Monday, October 14, 2024

Genetic Insights Into Alopecia Areata

New Genetic Insights Into Alopecia Areata


Alopecia areata has a genetic relationship with trace elements, serum metabolites, and inflammatory factors that highlights the potential value of targeted therapeutic strategies and preventive measures, according to a study published in Skin Research and Technology.1

Genetics, environmental factors, and immune dysregulation influence alopecia areata development. There is an increased risk between alopecia areata and atopy and allergies such as hay fever, eczema, asthma, and allergies to pollen, dust, and cats.2 Hypothyroidism has also been found to contribute to the development of alopecia areata among patients.3 Currently, there is little research that explores the association between developing alopecia areata and the progression of trace elements, serum modalities, and inflammatory cytokines that could be influencing the onset of the disease.1

Trace elements are essential building blocks for cells that play a crucial role in processes like energy production, tissue repair, and nerve function. They help maintain the balance of immune cells, which is vital for preventing autoimmune diseases. Fluctuations in trace element levels can disrupt these functions and potentially contribute to the development of autoimmune conditions.

Serum metabolites serve as biomarkers of metabolic activity, reflecting the alterations in metabolic pathways associated with disease states. Monitoring these metabolites in alopecia areata can provide a better understanding of the metabolic underpinnings of the disease and how it will evolve over time.

Monocytes, a type of immune cell, may play a role in the development of alopecia areata but understanding the connection between these cells could help us better understand the causes of the disease and develop new treatments.

A Mendelian randomization analysis was conducted to genetically confirm the link between trace elements, metabolites, and inflammatory markers with the risk of alopecia areata. This study aimed to identify novel biological pathways and potential therapeutic targets.

The study examined 15 common trace elements and a total of 198 single nucleotide polymorphisms were labeled as inverse variance weighted (IVW). The IVW analysis highlights the possible connection between copper levels and the risk of developing alopecia areata (OR, 0.86; 95% CI, 0.75-0.99; P = .041). No heterogeneity was revealed (P = .922) and there was no evidence of horizontal pleiotropy detected (P = .749).

There was an inverse correlation between alopecia areata development and the levels of Gamma-glutamylglutamine (OR, 0.35; 95% CI, 0.16-0.76; P = .007), X-12707 (OR, 0.55; 95% CI, 0.32-0.93; P = .026), and (N(1) + N (8))-acetylspermidine (OR, 0.61; 95% CI, 0.41-0.91; P = .015). Alopecia areata risk also has possible positive correlations with levels of N-acetylarginine (OR, 1.31; 95% CI, 1.03-1.65; P = .025) and 12 additional serum metabolites.

Inflammatory factors with an inverse correlation to an increased risk of alopecia areata development included levels of C-C motif chemokine 23 (OR, 0.56; 95% CI, 0.39-0.81; P = .001), monocyte chemoattractant protein-3 (OR, 0.64; 95% CI, 0.42-0.97; P = .035), and Cystatin D (OR, 0.78; 95% CI, 0.61-0.99; P = .042).

Additional positive correlations with alopecia areata risk were found in transforming growth factor-alpha (OR, 1.72; 95% CI, 1.01-2.94; P = .044), interleukin-2 receptor subunit beta (OR, 1.80; 95% CI, 1.01-3.19; P = .044), and interferon gamma (OR, 2.23; 95% CI, 1.34-3.71; P = .001).

One of the limitations is the study design because it relies on the effectiveness of genetic tools and may not consider all relevant biological pathways, the authors noted. The largely European population included in the study limits the results to specific ethnicities and geographical locations. Overall data interpretation is limited because the casual mechanism between alopecia areata risk and some biomarkers remains unclear.

Higher levels of copper were found to be casually associated with a reduced risk of alopecia areata, suggesting its potential protective effect against autoimmune hair loss. Conversely, elevated levels of specific inflammatory markers were linked to a higher risk of hair follicle damage, highlighting the importance of further research to better understand the underlying mechanisms of alopecia areata.

#Genetics #Neuroanatomy #BrainResearch #GeneExpression #SynapticPlasticity #Neurodevelopment #AutismResearch #Schizophrenia #Neurogenetics #MolecularPathways #Neurodegeneration #Alzheimers #Parkinsons #CRISPR #BrainConnectivity #Neuroplasticity #MentalHealthGenetics #CognitiveNeuroscience #Endophenotypes #GeneEnvironmentInteraction

International Conference on Genetics and Genomics of Diseases 

Sunday, October 13, 2024

Sex-Based Genetic Risk

Sex-Based Genetic Risk and Immune Response Differences in Alzheimer Disease


Alzheimer disease (AD) impacts millions of patients globally, with women disproportionately affected as prior research has shown that nearly twice as many women develop the disease compared with men. In a new preclinical study, findings revealed that female mice with both APOEe4 and TREM2 R47H exhibited significant damage to the brain region. Published in Neuron, these results highlight the importance of considering sex differences in AD research which could lead to more precise and effective treatments.

The study, conducted by senior author Li Gan, PhD, and colleagues, established mouse models for AD carrying human versions of APOEe4 and TREM2 R47H, 2 genetic variants that both confer high risk of AD. Authors noted that the mice also carried a mutation that led to the development of clumps of tau protein, abundant in AD brains and closely associated with cognitive decline in patients. Thus, investigators assessed the mice at 9-10 months of age, which was noted as roughly equivalent to middle age in humans, to explore how the genetic variants impacted brain health.

Gan, the director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine recently sat down with NeurologyLive® in an interview to further discuss how APOEe4 and TREM2 mutations affected immune responses, observed in male and female mouse models, differently in AD. Gan, who also serves as a professor or neuroscience at Weill Cornell Medicine, talked about the limitations of using mouse models to study AD, and how human-derived models can enhance research accuracy. In addition, she spoke about why sex stratification may be important when conducting AD clinical trials and assessing biomarker changes.

#SexBasedGenetics, #GeneticRisk, #XLinkedDiseases, #YChromosome, #GeneExpression, #Epigenetics, #MitochondrialInheritance, #PersonalizedMedicine, #SexChromosomes, #Estrogen, #Testosterone, #DiseaseSusceptibility, #CancerRisk, #AutoimmuneDisorders, #CardiovascularHealth, #NeurologicalResearch, #PrecisionMedicine, #GeneticScreening, #CRISPR, #FertilityResearch

International Conference on Genetics and Genomics of Diseases 

Friday, October 11, 2024

Discovery of microRNA

The discovery of microRNA wins the 2024 Nobel Prize in physiology

These tiny bits of genetic material play a big role in making sure cells work as they should



Tiny bits of genetic material known as microRNAs help control how cells throughout the body produce proteins. And that may give these genetic bits an outsized role in health and disease. For the discovery of microRNAs, two scientists will take home this year’s Nobel Prize in physiology or medicine.

Their award was announced October 7 at the Karolinska Institute in Stockholm, Sweden.

Victor Ambros and Gary Ruvkun will split the prize of 11 million Swedish kroner (about $1 million). Ambros works at the University of Massachusetts Chan Medical School. It’s in Worcester. Ruvkun is based at Harvard Medical School in Cambridge, Mass.

When microRNA was discovered, it “introduced a new and unexpected [method] of gene regulation,” said Olle Kämpe. Vice Chair of the Nobel Committee that made this award, Kämpe spoke at the prize’s announcement.

The two new Nobel laureates “are both brilliant scientists and wonderful people,” says H. Robert Horvitz. He’s a biologist at MIT in Cambridge, Mass. He knows Ambros and Ruvkun. At one time, they worked in his lab.


Controlling protein production

Every cell in the body contains the same set of DNA. These molecules hold the instructions that every cell needs to make the proteins that do various jobs throughout the body. Those jobs include making muscles contract. Or helping the gut digest food. Or sending signals via nerves to the brain.

But if every cell has the same DNA, how do different types of cells know to make only the proteins needed for their particular jobs? A process called gene regulation does this. It helps each cell use only the right bits of DNA when it comes time to make proteins.

Here’s how microRNA helps regulate genes.

DNA holds the protein-making instructions in long-term storage. Cells don’t convert those DNA data directly into proteins. That genetic material is too valuable and much too big. Instead, cells copy data from DNA into molecules called messenger RNA, or mRNA. That copying process is known as transcription.

Mini machines in each cell read the mRNA instructions to build proteins. That process is called translation. (This is because the cell reads instructions in one chemical language, RNA, and then converts it to a different one, proteins.)

It’s the step between copying DNA and translating mRNA where microRNAs work.

These tiny, micro snippets of RNA latch onto much longer mRNAs. Any mRNA that has microRNAs clinging to it will break down. That prevents its instructions from being made into a protein. This process is important because cells need to make just the right proteins at the correct time. MicroRNAs help make sure the process goes smoothly.

MicroRNAs “are not on-off switches,” adds Tamas Dalmay. Instead, they work like a dimmer switch to dampen production of proteins. Dalmay is a molecular biologist at the University of East Anglia in Norwich, England.

MicroRNA’s humble origins

The discovery of microRNA goes back to a tiny worm that refused to grow up.

Ambros and Ruvkun were working in Horvitz’s lab on this see-through worm, called C. elegans. The pair worked to discover key steps in the worm’s development controlled by two bits of DNA, or genes. One gene was called lin-4. The other was lin-14.

Worms with a mutant form of lin-4 repeated certain steps in the larval stage of its growth. The result: Their bodies never made some adult parts.

Ambros narrowed the location of lin-4 in the worm’s DNA. But he found no protein-making gene there. Instead, he saw little bits of RNA showing up. At first, he brushed them off as some sort of grime. “It turned out that was the microRNA that we’re all talking about,” Ambros said at a news conference on October 7. Yet it was “so unexpected that we had kind of ignored it for a while as just, you know, schmutz.”

In 1993, Ambros discovered that lin-4 makes a microRNA. Ruvkun found that the lin-4 microRNA latches onto part of the lin-14 mRNA. That linkage turns down production of lin-14 protein. The lin-14 protein, in turn, regulates other genes needed for the worm to mature.

This way of controlling protein-making was unexpected and entirely new. “It wasn’t really taken super seriously because it was in this little worm,” recalls Luisa Cochella. “People thought this was something that these funny worms do.” Cochella is a molecular biologist at the Johns Hopkins School of Medicine. That’s in Baltimore, Md.

Seven years later, Ruvkun went on to find that many animals have a microRNA called let-7. That includes humans. “That’s when people noticed,” Cochella says. It “started a frenzy to find all the microRNAs that are present in animals.”


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A little worm’s big legacy

More than 1,000 microRNAs are now known to regulate genes in people. Other animals and plants also use them. Some microRNAs evolved a long time ago. Those old types tend to control basic life processes common to all plant and animal cells. Newer microRNAs tend to regulate processes found only in certain species.

When gene regulation errs, it can lead to disease. So microRNAs not only play an important role in the workings of healthy cells. For instance, malfunctioning microRNAs play key roles in cancer, pain, itchiness and eye diseases.

“The critical role that microRNAs play in health and disease has become more and more apparent,” said David Brown. He’s the president of the academic medical centers of Mass General Brigham in Boston. He spoke at a news conference honoring Ruvkun on October 7.

New disease treatments based on microRNAs are now being tested in people. These include treatments for heart disease and cancer.

The discovery of microRNA came “completely out of the blue! And it shows that curiosity research is very important,” Kämpe said. “They were looking at two worms that looked a bit funny and decided to understand why. Then, they discovered an entirely new mechanism for gene regulation. I think that’s beautiful.”

microRNA discovery, gene regulation, post-transcriptional regulation, cancer biology, disease biomarkers, cell differentiation, apoptosis, immune response, cardiovascular diseases, neurological disorders, miRNA dysregulation, personalized medicine, therapeutic targets, miRNA profiling, next-generation sequencing, gene expression, RNA interference, cancer therapeutics, small non-coding RNA, molecular diagnostics.

#microRNA #miRNAdiscovery #generegulation #cancerbiology #biomarkers #cellfunction #apoptosis #immuneresponse #cardiovasculardisease #neurologicaldisorders #dysregulation #personalizedmedicine #miRNAtargets #miRNAprofiling #nextgensequencing #RNAi #therapeutics #smallRNA #moleculardiagnostics #diseasebiomarkers

International Conference on Genetics and Genomics of Diseases 



 

Wednesday, October 9, 2024

Human genetic disease

Human genetic disease - Prevention, Diagnosis, Treatment


The management of genetic disease can be divided into counseling, diagnosis, and treatment. In brief, the fundamental purpose of genetic counseling is to help the individual or family understand their risks and options and to empower them to make informed decisions. Diagnosis of genetic disease is sometimes clinical, based on the presence of a given set of symptoms, and sometimes molecular, based on the presence of a recognized gene mutation, whether clinical symptoms are present or not. The cooperation of family members may be required to achieve diagnosis for a given individual, and, once accurate diagnosis of that individual has been determined, there may be implications for the diagnoses of other family members. Balancing privacy issues within a family with the ethical need to inform individuals who are at risk for a particular genetic disease can become extremely complex.

Although effective treatments exist for some genetic diseases, for others there are none. It is perhaps this latter set of disorders that raises the most troubling questions with regard to presymptomatic testing, because phenotypically healthy individuals can be put in the position of hearing that they are going to become ill and potentially die and that there is nothing they or anyone else can do to stop it. Fortunately, with time and research, this set of disorders is slowly becoming smaller.

Genetic counseling

Genetic counseling represents the most direct medical application of the advances in understanding of basic genetic mechanisms. Its chief purpose is to help people make responsible and informed decisions concerning their own health or that of their children. Genetic counseling, at least in democratic societies, is nondirective; the counselor provides information, but decisions are left up to the individual or the family.

Calculating risks of known carriers

Most couples who present themselves for preconceptional counseling fall into one of two categories: those who have already had a child with genetically based problems, and those who have one or more relatives with a disease they think might be inherited. The counselor must confirm the diagnosis in the affected person with meticulous accuracy, so as to rule out the possibility of alternative explanations for the clinical symptoms observed. A careful family history permits construction of a pedigree that may illuminate the nature of the inheritance (if any), may affect the calculation of risk figures, and may bring to light other genetic influences. The counselor, a certified health-care professional with special training in medical genetics, must then decide whether the disease in question has a strong genetic component and, if so, whether the heredity is single-gene, chromosomal, or multifactorial.

In the case of single-gene Mendelian inheritance, the disease may be passed on as an autosomal recessive, autosomal dominant, or sex-linked recessive trait, as discussed in the section Classes of genetic diseases. If the prospective parents already have a child with an autosomal recessive inherited disease, they both are considered by definition to be carriers, and there is a 25 percent risk that each future child will be affected. If one of the parents carries a mutation known to cause an autosomal dominant inherited disease, whether that parent is clinically affected or not, there is a 50 percent risk that each future child will inherit the mutation and therefore may be affected. If, however, the couple has borne a child with an autosomal dominant inherited disease though neither parent carries the mutation, then it will be presumed that a spontaneous mutation has occurred and that there is not a markedly increased risk for recurrence of the disease in future children. There is a caveat to this reasoning, however, because there is also the possibility that the new mutation might have occurred in a progenitor germ cell in one of the parents, so that some unknown proportion of that individual’s eggs or sperm may carry the mutation, even though it is absent from the somatic cells—including blood, which is generally the tissue sampled for testing. This scenario is called germline mosaicism. Finally, with regard to X-linked disorders, if the pedigree or carrier testing suggests that the mother carries a gene for a sex-linked disease, there is a 50 percent chance that each son will be affected and that each daughter will be a carrier.

Counseling for chromosomal inheritance most frequently involves either an inquiring couple (consultands) who have had a child with a known chromosomal disorder, such as Down syndrome, or a couple who have experienced multiple miscarriages. To provide the most accurate recurrence risk values to such couples, both parents should be karyotyped to determine if one may be a balanced translocation carrier. Balanced translocations refer to genomic rearrangements in which there is an abnormal covalent arrangement of chromosome segments, although there is no net gain or loss of key genetic material. If both parents exhibit completely normal karyotypes, the recurrence risks cited are low and are strictly empirical.

Most of the common hereditary birth defects, however, are multifactorial. (See the section Diseases caused by mutifactorial inheritance.) If the consulting couple have had one affected child, the empirical risk for each future child will be about 3 percent. If they have borne two affected children, the chance of recurrence will rise to about 10 percent. Clearly these are population estimates, so that the risks within individual families may vary.

Estimating probability: Bayes’s theorem

As described above, the calculation of risks is relatively straightforward when the consultands are known carriers of diseases due to single genes of major effect that show regular Mendelian inheritance. For a variety of reasons, however, the parental genotypes frequently are not clear and must be approximated from the available family data. Bayes’s theorem, a statistical method first devised by the English clergyman-scientist Thomas Bayes in 1763, can be used to assess the relative probability of two or more alternative possibilities (e.g., whether a consultand is or is not a carrier). The likelihood derived from the appropriate Mendelian law (prior probability) is combined with any additional information that has been obtained from the consultand’s family history or from any tests performed (conditional probability). A joint probability is then determined for each alternative outcome by multiplying the prior probability by all conditional probabilities. By dividing the joint probability of each alternative by the sum of all joint probabilities, the posterior probability is arrived at. Posterior probability is the likelihood that the individual, whose genotype is uncertain, either carries the mutant gene or does not. One example application of this method, applied to the sex-linked recessive disease Duchenne muscular dystrophy (DMD), is given below.

In this example, the consultand wishes to know her risk of having a child with DMD. The family’s pedigree is illustrated in the figure. It is known that the consultand’s grandmother (I-2) is a carrier, since she had two affected sons (spontaneous mutations occurring in both brothers would be extremely unlikely). What is uncertain is whether the consultand’s mother (II-4) is also a carrier. The Bayesian method for calculating the consultand’s risk is as follows:

If II-4 is a carrier (risk = 1/5), then there is a 1/2 chance that the consultand is also a carrier, so her total empirical risk is 1/5 × 1/2 = 1/10. If she becomes pregnant, there is a 1/2 chance that her child will be male and a 1/2 chance that the child, regardless of sex, will inherit the familial mutation. Hence, the total empirical risk for the consultand (III-2) to have an affected child is 1/10 1/2 1/2 = 1/40. Of course, if the familial mutation is known, presumably from molecular testing of an affected family member, the carrier status of III-2 could be determined directly by molecular analysis, rather than estimated by Bayesian calculation. If the family is cooperative and an affected member is available for study, this is clearly the most informative route to follow, because the risk for the consultand to carry the familial mutation would be either 1 or 0, and not 1/10. If her risk is 1, then each of her sons will have a 1/2 chance of being affected. If her risk is 0, none of her children will be affected (unless a new mutation occurs, which is very rare).

Diagnosis

Prenatal diagnosis

Perhaps one of the most sensitive areas of medical genetics is prenatal diagnosis, the genetic testing of an unborn fetus, because of fears of eugenic misuse or because some couples may choose to terminate a pregnancy depending on the outcome of the test. Nonetheless, prenatal testing in one form or another is now almost ubiquitous in most industrialized nations, and recent advances both in testing technologies and in the set of “risk factor” genes to be screened promise to make prenatal diagnosis even more widespread. Indeed, parents may soon be able to ascertain information not only about the sex and health status of their unborn child but also about his or her complexion, personality, and intellect. Whether parents should have access to all of this information and how they may choose to use it are matters of much debate.

Current forms of prenatal diagnosis can be divided into two classes, those that are apparently noninvasive and those that are more invasive. At present the noninvasive tests are generally offered to all pregnant women, while the more-invasive tests are generally recommended only if some risk factors exist. The noninvasive tests include ultrasound imaging and maternal serum tests. Serum tests include one for alphafetoprotein (AFP) or one for alphafetoprotein, estriol, and human chorionic gonadotropin (triple screen). These tests serve as screens for structural fetal malformations and for neural tube closure defects. The triple screen also can detect some cases of Down syndrome, although there is a significant false-positive and false-negative rate.

More-invasive tests include amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, and, upon rare occasion, preimplantation testing of either a polar body or a dissected embryonic cell. Amniocentesis is a procedure in which a long, thin needle is inserted through the abdomen and uterus into the amniotic sac, enabling the removal of a small amount of the amniotic fluid bathing the fetus. This procedure is generally performed under ultrasound guidance between the 15th and 17th weeks of pregnancy, and, although it is generally regarded as safe, complications can occur, ranging from cramping to infection or loss of the fetus. The amniotic fluid obtained can be used in each of three ways: (1) living fetal cells recovered from this fluid can be induced to grow and can be analyzed to assess chromosome number, composition, or structure; (2) cells recovered from the fluid can be used for molecular studies; and (3) the amniotic fluid itself can be analyzed biochemically to determine the relative abundance of a variety of compounds associated with normal or abnormal fetal metabolism and development. Amniocentesis is typically offered to pregnant women over age 35, because of the significantly increased rate of chromosome disorders observed in the children of older mothers. A clear advantage of amniocentesis is the wealth of material obtained and the relative safety of the procedure. The disadvantage is timing: results may not be received until the pregnancy is already into the 19th week or beyond, at which point the possibility of termination may be much more physically and emotionally wrenching than if considered earlier.

Genetic testing

In the case of genetic disease, options often exist for presymptomatic diagnosis—that is, diagnosis of individuals at risk for developing a given disorder, even though at the time of diagnosis they may be clinically healthy. Options may even exist for carrier testing, studies that determine whether an individual is at increased risk of having a child with a given disorder, even though he or she personally may never display symptoms. Accurate predictive information can enable early intervention, which often prevents the clinical onset of symptoms and the irreversible damage that may have already occurred by waiting for symptoms and then responding to them. In the case of carrier testing, accurate information can enable prospective parents to make more-informed family-planning decisions. Unfortunately, there can also be negative aspects to early detection, including such issues as privacy, individual responses to potentially negative information, discrimination in the workplace, or discrimination in access to or cost of health or life insurance. While some governments have outlawed the use of presymptomatic genetic testing information by insurance companies and employers, others have embraced it as a way to bring spiraling health-care costs under control. Some communities have even considered instituting premarital carrier testing for common disorders in the populace.

Genetic testing procedures can be divided into two different groups: (1) testing of individuals considered at risk from phenotype or family history and (2) screening of entire populations, regardless of phenotype or personal family history, for evidence of genetic disorders common in that population. Both forms are currently pursued in many societies. Indeed, with the explosion of information about the human genome and the increasing identification of potential “risk genes” for common disorders, such as cancer, heart disease, or diabetes, the role of predictive genetic screening in general medical practice is likely to increase.

At present, adults are generally tested for evidence of genetic disease only if personal or family history suggests they are at increased risk for a given disorder. A typical example would be a young man whose father, paternal aunt, and older brother have all been diagnosed with early onset colorectal cancer. Although this person may appear perfectly healthy, he is at significantly increased risk to carry mutations associated with familial colorectal cancer, and accurate genetic testing could enable heightened surveillance (e.g., frequent colonoscopies) that might ultimately save his life.

Carrier testing for adults in most developed nations is generally offered only if family history or ethnic origins suggest an increased risk of having a particular disease. A typical example would be to offer carrier testing for cystic fibrosis to a couple including one member who has a sibling with the disorder. Another would be to offer carrier testing for Tay-Sachs disease to couples of Ashkenazic Jewish origin, a population known to carry an increased frequency of Tay-Sachs mutations. The same would be true for couples of African or Mediterranean descent with regard to sickle cell anemia or thalassemia, respectively. Typically, in each of these cases a genetic counselor would be involved to help the individuals or couples understand their options and make informed decisions.

genetic screening, gene therapy, genome editing, carrier testing, personalized medicine, prenatal diagnosis, genetic counseling, CRISPR technology, pharmacogenomics, biomarkers, epigenetics, molecular diagnostics, genetic risk factors, family history, gene mutation, next-generation sequencing, rare diseases, therapeutic cloning, stem cell therapy, bioinformatics 



Tuesday, October 8, 2024

Genetic switches with big potential

Nobel scientist uncovered tiny genetic switches with big potential

Harvard geneticist Gary Ruvkun vividly remembers the late-night phone call with his longtime friend and now 2024 Nobel Prize in Medicine co-laureate Victor Ambros, when they made their groundbreaking discovery of genetic switches that exist across the tree of life.

It was the early 1990s. The pair, who had met a decade earlier and bonded over their fascination with an obscure species of roundworm, were exchanging datapoints at 11 pm—one of the rare moments Ambros could steal away from tending to his newborn baby.

"It just fit together like puzzle pieces," Ruvkun told AFP in an interview from his home in a Boston suburb, shortly after learning of the award on Monday. "It was a eureka moment."

What they had uncovered was microRNA: tiny genetic molecules that act as key regulators of development in animals and plants, and hold the promise of breakthroughs in treating a wide range of diseases in the years ahead.

Although these molecules are only 22 "letters" long—compared to the thousands of lines of code in regular protein-coding genes—their small size belies their critical role as molecular gatekeepers.

"They turn off target genes," Ruvkun explained.

"It's a little bit like how astronomy starts with looking at the visible spectrum, and then people thought 'If we look with X rays, we can see much higher energy events,'" he added.

"We were looking at genetics at much smaller scales than it had been looked at before."

Dismissed at first

Their discovery had its roots in early investigations into C. elegans, a one-millimeter-long roundworm.

Ambros and Ruvkun were intrigued by the interplay between two genes that seemed to disrupt the worm's normal development—causing them either to stay in a juvenile state or acquire adult features prematurely.

The genetic information contained in all our cells flows from DNA to messenger RNA (mRNA) through a process called transcription, and then on to the cellular machinery where it provides instructions on which proteins to create.

It's through this process, understood since the mid-20th century, that cells become specialized and carry out different functions.

But Ambros and Ruvkun, who began their work in the same lab before moving to different institutions, discovered a fundamentally new pathway for regulating gene activity through microRNAs, which control gene expression after transcription.

They published their findings in back-to-back papers in Cell in 1993, but at first, the discovery was dismissed as an esoteric detail, likely irrelevant to mammals.

"We were considered an oddity in the world of developmental biology," Ruvkun recalled. Even he had little idea their work would one day be celebrated by the wider scientific community.

That all changed in 2000 when Ruvkun's lab discovered another microRNA that was present throughout the tree of life—from roundworms to mollusks, chickens, and humans.

At the time, the human genome was still being mapped, but the portion that was complete was available to researchers.

"I think it was probably one-third done, and I could already see (the new microRNA) in that one-third of the human genome," said Ruvkun. "That was a surprise!"

Since then, the microRNA field has exploded, with more than 170,000 citations currently listed in biomedical literature.

More than 1,000 microRNAs have been identified in human DNA, and some are already being used to better understand tumor types and develop treatments for people with chronic lymphocytic leukemia.

Trials are also underway to develop microRNAs as treatments for heart disease.

On the morning of their Nobel win, the two old friends "Facetimed and high-fived," Ruvkun said. "It's magnificent, and we're going to be celebrating like crazy."

genetic circuits, gene regulation, synthetic biology, transcription factors, promoter regions, CRISPR technology, inducible systems, feedback loops, RNA interference, protein engineering, biosensors, optogenetics, epigenetics, metabolic pathways, genome editing, cell differentiation, personalized medicine, drug delivery, microbial engineering, therapeutic applications.

#GeneticSwitches, #SyntheticBiology, #GeneTherapy, #CRISPR, #Optogenetics, #Bioengineering, #GeneRegulation, #Biotechnology, #Epigenetics, #PersonalizedMedicine, #GenomeEditing, #RNAInterference, #MetabolicEngineering, #PromoterRegions, #ProteinEngineering, #TissueEngineering, #DrugDelivery, #MicrobialEngineering, #Therapeutics, #Biosensors

International Conference on Genetics and Genomics of Diseases 

Monday, October 7, 2024

Psychiatric Disorders in the Brain

Uncovering Genetic Links to Psychiatric Disorders in the Brain


Scientists have identified how genetic variants influence the risk of neurological and psychiatric disorders, including schizophrenia and autism. Using live neural cells and DNA sequencing, researchers discovered thousands of “non-coding” genetic variants with context-dependent functions, activated during brain development.

These variants act like switches, turning genes on or off depending on cellular pathways. This research offers new insights into the biological mechanisms behind psychiatric disorders and could lead to personalized treatments based on genetic profiles.

Key Facts:Researchers found thousands of context-dependent genetic variants linked to psychiatric risk.
Non-coding variants act like “switches” that regulate brain development genes.
Future research may tailor psychiatric treatments based on individual genetic data.
Now, researchers at the UNC School of Medicine are using a combination of cell lines and DNA sequencing approaches to look closely at our genomes and identify which genetic variants and genes play roles in influencing one’s risk for neurological and psychiatric disorders.

A research team led by Jason Stein, PhD, associate professor of genetics and member of the UNC Neuroscience Center, has used a live-cell model system of the human brain to identify the function of genetic variants important for increasing the risk of developing schizophrenia, autism spectrum disorder, and bipolar disorder.

“There are hundreds of different locations on our genome that are associated with psychiatric disorders,” said Stein, who is also a member of UNC Lineberger Comprehensive Cancer Center.

“But these locations are in regions of the genome where the function is not well understood. We supposed that some genetic variants function only when stimulated by certain neural pathways important for brain development.”

Out of our entire genome, just 3% is responsible for creating codes that lead to the formation of proteins – the “machines” that perform needed tasks in our bodies. The other 97% of the genome does not code for proteins. It is in these “non-coding” regions where most genetic variants implicated in psychiatric illness can be found.

Non-coding variants are expected to be similar to light switches. They can “turn on” and “turn off” genes that code for proteins. But finding the precise function of these non-coding genetic variants has proven difficult for researchers.

This is because “non-coding” genetic variants can have a “context dependent” function, which means they only work when specific cellular pathways are stimulated. In other words, the downstream effects of these genetic variants can only be observed when brain cells are alive and responding to stimulation.

The Stein lab decided to study the function of these genetic variants in neural progenitor cells, which are cells involved in brain development. Every cell line has a different genetic background, which allows researchers to compare and contrast genetic variants in both active and inactive states.

Stein’s lab members exposed the stem cells to different chemical compounds and controls to measure the differences in response.

These compounds stimulate the Wnt pathway, a cascade of proteins that play important roles in brain development. Using the living model, researchers found thousands of non-coding genetic variants that have a context-dependent function.

“Through the activation of Wnt-responsive genes, we found variants with context-dependent function that are implicated in schizophrenia risk,” said Stein.

“Finding these genetic variants represents an important step forward in our understanding of the mechanisms that cause someone to be at greater risk of developing a neuropsychiatric disorder.”

Stein said that a similar study design using this live-cell model system of the human brain could be helpful for testing how genetic variation influences risk for environmental exposures, like lead exposure, and their impacts on the brain.

Similarly, future applications of this approach could be used to prescribe psychiatric treatments based on an individual’s genetics.

neuroplasticity, neurotransmitters, dopamine dysregulation, serotonin imbalance, cortical thinning, hippocampal atrophy, prefrontal cortex dysfunction, amygdala hyperactivity, genetic predisposition, epigenetic changes, neuroinflammation, oxidative stress, synaptic pruning, neurocircuitry disruption, white matter abnormalities, hypothalamic-pituitary-adrenal axis, psychosis, mood dysregulation, cognitive deficits

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Sunday, October 6, 2024

Disappearing Y chromosome

Disappearing Y chromosome: Could the future of humanity be at risk?


The sex of human and other mammal babies is determined by a male-determining gene on the Y chromosome. However, this crucial chromosome is gradually degenerating and may disappear in a few million years, potentially leading to our extinction unless a new sex-determining gene evolves.
The good news is that two branches of rodents have already lost their Y chromosome and survived. A 2022 study published in peer review journal ‘Proceedings of the National Academy of Science’ reveals that the spiny rat has successfully evolved a new male-determining gene, offering hope for humanity’s future.

Role of the Y chromosome

In humans, females have two X chromosomes, while males possess one X and one Y chromosome. The Y chromosome, though much smaller with only about 55 genes compared to the X chromosome’s 900, plays a vital role in determining male sex by triggering the development of the testis in an embryo.
At around 12 weeks after conception, the master gene on the Y chromosome, known as SRY (sex-determining region Y), activates a genetic pathway that leads to the formation of male reproductive organs. This gene works by stimulating another key gene, SOX9, which is crucial for male development across vertebrates.

Decline of the Y chromosome

Most mammals share a similar X and Y chromosome structure, but this system presents challenges due to the unequal gene dosage between males and females. Interestingly, Australia’s platypus possesses entirely different sex chromosomes, resembling those of birds, suggesting that the mammal X and Y chromosomes were once ordinary chromosomes.
Over the 166 million years since humans and platypuses diverged, the Y chromosome has lost a significant number of active genes, shrinking from 900 to just 55. If this trend continues, the Y chromosome could vanish entirely within the next 11 million years.

Rodents without a Y chromosome

Fortunately, two rodent lineages—the mole voles of eastern Europe and the spiny rats of Japan—have already lost their Y chromosome and continue to thrive. In these species, the X chromosome remains in both males and females, but the Y chromosome and SRY gene have disappeared.

A research team led by Asato Kuroiwa from Hokkaido University discovered that in spiny rats, most genes from the Y chromosome had been relocated to other chromosomes. However, the SRY gene was missing, and they found a small duplication near the SOX9 gene on chromosome 3 in males, which could substitute for SRY.

When introduced into mice, this duplication increased SOX9 activity, suggesting that spiny rats have evolved a new mechanism for male sex determination without the Y chromosome.

Implications for the future of humanity

The possible disappearance of the human Y chromosome raises concerns about the future of our species. Unlike some reptiles that can reproduce asexually, mammals, including humans, require sperm to reproduce, making men indispensable for the continuation of our species.

However, the evolution of a new sex-determining gene, as seen in spiny rats, offers a glimmer of hope. Yet, this process comes with risks — if multiple new sex-determination systems evolve in different regions, it could lead to the emergence of new human species, each with distinct sex chromosomes.

X chromosome, Y chromosome, genetic inheritance, sex-linked traits, autosomes, chromosomal abnormalities, Turner syndrome, Klinefelter syndrome, dosage compensation, X-inactivation, non-disjunction, SRY gene, pseudoautosomal regions, genomic imprinting, sex determination, XY system, XX system, homologous recombination, meiotic division, and chromatin structure.

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