to analyze.”

At first, geneticists ignored transposons. Most genetic studies have focused solely on the exome (the small protein-coding region in the genome). But in the past decade, the advent of advanced DNA sequencing technologies has allowed geneticists to study the dark genome in greater detail.

An experiment in which researchers deleted a specific transposon fragment in mice, causing half the pups to die before birth, showed that some transposon sequences may be critical to our survival.

Perhaps the best explanation for why transposons are present in our genomes is that they are very old, dating back to the earliest life forms, Bocke says. Other scientists have suggested that transposons come from viruses that invaded our DNA throughout human history and then gradually repurposed in the body to find useful targets.

“In most cases, transposons are pathogens that infect us, and they can infect germline cells, the cells that we pass on to the next generation,” says Dirk Hockmeyer, assistant professor of cell biology at the University of California, Berkeley. “They can then be inherited and permanently integrated into the genome.” Bokeh describes the dark genome as something that acts like a living fossil record of vital changes in our DNA that occurred long ago in ancient history.

One of the most interesting properties of transposons is that they can jump from one part of the genome to another and cause mutations that sometimes have significant consequences.

The movement of a transposon to a different gene may have caused the loss of the tail in the family of large copies, which led to our species gaining the ability to walk upright. “This unique event had a great impact on evolution and gave rise to a lineage of large replicas, including humans,” says Boke.

But as our growing understanding of the dark genome continues to shed more light on evolution, the dark genome could also provide insights into how diseases arise.

Onezin points out that if you look at genome-wide association studies (GWAS), most of the genetic sequences associated with chronic diseases such as Alzheimer’s, diabetes, and heart disease are not in protein-coding regions, but in the dark genome. Genome-wide association studies examine genetic variation in large numbers of individuals to identify genetic variants associated with diseases.

Dark matter secrets of the human genome

The dark genome and diseases

Panay Island in the Philippines is famous for its sparkling white sands and constant influx of tourists, but this amazing place hides a sad secret.

This island has the highest frequency of incurable movement disorder called X-linked parkinsonism dystonia, abbreviated as XDP. Like Parkinson’s disease, people with XDP experience a range of symptoms that affect the ability to walk as well as the ability to react quickly to different situations.

Since XDP was first discovered in the 1970s, the disorder has so far only been seen in people of Filipino descent. The reason for this was a mystery for a long time until geneticists realized that all these people had a unique variant of a gene called TAF1.

The onset of symptoms appears to be driven by a transposon in the middle of this gene, which can alter its function in ways that damage the body over time. This gene variant is thought to have appeared for the first time about two thousand years ago and then became fixed in the population. “The TAF1 gene is an essential gene, meaning that it is needed for the growth and reproduction of all types of cells,” Boke says. “When you change its expression, you end up with this very specific defect that appears in this horrible form of parkinsonism.”

The above case is a simple example of why some DNA sequences in the dark genome can control the function of different genes or activate or suppress the process of converting genetic information into protein in response to environmental signals.

The dark genome also carries instructions for making different types of molecules known as non-coding RNAs. Non-coding RNA molecules have different roles such as helping to form proteins, inhibiting the protein production process, or helping to regulate gene activity. “The RNAs produced by the dark genome act like conductors, directing how the DNA responds to the environment,” Onezin says.

Non-coding RNA is now increasingly considered as a link between the dark genome and various chronic diseases.

The common thinking is that if we continuously give the dark genome the wrong signal (eg, through a smoking lifestyle, poor diet, and inactivity), the RNA molecules that are produced can put the body into a disease state and alter gene activity in some way. which increases inflammation in the body or causes cell death.

Some non-coding RNAs are thought to affect the activity of a gene called p53, which normally acts to prevent the formation of tumors. In complex diseases such as schizophrenia or depression, the unfavorable set of non-coding genes may act in concert to decrease or increase the expression of some genes.

Our growing understanding of the importance of the dark genome has now led to new approaches to treat these diseases. While the pharmaceutical industry usually focuses on proteins, some believe that trying to disrupt the non-coding RNAs that control the genes responsible for these processes may be a more effective approach.

In the field of cancer vaccines, where companies genetically sequence a patient’s tumor sample to identify a suitable target for the immune system to attack, most approaches have focused only on protein-coding regions. However, the German pharmaceutical company Curroc is pioneering an approach in which it also analyzes non-coding regions of proteins in the hope of finding a target that can disrupt the source of cancer.

Onezin’s company, Haya Therapeutics, is pursuing a drug development program that targets a set of non-coding RNAs that cause scar tissue, or fibrosis, in the heart. The formation of scar tissue in the heart can lead to heart failure.

Researchers hope that this approach can minimize the side effects of many common drugs. “The problem with protein-based medicine is that there are only about 20,000 proteins in the body, and most of them are expressed in different cells and in pathways unrelated to disease,” Onezin says. However, the dark genome is very specific in its activity. “There are non-coding RNAs that regulate fibrosis only in the heart, so with a drug based on those, you might get a very safe drug.”

Dark matter secrets of the human genome

We know very little about what geneticists describe as ground rules: how these non-coding sequences interact to regulate gene activity. And how do these complex chains of interactions manifest themselves over time in the form of disease and, for example, cause the neurodegeneration seen in Alzheimer’s disease?

Dark matter secrets of the human genome

“Right now, we’re at the beginning of the journey,” Hockmeyer says. The next 15 to 20 years will be important. In the coming years, researchers will work on identifying specific behaviors in cells that can lead to disease, as well as identifying parts of the dark genome that can play a role in modifying these behaviors. “We now have tools to explore this that we didn’t have access to before.”

One of these tools is gene editing. By cloning the TAF1 gene transposon in the mouse genome, Boke and his team are trying to learn more about how XDP symptoms develop. In the future, a more ambitious version of the project could try to find out how non-coding DNA sequences regulate genes by making pieces of DNA and transferring them to mouse cells.

“We’re currently working on two projects where we’re taking a large piece of non-functional DNA and then trying to insert these elements into it,” says Boke. We insert a gene into that sequence, then we insert a neutralizing sequence right in front of it and another sequence further away from it, and we study how the gene behaves. “We now have the tools to make pieces of the dark genome and study and understand it.”

Hackmeier predicts that as we gain more knowledge, just like when the first genome was sequenced 20 years ago, the Book of Life will continue to yield unexpected surprises. “There are so many questions,” he says: “Is our genome still evolving?” Can we fully decipher it? “We are still in this unknown space and we are exploring it and there are some very interesting discoveries that we can make.”

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The study that first showed the benefits of ADHD

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ADHD

In a new study, it has been hypothesized that some genetic traits associated with attention deficit hyperactivity disorder (ADHD) can actually be beneficial by increasing exploratory behaviors.

The study that first showed the benefits of ADHD

While current diagnostic definitions of attention-deficit/hyperactivity disorder (ADHD) are relatively new, the condition has been recognized and defined by clinicians under various names for centuries.

According to NA, recent genetic studies have shown that this disease is highly hereditary, which means that most people with this disease genetically inherited it from their parents.

Depending on the diagnostic criteria, between 2% and 16% of children can be classified as having ADHD. In fact, the increase in diagnosis rates in recent years has led some doctors to argue that the disease is overdiagnosed.

What is relatively clear, however, is that the behavioral traits that underlie ADHD have potentially been genetically present in human populations for a long time, leading some researchers to speculate on the evolutionary advantages of this What could be the conditions?

Imagine you are part of a wandering tribe of early humans. Your group comes across a field full of one type of fruit and everyone is faced with one big question. Do you settle on a farm and exploit its fruit supply until it’s all gone, or do you quickly pick up what you can and continue exploring for more diverse foods?

This opposition to exploitation or exploration is fundamental to the survival of all animals. At what point does the risk of staying in one place outweigh the risk of moving to find what’s next?

In the early 2000s, a team of scientists studied the genetics of a unique tribe of people in northern Kenya. This tribe, known as Ariaal, has traditionally been incredibly nomadic and nomadic since ancient times, and they have continued to live in this way. Some members of the Arial tribe settled down during the 20th century and adopted modern farming methods, while others continued to live as nomadic herders.

Read More: Flu-killer cells have been discovered in the lungs

Scientists compared the genetic and health differences between these two groups of the Arial tribe and discovered something incredibly interesting. In general, all people of the Arial tribe carry a unique genetic mutation called DRD4/7R. This genetic trait has previously been commonly identified in people with ADHD.

This genetic mutation in today’s children who have been diagnosed with ADHD is generally associated with restlessness and distraction, and in those children of the Ariel tribe who were used to the behaviors of staying still settling down, and avoiding moving, this gene was associated with health. Poor and disruptive behaviors in class were related. But in Aryalees who still lived a traditional nomadic life, this gene mutation was associated with better nutritional health and strength.

The DRD4/7R mutation is associated with increased food and drug cravings, novelty seeking, and ADHD symptoms, explained Dan Eisenberg, lead author of the 2008 study. It is possible that in a nomadic environment, a boy with this gene mutation would be able to more effectively defend livestock against invaders or find water and food sources, but these same tendencies may be limited to fixed jobs such as setting up a school, farming, or selling goods. not useful

So an interesting hypothesis emerged. Whether the genetic traits of ADHD can be somewhat beneficial to a tribe, as it predisposes some individuals to “exploration” What appears in modern times as unrest and restlessness could actually have been beneficial to tribes that were looking for food.

David Barak from the University of Pennsylvania along with a team of colleagues tested this hypothesis experimentally. They produced a unique game where players were given eight minutes to collect as many berries as possible by hovering over a bush. Each time they picked berries from a bush, the player’s harvest was reduced slightly, but if they went to a new bush, there was a time penalty.

So what did most players do? Did they stick to the original bush? Or risk wasting time trying another plant to see if it bears more fruit? The same basic question, exploration or exploitation?

About 450 people participated in this experiment and all were simultaneously screened for ADHD symptoms. Not surprisingly, the researchers found that people with higher ADHD scores reached out to new plants sooner than others, but more importantly, people with ADHD tended to collect a larger volume of berries overall.

In a recently published study, Barak and his colleagues noted that participants without ADHD traits tended to overeat individual plants.

Finally, looking at the optimal withdrawal strategy for this game, it was found that players with high ADHD scores were more successful overall.

“We found that participants who screened positive for ADHD gave up the bushes more easily and achieved higher rates of reward than participants who screened negative,” the researchers wrote in their conclusion. Given that participants stayed more on a plant in general, those with high ADHD scores made more exploratory decisions, consistent with the predictions of optimal search theory, and thus behaved more optimally.
It should be noted that these findings do not represent a definitive verdict on the possible evolutionary benefits of ADHD, but they provide compelling and plausible reasons why a small percentage of humans still have these traits.

In the 21st century, we may have pathologized ADHD as a negative disorder, but this could simply be because these characteristics no longer fit the world we have constructed. So in a different context, a person with ADHD may be the savior of a society with their restless exploration of new fields.

This new study is published in the journal Proceedings of the Royal Society B.​

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Flu-killer cells have been discovered in the lungs

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A hidden army of flu-killer cells has been discovered in the lung

A hidden army of flu-killer cells has been discovered in the lungs. A group of “University of California Riverside” researchers in their new research have discovered a group of virus-eating cells in the lung that can fight influenza.

A hidden army of flu-killer cells has been discovered in the lungs

Scientists have long thought of the fluid-filled sac around our lungs as merely a barrier to external damage, but new research shows that this sac also contains powerful virus-eating cells that enter when an influenza infection occurs.

According to ScienceMag, these cells should not be confused with phages that infect bacteria. These cells, called macrophages, are immune cells produced in the body.

“Juliet Morrison” (Juliet Morrison), a virologist at, “The University of California Riverside” (UC Riverside) and head of this research said: Macrophages swallow bacteria, viruses, cancer cells, and dying cells. They grab and destroy anything that looks alien. We were surprised to find them in the lungs because no one had seen anything like that before.

In this research, it is explained how macrophages leave the external cavity and enter the lungs during influenza. They reduce inflammation there and lower the level of disease. “This research shows that it’s not just what happens in the lung that matters, but what happens outside the lung as well,” Morrison said. Cells not normally associated with the lung can have important effects on lung disease and health.

He added: Since this structure contains liquid, it prevents the lungs from collapsing. Despite this, researchers haven’t thought much about the fact that it might contain an entire organ. Our research may change this perception.

Researchers initially sought to answer a more general question. The question was which type of cells are present in the lung when you get influenza? They obtained existing data on lung-related genes from research on mice that either died or survived the flu. Then, they mined the data using an algorithm to predict the types of cells that change in the lungs during influenza. “We analyzed the data to determine which immune cells were present in the lung tissues,” Morrison said. That’s when I realized that maybe we have an unknown external source of cells in the lung.

Read More: This robot can open the veins with high precision

Then, using a laser-based method, the researchers tracked the macrophages entering the mice’s lungs and found out what would happen if they took these cells out. “When you take them out of the mouse lung, you see disease progression and increased lung inflammation,” Morrison continued.

A hidden army of flu-killer cells has been discovered in the lung
Morrison hopes the research will encourage other scientists to re-evaluate data sets from older studies. He added: Our method was to make a new use of the available information and finally we were able to see something new.

In their future research, the research group hopes to understand which protein tells the macrophages to move into the lungs. Once the protein signals are identified, it may be possible to discover drugs that increase macrophage numbers or activity.

A strategy to strengthen the human defense system against infection rather than developing another antiviral drug could provide a treatment for influenza that is effective for a longer period of time. Morrison is interested in host therapy because antibiotic and antiviral drug resistance is a growing problem.

This problem occurs when microbes, such as bacteria and fungi, gain the ability to defeat drugs designed to kill them. Improper use and overdose of drugs accelerate this problem. According to the report of the “American Center for Disease Control and Prevention” (CDC), more than 2.8 million drug-resistant infections occur in this country every year, and as a result, more than 35 thousand people die.

“If we can boost what’s killing the infection in us, we’re probably going to have a better outcome and be less likely to become resistant to the drug,” Morrison said. The immune system is very complex, but our best long-term job is to work with what we have instead of chasing treatment-evasive viruses.

This research was published in the journal “PNAS”.​

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Why do we get old?

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Aging is an inevitable fate for all living organisms and many scientists are trying to reverse this process by discovering effective factors. Now a new study shows that DNA damage may be the main cause of aging. So why do we get old?

Why do we get old?

Processes and pathways that run smoothly in our youth begin to fail as we age. Over time, these breaks build up and lead to symptoms like loss of muscle mass, weakened immune systems, memory problems, and more that we will all experience in the future.

According to Forbes, what we see on the skin is reflected at the genetic level, creating obvious differences between young and old adults, but the exact reasons for these age-related genetic changes have not been well understood. A new study suggests that DNA damage may be to blame for aging. So why do we get old?

The genetic fingerprint of aging

Genes make the world go round. It sounds like an exaggeration, but it’s true. Each of the processes we depend on for life is somehow shaped by genes. Remember that genes serve as blueprints for protein production. Without proteins, everything stops, and ultimately, they are molecules that perform functions.

Whether a protein is produced when, where, and how much it is produced is precisely regulated by a process called gene expression. Gene expression is essentially a genetic on/off switch. For example, when a person becomes ill due to a viral infection, their body begins to turn on genes related to the immune response, thereby mobilizing the appropriate immune cells to help defend against the threat. When gene expression is properly regulated, cell function proceeds smoothly, but if the balance is disturbed, genes that should be off may remain on, and vice versa. Also, too much or too little protein may be produced.

Aging is characterized by a specific pattern of gene expression. In a sense, it can be said that aging has a specific genetic fingerprint. Just like a thief leaves his fingerprints at a crime scene, age leaves its mark, and this is true of all animal species, from tube worms to humans.

Read More: Can the aging process be slowed down?

Changes in gene expression associated with aging have been known for some time, but answering what triggers these changes in the first place has been surprisingly difficult. We know what aging looks like at the genetic level, but we don’t know why it happens.

Why do we get old?

From DNA to RNA

Protein production is a complex, multi-step process, and as with any complex process that has multiple moving parts, there is room for error. In fact, the findings of this new research show that changes in gene expression with age may be related to defects in protein production. It seems that damage to DNA is associated with damage to an important step called “transcription”.

Proteins are made from RNA, but our genes are stored in the form of DNA. Therefore, DNA must first be converted into RNA. In technical language, this work is called transcription. Why is this genetic procedure needed? Our DNA is stored in the nucleus of cells and does not leave this area of the cell to minimize damage, but protein production takes place in the cytoplasm. Therefore, genetic information must reach the cytoplasm from the nucleus.

This is where mRNA, or to be more precise, “messenger RNA” (mRNA) comes into play. While DNA is used for long-term storage, messenger RNA serves as a single-use set of genetic instructions. A messenger RNA encodes a copy of a specific gene and transfers it from the nucleus to the cytoplasm; Where the gene can be converted into a protein. The process is similar to copying part of a rare book that you need but can’t get out of the library.

The body even has its own genetic photocopying machine called RNAi polymerase II, or RNAPII. Arane polymerase II is a complex of several proteins that, depending on the gene that needs to be transcribed, attaches to a specific segment of DNA and then moves along the target gene, delivering a copy of the complementary arane. The resulting RNA strand, called the transcript, is the precursor to the messenger RNA.

In this study, Akos Gyenis, Jiang Chang, and their colleagues at the Erasmus MC Medical Center in the Netherlands discovered that in older mice, RNAi polymerase II often fails when transcribing DNA into Arani starts to stop. Analyzing the livers of two-year-old mice, they found that up to 40% of all polymerase II arane complexes were stopped. Additionally, each stalled set likely blocks three others behind it, causing the DNA strands to line up until the blockage is resolved. The researchers found that larger genes were particularly susceptible to these issues, leading to a bias towards the expression of small genes.

When transcription stops, gene expression also stops. As a result, many cellular pathways begin to fail. They are deprived of the proteins they need to function properly. This includes all pathways that malfunction with age. In other words, the genetic fingerprint created by interrupted transcription is the same as that created by aging, suggesting that they are closely related. Pathways affected include those involved in nutrient sensing, cellular debris clearance, energy metabolism, immune system function, and the ability of cells to cope with injury. All of these things play a vital role in shaping longevity.
In the next step, the researchers sought to understand the cause of the arrest of Aran polymerase II in aged mice. Their suspicions led to DNA damage that was spontaneous and internal. Gene expression patterns in cells exposed to DNA-damaging agents are very similar to those seen during normal aging. Premature aging disorders such as Cockayne syndrome are also characterized by DNA damage. Normal DNA repair mechanisms malfunction and result in the stalling of polymerase II at sites of damage known as lesions. Considering these similarities, scientists speculated that DNA damage could also be involved in normal aging.

To test their hypothesis, the researchers looked at genetically modified mice that lacked the normal DNA repair system and were prone to DNA damage. These mice showed many features of premature aging; Including their life span which was significantly shortened. As expected, the transcription speed was significantly lower in these mice compared to the healthy group.

Although we have a good understanding of how gene expression changes with age, we do not fully understand what causes these genetic changes. This situation is just like looking at the symptoms of a disease without knowing the root cause. This new research suggests one possible mechanism is the DNA damage that accumulates in RNAi polymerase II as it attempts to transcribe the template strand into RNAi. When RNAi polymerase II hits a site of damage, it stalls and interferes with transcription, disrupting several important cellular pathways.

Although this research does not yet have any immediate therapeutic implications, research of this type helps us better understand the inner workings of the aging process. The deeper our understanding, the more likely it is to develop effective drug interventions. Until then, it’s best to avoid behaviors that pose a risk of DNA damage, such as smoking and exposure to UV rays. Temporary programmed caloric restriction may also help reduce transcriptional pressure.

This research was published in “Nature Genetics” magazine.

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