Tag: Genetics

ASO Success Treating Fragile X Syndrome

Posted on by phoffman@channelchek.com
Image Credit: Thom Leach, The Conversation

Fragile X Syndrome Often Results from Improperly Processed Genetic Material – Correctly Cutting RNA Offers a Potential Treatment

Fragile X syndrome is a genetic disorder caused by a mutation in a gene that lies at the tip of the X chromosome. It is linked to autism spectrum disorders. People with fragile X experience a range of symptoms that include cognitive impairment, developmental and speech delays and hyperactivity. They may also have some physical features such as large ears and foreheads, flabby muscles and poor coordination.

This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of, Joel Richter, Professor of Neuroscience, UMass Chan Medical School and Sneha Shah, Assistant Professor of Molecular Medicine. UMass Chan Medical School

Along with our colleagues Jonathan Watts and Elizabeth Berry-Kravis, we are a team of scientists with expertise in molecular biology, nucleic acid chemistry and pediatric neurology. We recently discovered that the mutated gene responsible for fragile X syndrome is active in most people with the disorder, not silenced as previously thought. But the affected gene on the X chromosome is still unable to produce the protein it codes for because the genetic material isn’t properly processed. Correcting this processing error suggests that a potential treatment for symptoms of fragile X may one day be available.

Repairing Faulty RNA Splicing

The FMR1 gene encodes a protein that regulates protein synthesis. A lack of this protein leads to overall excessive protein synthesis in the brain that results in many of the symptoms of fragile X.

The mutation that causes fragile X results in extra copies of a DNA sequence called a CGG repeat. Everyone has CGG repeats in their FMR1 gene, but typically fewer than 55 copies. Having 200 or more CGG repeats silences the FMR1 gene and results in fragile X syndrome. However, we found that around 70% of people with fragile X still have an active FMR1 gene their cellular machinery can read. But it is mutated enough that it is unable to direct the cell to produce the protein it encodes.

Genes are transcribed into another form of genetic material called RNA that cells use to make proteins. Normally, genes are processed before transcription in order to make a readable strand of RNA. This involves removing the noncoding sequences that interrupt genes and splicing the genetic material back together. For people with fragile X, the cellular machinery that does this cutting incorrectly splices the genetic material, such that the protein the FMR1 gene codes for is not produced.

Fragile X syndrome is the most common inherited form of intellectual disability.

Using cell cultures in the lab, we found that correcting this missplice can restore proper RNA function and produce the FMR1 gene’s protein. We did this by using short bits of DNA called antisense oligonucleotides, or ASOs. When these bits of genetic material bind to RNA molecules, they change the way the cell can read it. That can have effects on which proteins the cell can successfully produce.

ASOs have been used with spectacular success to treat other childhood disorders, such as spinal muscular atrophy, and are now being used to treat a variety of neurological diseases.

Beyond Mice Models

Notably, fragile X syndrome is most often studied using mouse models. However, because these mice have been genetically engineered to lack a functional FMR1 gene, they are quite different from people with fragile X. In people, it is not a missing gene that causes fragile X but mutations that lead the existing gene to lose function.

Because the mouse model of fragile X lacks the FMR1 gene, the RNA is not made and so cannot be misspliced. Our discovery would not have been possible if we used mice.

With further research, future studies in people may one day include injecting ASOs into the cerebrospinal fluid of fragile X patients, where it will travel to the brain and hopefully restore proper function of the FMR1 gene and improve their cognitive function.

Your Genome is Partially Built by Ancient Viruses

Posted on by phoffman@channelchek.com
Image: Plum Island (USDA – Public Domain)

Humans are 8% Virus – How the Ancient Viral DNA in Your Genome Plays a Role in Human Disease and Development

HERVs, or human endogenous retroviruses, make up around 8% of the human genome, left behind as a result of infections that humanity’s primate ancestors suffered millions of years ago. They became part of the human genome due to how they replicate.

Like modern HIV, these ancient retroviruses had to insert their genetic material into their host’s genome to replicate. Usually this kind of viral genetic material isn’t passed down from generation to generation. But some ancient retroviruses gained the ability to infect germ cells, such as egg or sperm, that do pass their DNA down to future generations. By targeting germ cells, these retroviruses became incorporated into human ancestral genomes over the course of millions of years and may have implications for how researchers screen and test for diseases today.

Active Viral Genes in the Human Genome

Viruses insert their genomes into their hosts in the form of a provirus. There are around 30 different kinds of human endogenous retroviruses in people today, amounting to over 60,000 proviruses in the human genome. They demonstrate the long history of the many pandemics humanity has been subjected to over the course of evolution. Scientists think these viruses once widely infected the population, since they have become fixed in not only the human genome but also in chimpanzee, gorilla and other primate genomes.

This article was republished with permission from The Conversation, a news site dedicated to sharing ideas from academic experts. It represents the research-based findings and thoughts of Seth Blumsack, Professor of Energy and Environmental Economics and International Affairs, Penn State and Aidan Burn, PhD Candidate in Genetics, Tufts University.

Research from our lab and others has demonstrated that HERV genes are active in diseased tissue, such as tumors, as well as during human embryonic development. But how active HERV genes are in healthy tissue was still largely unknown.

To answer this question, our lab decided to focus on one group of HERVs known as HML-2. This group is the most recently active of the HERVs, having gone extinct less than 5 million years ago. Even now, some of its proviruses within the human genome still retain the ability to make viral proteins.

We examined the genetic material in a database containing over 14,000 donated tissue samples from all across the body. We looked for sequences that matched each HML-2 provirus in the genome and found 37 different HML-2 proviruses that were still active. All 54 tissue samples we analyzed had some evidence of activity of one or more of these proviruses. Furthermore, each tissue sample also contained genetic material from at least one provirus that could still produce viral proteins.

The Role of HERVs in Human Health and Disease

The fact that thousands of pieces of ancient viruses still exist in the human genome and can even create protein has drawn a considerable amount of attention from researchers, particularly since related viruses still active today can cause breast cancer and AIDS-like disease in animals.

Whether the genetic remnants of human endogenous retroviruses can cause disease in people is still under study. Researchers have spotted virus-like particles from HML-2 in cancer cells, and the presence of HERV genetic material in diseased tissue has been associated with conditions such as Lou Gehrig’s disease, or amyotrophic lateral sclerosis, as well as multiple sclerosis and even schizophrenia.

Our study adds a new angle to this data by showing that HERV genes are present even in healthy tissue. This means that the presence of HERV RNA may not be enough to connect the virus to a disease.

Importantly, it also means that HERV genes or proteins may no longer be good targets for drugs. HERVs have been explored as a target for a number of potential drugs, including antiretroviral medication, antibodies for breast cancer and T-cell therapies for melanoma. Treatments using HERV genes as a cancer biomarker will also need to take into account their activity in healthy tissue.

On the other hand, our research also suggests that HERVs could even be beneficial to people. The most famous HERV embedded in human and animal genomes, syncytin, is a gene derived from an ancient retrovirus that plays an important role in the formation of the placenta. Pregnancy in all mammals is dependent on the virus-derived protein coded in this gene.

Similarly, mice, cats and sheep also found a way to use endogenous retroviruses to protect themselves against the original ancient virus that created them. While these embedded viral genes are unable to use their host’s machinery to create a full virus, enough of their damaged pieces circulate in the body to interfere with the replication cycle of their ancestral virus if the host encounters it. Scientists theorize that one HERV may have played this protective role in people millions of years ago. Our study highlights a few more HERVs that could have been claimed or co-opted by the human body much more recently for this same purpose.

Unknowns Remain

Our research reveals a level of HERV activity in the human body that was previously unknown, raising as many questions as it answered.

There is still much to learn about the ancient viruses that linger in the human genome, including whether their presence is beneficial and what mechanism drives their activity. Seeing if any of these genes are actually made into proteins will also be important.

Answering these questions could reveal previously unknown functions for these ancient viral genes and better help researchers understand how the human body reacts to evolution alongside these vestiges of ancient pandemics.