Monthly Archives: July 2021

Its the rumour that wont go away that SARS-CoV-2 was accidentally leaked from a high biosecurity lab in Wuhan, China. The allegation is that the laboratory was conducting gain of function (GOF) research, and that this produced a potent version of coronavirus that led to the pandemic.

This has led to some scepticism and distrust of the field of research and whether it is necessary to conduct experiments using GOF techniques.

Essentially, GOF research is used to learn how viruses gain new functions through mutation and evolution.

A function is simply a property of an organism, such as plants that are more tolerant to drought or disease, or enzymes that evolved to make our bodies work.

The language about GOF has become loaded with negative connotations that associate this work with dangerous or risky research. But like rhetoric about genetic modification, these connections dont represent the diversity of the field or the security precautions that regulate the research. At its core, though, the research does exactly what the name suggests.

GOF research observes these mutations and sees how certain stimuli might affect evolutionary changes and properties of a virus or organism.

However, in our current climate its often spoken about in a much narrower context, as though its specifically about how a virus changes to move more easily between humans, or how viruses become more lethal. This just doesnt represent the full picture of GOF research.

Viruses evolve rapidly thats why there are so many new SARS-CoV-2 variants. GOF seeks to understand why and how these changes occur, and what environmental factors might influence the process.

In a sense, this is a know-your-enemy approach.

Beyond the benefit to fundamental biology research about the nature of viruses and evolution, GOF contributes to three clear areas: pandemic preparedness, vaccine development, and identification of new or potential pathogens.

GOF research can help us understand the rate at which mutations occur, and how many generations may be needed for a virus to change in a way that will require extra precautions in the community, which is information that is fed into epidemiological modelling.

This GOF information helps predict things such as how likely a virus is to become a nasty variant in a certain population size or density, during a certain season, or within a particular period or time. This informs how we react to a pandemic. Beyond this, it also informs how quickly a virus might mutate to overcome vaccines, and provides genetic information that may be useful in vaccine development. Specifically, GOF research can accumulate potential vaccine candidates in a database that can be accessed if an outbreak occurs because of natural evolution.

In turn, this means vaccine development can be sped up exponentially because candidates are already available.

For instance, a report from a 2015 GOF risk-assessment workshop for expert organisations revealed the genomics information from GOF research. This showed that bat-borne, SARS-like coronaviruses had many strains and mutations that had pandemic potential against which countermeasures need to be developed.

This information led to current pandemic responses and vaccine development the pandemic was already predicted because of a thorough understanding of the evolution of coronaviruses.

In another example, GOF experiments about influenza showed that the virus had the potential to be transmitted between different mammals with only a few changes to the genetic code, and has contributed to seasonal flu vaccines.

GOF research is based on observed evolution and changes to DNA or RNA.

The genome is the sum of all the genetic information in an organism. Some of this DNA or RNA is made up of genes, which often hold information on how to make a protein. These proteins perform functions in our body to make everything work.

These genes can naturally change a bit every generation. This happens because, to reproduce, the DNA of the parent must be replicated. The mechanisms that do this arent perfect, so little mistakes can be made when the DNA is copied.

Most of the time, the changes are tiny just a single unit of DNA (called a nucleotide) could be changed, and it may have no effect on the proteins made. At other times, the tiny change of a single nucleotide can make a gene gain a whole new function, which could be beneficial to an organism.

Natural mutations that occur during reproduction are one example of evolution in action.

These changes happen every generation, so organisms that can breed quickly, such as flies, can also evolve quickly as a species.

This process happens in essentially the same way with viruses, except that viruses have RNA instead of DNA and reproduce asexually. They still make proteins, and they still accumulate mutations, but the major difference is that they can reproduce very, very fast they can start reproducing within hours of being born and evolve at an exceptionally rapid rate.

This is why we have identified so many new variants of SARS-CoV-2 since the beginning of 2020. Every time the virus enters a new host, it reproduces rapidly, and mutations occur. Over time these mutations change the properties of the virus itself.

For example, new mutations may end up making the virus more virulent or cause worse symptoms because the proteins have changed their properties.

In these cases, we would say that the mutant strain has gained a function, and this is what GOF research aims to understand.

The viruses in a lab dont have a human host in which to grow, so researchers grow them in Petri dishes or animals instead.

There are two ways of using GOF in a lab: you can observe the virus mutate on its own (without intervention), or you can control small changes through genetic modification.

The first type of use involves putting the virus in different situations to see how it will evolve without intervention or aid.

This video is an example of GOF research with bacteria (not a virus, but the method is similar). The researchers put bacteria onto a giant petri dish with different concentrations of antibiotics. They leave the bacteria and watch how it naturally evolves to overcome the antibiotic.

The new strains of bacteria were able to be genetically sequenced to see what genetic changes had caused them to become antibiotic-resistant. This experiment can show how quickly the bacteria evolve, which can inform when or how often antibiotics are given, and whether there is a high-enough concentration of antibiotic that can halt the speed at which the antibiotic is overcome by resistance.

Similar experiments can be conducted with viruses to see how they might change to overcome human antibodies and other immune system protections.

Read more: What happens in a virology lab?

The second type of use is through small changes using genetic modification. This type of experiment occurs after a lot of other genetic information has already been gathered to identify which nucleotides in virus RNA might particularly contribute to a new function.

After these have been identified, a single or small nucleotide change will be made to the virus to confirm the predictions gained from genomic research. The modified virus will then be placed on a petri dish or inserted into an animal, such as a rabbit or a mouse, to see how the change affects the properties of the virus.

This type of research is done in specialised laboratories that are tightly controlled and heavily regulated under biosecurity laws that involve containment and decontamination processes.

Read more: How are dangerous viruses contained in Australia?

While the benefits of virus GOF research centre around pandemic preparedness, concerns have been raised about whether the research is ethical or safe.

In 2005, researchers used this technique for viruses when they reconstructed influenza (H1N1) from samples taken in 1918. The aim was to learn more about the properties of influenza and future pandemics, as influenza still circulates, but the controversial study sparked heavy debate about whether it should be acceptable.

The two major concerns are about whether this poses any threat to public health if a virus escapes the lab, or whether the techniques could be used for nefarious purposes.

In the past year, 16 years after the H1N1 study, there has been debate about whether SARS-CoV-2 had spontaneous zoonotic origins, or whether it was created in a lab in GOF experiments, and then escaped.

So now, 16 years after the first controversial H1N1 study, this speculation has pushed GOF research back into the public eye and led to many criticisms of the research field, and regulation of laboratories that use this technique.

In 2017, the US government lifted bans on GOF pathogen research after the National Institute of Health concluded that the risks of research into influenza and MERS were outweighed by the benefits, and that few posed significant threats to public health.

Following concerns about the origins of SARS-CoV-2, however, the rules surrounding GOF research, risk assessments and disclosure of experiments are now under review again, in order to clarify policy.

Read more: The COVID lab-leak hypothesis: what scientists do and dont know

Beyond this, the speculation has sparked further inquiries into the origin of SARS-CoV-2, although the World Health Organization concluded that viral escape from a laboratory was very unlikely.

Regardless, its never a bad thing to review biosafety, biosecurity and transparency policy as new evidence becomes available, and they have been frequently reviewed throughout history.

As for the concern that a government or private entity might abuse scientific techniques for malevolent purposes, scientists can, and do, support bans on research they deem ethically irresponsible, such as the controversial CRISPR babies.

Ultimately, the parameters around how scientific techniques like GOF are used and by whom is not a scientific question, but one that must be answered by ethicists.

Excerpt from:
What is gain of function research in genetics? - Cosmos Magazine

Global Animal Genetics Market 2021-2025 The analyst has been monitoring the animal genetics market and it is poised to grow by $ 1. 84 bn during 2021-2025, progressing at a CAGR of almost 7% during the forecast period.

New York, July 05, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Animal Genetics Market 2021-2025" - https://www.reportlinker.com/p06102913/?utm_source=GNW Our report on animal genetics market provides a holistic analysis, market size and forecast, trends, growth drivers, and challenges, as well as vendor analysis covering around 25 vendors.The report offers an up-to-date analysis regarding the current global market scenario, latest trends and drivers, and the overall market environment. The market is driven by the growing consumption of animal-derived food products and growing demand for genetic testing services to reduce livestock diseases. In addition, growing consumption of animal-derived food products is anticipated to boost the growth of the market as well.The animal genetics market analysis includes solution segment and geographic landscape.

The animal genetics market is segmented as below:By Geography North America Europe Asia ROW

By Solution Live animal Genetic testing services Genetic materials

This study identifies the growing focus on research and development in animal genomics as one of the prime reasons driving the animal genetics market growth during the next few years.

The analyst presents a detailed picture of the market by the way of study, synthesis, and summation of data from multiple sources by an analysis of key parameters. Our report on animal genetics market covers the following areas: Animal genetics market sizing Animal genetics market forecast Animal genetics market industry analysis

This robust vendor analysis is designed to help clients improve their market position, and in line with this, this report provides a detailed analysis of several leading animal genetics market vendors that include Animal Genetics Inc., AquaGen AS, Aviagen Inc., Cooperatie Koninklijke CRV u.a., Genetic Veterinary Sciences Inc, Genus Plc, Hendrix Genetics BV, Neogen Corp., Topigs Norsvin Holding B.V., and Zoetis Inc. Also, the animal genetics market analysis report includes information on upcoming trends and challenges that will influence market growth. This is to help companies strategize and leverage all forthcoming growth opportunities.The study was conducted using an objective combination of primary and secondary information including inputs from key participants in the industry. The report contains a comprehensive market and vendor landscape in addition to an analysis of the key vendors.

The analyst presents a detailed picture of the market by the way of study, synthesis, and summation of data from multiple sources by an analysis of key parameters such as profit, pricing, competition, and promotions. It presents various market facets by identifying the key industry influencers. The data presented is comprehensive, reliable, and a result of extensive research - both primary and secondary. Technavios market research reports provide a complete competitive landscape and an in-depth vendor selection methodology and analysis using qualitative and quantitative research to forecast the accurate market growth.Read the full report: https://www.reportlinker.com/p06102913/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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The Global Animal Genetics Market is expected to grow by $ 1.84 bn during 2021-2025, progressing at a CAGR of almost 7% during the forecast period -...

NEW YORK Foundation Medicine and Flatiron Health announced this week that Foundations comprehensive genomic profiling tests will be available to order through Flatiron's OncoEMR platform. The integration will allow clinicians to electronically order, track, and receive Foundations test through OncoEMR, the companies said. Both Flatiron and Foundation are planning further integrations with the others comprehensive genomic profiling tests and electronic medical record systems, respectively.

Myriad Genetics this week said it has completed the sale of its Myriad RBM unit which specializes in providing laboratory research services to pharmaceutical companies to IQVIA subsidiary Q2 Solutions. When Myriad announced its intent to sell this business unit in May, it did not disclose the deal's financial details.

GenetronHealth said this week that it has entered a new partnership with the World Economic Forum under its Health and Healthcare Platform, where it is contributing its research insights, technologies, and industry experience. The platform's overall goal is to ensure worldwide equal access to the highest standards of health and healthcare.Genetroniscurrentlyparticipating in a sub-project,dubbedMoving Genomics to the Clinic, which seeks to promote the use of genetic testing in routine clinical practices by proving its utility and efficacy.

AccessHope, a City of Hope subsidiary, said this week that it has partnered with the Dana-Farber Cancer Institute to bring the latest cancer care expertise to patients and oncologists in the community. By partnering withAccessHope, Dana-Farber's experts will support oncologistswiththe latest advances in oncology,includingpersonalized treatments, clinical trials, promising investigational medications, and molecular testing. Patients in Massachusetts, Maine, New Hampshire, Vermont, Connecticut, Rhode Island, New York,and New Jersey, as well asthosein other parts of the country,can access these services through their employee benefits programs. City of Hope and Northwestern University's Robert H. Lurie Comprehensive Cancer Center are also foundational members ofAccessHope.

Molecular breath analysis startup Deep Breath Intelligencesaid this week that it has entered a collaboration with Lwenstein Medical, a sleep and respiratory medicine firm based inRheinland-Pfalz, Germany.Rotkreuz, Switzerland-based DBI said that it is applying artificial intelligence to identify breath biomarkers related to obstructive sleep apnea syndrome. DBIsaid ithas initiated a study on OSASin collaboration with Lwenstein Medical,using participantsbreath samples and applying DBIs patterned analytical algorithms to provide results.

Enable Biosciences said this week it is partnering with the California Department of Public Health to survey state residents for the presence of antibodies against SARS-CoV-2. As part of the program, more than 200,000 households in California will be invited to submit dried blood samples collected at home using kits developed by Enable Bio andtheCDPH. The samples will then be tested by Enable Bio for the presence of antibodies against SARS-CoV-2 to distinguish antibody response fromviralinfection versusresponse fromvaccination. Test results will provide information about the spread of COVID-19 in California and the uptake of vaccines for the disease, South San Francisco, California-based Enable Bio said. The project is a collaboration betweenthe company,theCDPH, Stanford University, and Gauss Surgical. The first survey period concluded June 15 with the second and third enrollment periods slated tobeginat the start of 2022.

NeoGensaid this week that it has extended itsglobalanimal genomicspartnership withGencove. Thepartnership allowsNeoGento offerGencove'sSkimSeeklow-pass sequencing technology to customers in the agricultural sector, including those in the bovine, canine,poultry, and swine industries. UsingGencove'ssequencingimputationplatform,NeoGensaid it can deliver increased genomics data with improved accuracy and flexibility.

Bioceptsaid this week ithas been added to the Russell Microcap Index. Michael Nall, Biocept's president and CEO,called the nodexceptionally exciting, as a driver ofawarenessfor the cancer liquid biopsy firm within thelargerglobal investment community.

Immunoviasaid this week that its American subsidiary hasreceived a CLIA Certificate of Registration,which isan important step in the accreditation of its laboratory in Marlborough, Massachusetts, and a prerequisite to receiving clinical laboratory licensure fromtheMassachusetts Department of Public Health. Clinical laboratory licensure is required beforeImmunoviacan begin testing patients with itsImmrayPanCan-d test, the firm said.According to the Centers for Medicare and Medicaid Services, a Certificate of Registration allows a laboratory toconduct moderate and/or high complexity testing until it is inspected to determine its compliance with the CLIA regulations.

In Brief This Week is a selection of news items that may be of interest to our readers but had not previously appeared onGenomeWeb.

See more here:
In Brief This Week: Foundation Medicine, Myriad Genetics, Genetron Health, and More - GenomeWeb

Arabidopsis plants were used to develop the first CRISPR-Cas9-based gene drive in plants. Credit: Zhao Lab, UC San Diego

New technology designed to breed more robust crops to improve agricultural yield and resist the effects of climate change.

With a goal of breeding resilient crops that are better able to withstand drought and disease, University of California San Diego scientists have developed the first CRISPR-Cas9-based gene drive in plants.

While gene drive technology has been developed in insects to help stop the spread of vector-borne diseases such as malaria, researchers in Professor Yunde Zhaos lab, along with colleagues at the Salk Institute for Biological Studies, demonstrated the successful design of a CRISPR-Cas9-based gene drive that cuts and copies genetic elements inArabidopsisplants.

Breaking from the traditional inheritance rules that dictate that offspring acquire genetic materials equally from each parent (Mendelian genetics), the new research uses CRISPR-Cas9 editing to transmit specific, targeted traits from a single parent in subsequent generations. Such genetic engineering could be used in agriculture to help plants defend against diseases to grow more productive crops. The technology also could help fortify plants against the impacts of climate change such as increased drought conditions in a warming world.

A schematic representation of a new plant gene drive using CRISPR/Cas9 technology. Credit: Zhao Lab, UC San Diego

The research, led by postdoctoral scholar Tao Zhang and graduate student Michael Mudgett in Zhaos lab, ispublished in the journalNature Communications.

This work defies the genetic constraints of sexual reproduction that an offspring inherits 50% of their genetic materials from each parent, said Zhao, a member of the Division of Biological Sciences Section of Cell and Developmental Biology. This work enables inheritance of both copies of the desired genes from only a single parent.The findings can greatly reduce the generations needed for plant breeding.

The study is the latest development by researchers in theTata Institute for Genetics and Society(TIGS) at UC San Diego, which was built upon the foundation of anew technology called active genetics with potential to influence population inheritance in a variety of applications.

Developing superior crops through traditional genetic inheritance can be expensive and time-consuming as genes are passed through multiple generations. Using the new active genetics technology based on CRISPR-Cas9, such genetic bias can be achieved much more quickly, the researchers say.

I am delighted that this gene drive success, now achieved by scientists affiliated with TIGS in plants, extends the generality of this work previously demonstrated at UC San Diego, to be applicable in insects and mammals, said TIGS Global Director Suresh Subramani. This advance will revolutionize plant and crop breeding and help address the global food security problem.

Reference: Selective inheritance of target genes from only one parent of sexually reproduced F1 progeny in Arabidopsis by Tao Zhang, Michael Mudgett, Ratnala Rambabu, Bradley Abramson, Xinhua Dai, Todd P. Michael and Yunde Zhao, 22 June 2021, Nature Communications.DOI: 10.1038/s41467-021-24195-5

Coauthors of the paper include: Tao Zhang, Michael Mudgett, Ratnala Rambabu, Bradley Abramson, Xinhua Dai, Todd Michael and Yunde Zhao.

The research was funded by TIGS-UC San Diego and a training grant from the National Institutes of Health.

Original post:
New CRISPR/Cas9 Plant Genetics Technology to Improve Agricultural Yield and Resist the Effects of Climate Change - SciTechDaily

Research has shown that changes in certain genes can increase a persons risk of developing Alzheimers disease (AD). The strongest known genetic risk factor for AD is a form of the apolipoprotein E (APOE) gene called APOE 4. APOE helps carry cholesterol and other fats in the bloodstream, and problems in this process are thought to contribute to AD. NIA-supported researchers recently found that the level of APOE in the brain is dependent on the individuals genetic ancestry surrounding the APOE gene. Led by a team at the University of Miami, these study results were published in Alzheimers & Dementia on Feb. 1.

Everyone inherits two copies of the APOE gene, one from each biological parent. There are three forms, or variants, of APOE that have been shown to alter risk for AD: APOE 2, APOE 3, and APOE 4. On average, people of European ancestry who inherit two copies of APOE 4 have about 10 times the risk of AD compared with people who have only the other two variants. Interestingly, researchers have known for some time that carriers of APOE 4 in African ancestry populations, such as Africans and African Americans, have a lower risk for developing AD than European carriers, while carriers of APOE 4 from Asia have a much higher risk for AD from APOE 4 than Europeans. Earlier studies by the University of Miami researchers in individuals who had both European and African ancestries found that it was the genetic ancestry surrounding the APOE gene that determined the risk, not the gene itself. That is, if a person inherited their APOE 4 gene from their African ancestor, they had the African risk for AD; if they inherited it from their European ancestor, they had the European risk for AD. In the new study, researchers wanted to find out how the same gene variant can cause different levels of risk based on genetic ancestry.

The researchers tested whether genetic ancestry affects the expression of the APOE gene in the brain. They used a technique called single-nucleus RNA sequencing to measure how many APOE transcripts, or RNA copies of the gene, were in each individual cell in the brain. Because a genes transcripts have the instructions to make protein, this measurement gives an estimate of how much APOE protein is being produced in these cells. The researchers tested autopsy brain tissue samples from AD patients: four patients of African ancestry who had inherited APOE 4 from African ancestors and seven non-Hispanic white patients who had inherited APOE 4 from their European ancestors.

On average, the researchers found that cells in the brains of patients with European genetic ancestry surrounding APOE 4 had almost 40% more APOE transcripts than the samples from individuals who had African genetic ancestry surrounding APOE 4. Samples from the European genetic ancestry surrounding APOE 4 also had more of a type of brain cell called A1 reactive astrocytes, which are thought to be involved in the cellular degeneration process of AD. These reactive astrocytes produced the highest levels of APOE 4 expression compared to other cell types. The researchers hypothesize that the region of DNA surrounding APOE 4, which differs between people with European ancestry and people with African ancestry, has important information, such as regulatory elements, that controls how much APOE is produced.

The authors note that they had a small sample size because autopsy brain samples from individuals of African ancestry with AD are scarce. They emphasize that to advance the field of Alzheimers research, it is important to encourage people from all ancestral backgrounds to participate in clinical and genetic research, including tissue donation. The studys results could help researchers develop ways to block APOE 4 activity to reduce the risk of AD in people who have this gene variant.

This research was supported in part by NIA grants R01-AG059018, U01-AG052410, RF1-AG054074, U01-AG057659, P50-AG0256878, and P30-AG013854.

These activities relate to NIHs AD+ADRD Research Implementation Milestone 2.G, Maximize the translational potential of genetics research by ensuring rapid and broad sharing of large-scale genetic/genomic data.

Reference: Griswold AJ, et al. Increased APOE 4 expression is associated with the difference in Alzheimers disease risk from diverse ancestral backgrounds. Alzheimers & Dementia. 2021. ePub Feb 1. doi: 10.1002/alz.12287.

Read more from the original source:
Study finds differences in APOE 4 expression based on genetic ancestry - National Institute on Aging

Jul 01, 2021 5:30 PM

Author: Doug Dollemore

During his 17-year career with the New York Yankees, Lou Gehrig was famed for his prowess as a hitter and for his durability on the baseball field, which earned him his nickname "The Iron Horse. Then, mysteriously, in 1938, his iron body began to figuratively rust. He couldnt run, hit, or field his position as well as he once did. When doctors finally diagnosed his condition, the news was devastating.

Gehrig had amyotrophic lateral sclerosis (ALS), a rare progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. People who have ALS gradually lose their ability to control muscle movement. Eventually, the condition, now often referred to as Lou Gehrigs disease, leads to total paralysis and death. Then, as now, there is no cure.

In the 80 years since Gehrigs death at age 37, scientists have sought to unravel what causes the disease and develop better treatments for it.

In the latest advance, University of Utah Health researchers have detected a set of genetic mutations that appear to increase a persons risk of developing ALS. They say the discovery of mutations in TP73, a gene that has never been associated with ALS before, could help scientists develop new therapies to slow or even stop the progression of the disease.

Its really a novel discovery that suggests a very different pathway for the onset of at least some cases of ALS that hasnt been explored before, says Lynn Jorde, Ph.D., chair of the Department of Human Genetics at U of U Health and the senior author of the study. From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences.

The study appears in Neurology, the medical journal of the American Academy of Neurology.

"From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences."

About 85% of ALS cases are sporadic, meaning that no one in a patients family has a history of the disease. However, researchers suspect that up to 61% of sporadic ALS cases are influenced by genetic factors. But detecting those factors has been challenging.

In the past, it has been difficult to determine ALS-causing genes because only recently has sequencing technology advanced enough to feasibly sequence many patients, says Kristi L. Russell, a graduate research assistant at U of U Health and lead author of the study. Additionally, many mutations in a single patient could be considered deleterious, so one must test the candidate mutations in animal models or cell culture, an incredibly time-consuming process.

For this study, Jorde, Russell, and colleagues analyzed blood samples provided by 87 people with sporadic ALS who were being treated at U of U Health. Using a technique called exome sequencing, which zeroes in on the protein-coding regions within genes, they found five people who had rare, deleterious mutations in the TP73 gene, which plays a key role in apoptosis or programmed cell death. Then, the researchers studied data from 2,900 other sporadic ALS patients from the Utah Heritage 1K Project and the ALSdb cohort. Within these groups, they identified 24 different, rare protein-coding variants in TP73.

When the researchers did a similar analysis among 324 people who did not have ALS, the patient mutations in TP73 were not present.

In subsequent laboratory studies, knocking out or disabling TP73 in zebrafish impaired the development of nerve cells in a way that mimicked what appears to occur in ALS. Like in ALS, the zebrafish had fewer motor neurons and shorter axons, nerve fibers that transmit electrical impulses from neurons to muscle cells. This shortening could impede the axons ability to transmit impulses. Shorter axons transmit these impulses far less efficiently.

During their experiments, the researchers also found evidence that mutant TP73, which normally inhibits apoptosis in motor neurons, doesnt work properly. As a result, they suspect that apoptosis is more likely to occur.

It seems that mutant TP73 disrupts apoptosis, which leads to more neuronal death, Russell says. Many biological pathways have been implicated in ALS progression, but our study highlights the underappreciated role of apoptosis in ALS pathology. Apoptosis could potentially become a new focus or target for treatment drug screens.

More here:
Newly Discovered Genetic Mutations May Increase Risk for Lou Gehrig's Disease - University of Utah Health Sciences

With so many great cannabis brands releasing exciting new products in new markets, it can be hard to keep track of every release. So we're rounding up a few significant releases. This week, we look at releases by Insane, Kal, and more.

Insane just came out with a new strain available at all Dr. Greenthumb dispensaries in California. Stuffed French Toast is a cross between Paris OG and Faceoff OG, and appeals to the wake 'n' bake crowd with a flavor profile of cinnamon, pine, and orange, tasting just like the breakfast staple it was named after.

Available: California

California-based topicals brand Papa & Barkley just announced infused THC capsules to its lineup. The two-ingredient, whole-plant THC Releaf Capsules are made from coconut and cannabis oils and contain 25 to 50 milligrams of THC.

Available: California

Compound Genetics started dropping three strains at the June 26 grand opening of the Cookies Santa Ana location. These strains include Apples and Bananas, Gummiez, dropping on July 1, and Pav, which was made in collaboration with rapper Quavo.

Available: California

Kal will be dropping new flavors on July 2 in its seltzer line in time for summer. Each 12-ounce can of Kal contains 15 milligrams of hemp-derived CBD and 2 grams of sugar. The new flavors include black cherry, ruby red grapefruit, ginger lemonade, and blood orange mango.

Available: Nationwide

High Tales, a video series produced by Monogram, the cannabis line from Jay-Z, just dropped its latest episode featuring rapper Curren$y. The episode shows Curren$y's very own grilled-cheese recipe, along with weed-related stories he's experienced throughout his life and career.

Available: Nationwide

Featured image by Gina Coleman/Weedmaps

Hannah is a Seattle-based writer and editor. Shes worked in the cannabis industry for three years and continues to learn and explore.

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4 new weed products to try from Compound Genetics, Papa & Barkley, and more - Weedmaps News

Introduction

Fragile X syndrome (FXS), OMIM # 300624, is a X-linked inherited genetic disease classified as a triplet repeat condition. FXS is the most common cause of inherited intellectual disability and autism in the world. It has a prevalence of 1 in 5000 men and 1 in 8000 women. Affected individuals are characterized by intellectual disability, autism, language deficit, typical facies, and macroorchidism.1,2

Alterations in the FMR1 gene with locus Xq27.3 are causative of Fragile X Syndrome and other disorders. This gene harbors a CGG repeat within the 5 untranslated region and, depending on the number of repetitions, 4 types of alleles are defined with different clinical manifestations:3 Normal alleles, which have up to 44 CGG repeats; grey zone or intermediate alleles that contain between 45 and 54 repeats; premutation (PM) alleles with between 55 and 200 repeats; and full mutation (FM) alleles, with more than 200 repeats. In most cases, this is due to an expansion of the CGG triplet from one generation to the next.4

The Fragile Mental Retardation Protein (FMRP) is coded by the FMR1 gene. The absence of FMRP expression is usually secondary to the methylation of the FMR1 gene that occurs when more than 200 CGG repeats are present in the 5UTR region; this can also be explained by a point mutation in the coding region for FMR1 or a deletion that includes this gene, but these changes have only been reported in a few cases. The absence of FMRP is related to the classic FXS phenotype.5,6

FMRP expression is slightly lower in the carriers of a PM allele. Lower levels of FMRP are found particularly in the upper premutation (PM) range however, they typically do not present the classic FXS syndrome phenotype.7 Furthermore, they have elevated FMR1 mRNA levels between 2 to 8 times normal levels, which also leads to RNA toxicity. These elevated levels of mRNA are a risk for a number of medical conditions that are not explained by decreased FMRP.2,4,8

FMRP has roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation9,10 and for certain subgroups of cerebral transcripts.11

This protein is involved in the regulation of RNA stability, subcellular transport and translation of neural mRNAs that codify proteins involved in synapsis development, neural plasticity and brain development.8

In addition, FMRP interacts with at least 180 proteins expressed in the brain and connective tissue. This interactome comprises known FMRP-binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin-1, and other novel FMRP-interacting candidate proteins located in different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1 and TRIM28. This interactome suggests that, besides its known functions, FMRP is involved in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis and mitochondrial organization.9

Several studies have shown that in the absence of FMRP, a wide range of neural mRNAs are affected, boosting neural protein synthesis, which results in dendritic spine dysmorphogenesis and glutamate/GABA imbalance, which in turn produce variations in neural excitation/inhibition, phenomena that are present in FXS. Dendritic spine dysmorphogenesis plays a role in the intellectual deficits and behavioral problems, due to the weak synaptic connections found in this syndrome.12,13

Fragile X syndrome (FXS) has incomplete penetrance and variable expressivity and biological sex is a decisive factor of the phenotype. Full mutation of the FMR1 gene has a 100% penetrance of intellectual disability in males and 60% in females. Other characteristics associated with FXS Appear with varying frequencies in affected individuals. Autism spectrum disorder (ASD) symptoms appear during early childhood in 50% to 60% of males and 20% of females with FXS.1417

Physical features include elongated face, large and prominent ears (7578% of affected males), mandibular prognathism (80% of adult men), hyperlaxity and macroorchidism (95% of adult men). Other characteristics also vary in their frequency of presentation: seizures (23%), strabismus (8%), and cardiac abnormalities such as abnormal aortic root dimensions (18%) and mitral valve prolapse (55%). In general, the female phenotype is less severe and less specific.4,18

The variation in the phenotype of monogenic diseases is common,19,20 it is explained by a combination of genetic, environmental, and lifestyle factors,21 and FXS is not an exception.

Here, we present a review of the knowledge about the molecular factors involved in the variable expressivity of FXS.

The presence of a full mutation in FMR1 is associated with the hypermethylation of a CpG island located in the promoter of the FMR1 gene. Methylation of DNA regions (mDNA) is one of the main epigenetic modifications related to transcription regulation.22 A CpG island is located proximal to the CGG repeat tract, which is expanded in FXS. Hypermethylation of the CpG island generates transcriptional silencing of the FMR1 gene.23 As a consequence, the Fragile Mental Retardation Protein (FMRP), codified by the FMR1 gene, is not produced24 and in turn, the absence or low expression of FMRP causes FXS.

CGG tract repetition expansion in the untranslated region (UTR) of exon 1 in the FMR1 gene generates instability of that region during the replication process, inducing size mosaicism, which is defined as the presence of premutation and mutation alleles in several cells.25

In males with FXS caused by full mutation, the detection of FMR1 mRNA levels in peripheral blood lymphocytes is common. This phenomenon is due to both size mosaicism and mDNA in the CpG island and nearby regions that vary between cells and tissues.26 Furthermore, longitudinal studies in women with FXS have shown that levels of mRNA transcribed from FMR1 decrease significantly with age.23 Complicating even more the behavior of mDNA and FXS, it has been found that in premutation alleles, a considerable number of cells have mDNA.27 The variation between methylation states of the CpG island and nearby regions among different cells and tissue of the same person is known as methylation mosaicism.28 It is estimated that around 50% of people with FXS have this type of mosaicism.29 In cells where mutated alleles are not methylated, they are transcriptionally active and can be expressed.30 However, in these cells there is no FMRP synthesis since mRNA with CGG expansion greater than 200 repeats is not translated efficiently in ribosomes.31,32

The absence or low levels of FMRP is a decisive factor for FXS development, as several studies have aimed to discover the relationship between protein levels and phenotypic characteristics of the patients. Since the late 1990s, correlations between FMRP levels and the neurological phenotype of FXS have been established.29,33,34 The first studies about this topic established the standard levels of FMRP in peripheral blood leucocytes through immunoblotting. When comparing protein levels with the allele type and the presence of size mosaicism, it was demonstrated that people with the lowest FMRP levels were males with FM. Males with size mosaicism and females with FM had slightly higher levels of FMRP than males with FM.33,35,36 Via multiple regression models, it was found that FMRP levels were significantly correlated with the intelligence quotient (IQ) of the patients in the study.33 However, studies did not identify the same relation between FMRP levels and behavioral symptoms.34,37 More recent evidence supports a partial overlap between the pathogenic mechanisms that lead to FXS and ASD.38 Lower FMRP levels have been documented in samples of individuals with FXS and ASD compared to patients with FXS only.29,34 The relation between FMRP levels and IQ in males and females with different expansions in CGG repeats was studied recently.39 This last study has two important advantages compared with previous studies: firstly, the use of fluorescence resonance energy transfer (FRET), which has a higher sensibility when measuring protein levels, and also FMRP levels were measured in dermal fibroblasts. Unlike leucocytes, fibroblasts derive from the ectoderm, the same germ layer from which nervous system cells originate. Researchers found a strong and positive relation between FMRP levels and cognitive skills in patients with levels below 30% of the standard levels in controls. Interestingly, above this level, there was a higher dependence between low FMRP levels and low IQ.39

In parallel with the aforementioned studies, researchers reported the incidence of size and methylation mosaicism in cognitive impairment severity.4042 The classic definition of premutation alleles behavior as non-methylated alleles, and mutated alleles as methylated or partially methylated ones in order to categorize premutation carriers and patients with FXS has been extended progressively to include a detailed classification that takes into account the existence of size and methylation mosaicisms.

Regarding size mosaicisms, different combinations have been described, including patients with some FM cells and other cells with PM. Indeed, patients with FM, PM, grey zone alleles and even alleles with normal size have been reported.40 The presence of size mosaicisms with PM and FM alleles is related with a less severe phenotype and a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).43

When exploring the possible relation between size mosaicisms and the intellectual functioning of patients with FXS disregarding sex, it was found that patients with FM/PM had better intellectual functioning and less maladaptive behavior, compared with FM-affected individuals.42 Interestingly, the same study found that ASD features and maladaptive behaviors were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. A limitation of this study is that they used venous blood and real time PCR and Southern blot analysis to quantify the level of methylation.

Recently, methylation mosaicism has been taken into account as an important variable in phenotype traits. The most frequent mosaicism found in males is the presence of FM-methylated alleles and non-methylated FM and PM alleles (combination of size and methylation mosaicism).25,44 However, in patients with FM and not PM mosaicisms, methylated alleles do not express mRNA, while non-methylated alleles do. An aspect that highlights the importance of detecting the presence of this kind of mosaicism is the influence on phenotype severity. Additionally, according to some case reports, the presence of synthesized mRNA from PM and FM alleles increases the odds of developing the FXTAS phenotype.45,46 The final consequence of methylation mosaicism is the cells reduced ability to express FMR1 mRNA, measure mRNA and determine if there is a relation with phenotypic traits. When analyzing mRNA levels between males and females, it was found that females had higher levels. Also, in females, higher levels of FMR1 mRNA were related positively with age but not with intellectual functioning and autistic features. Males with FM that express FMR1 mRNA had significantly higher ADOS calibrated severity scores, when compared with males with fully methylated FM. Interestingly, no differences were found regarding intellectual functioning.41 Likewise, when contrasting FMR1 mRNA levels and scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CfX) it was found that in males with FM, higher values of FMR1 mRNA were related with elevated irritability and lower health-related quality of life scores.47 This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations, it is essential to take into consideration not only sex but also size and methylation mosaicism.

Recent investigations explored simultaneously how FMR1 mRNA levels of FMRP are related to phenotypic alterations in males with PM and FM.48 In a study composed of 14 cases of patients with PM or PM and FM mosaicism and mental illnesses such as bipolar disorder, schizophrenia and psychosis, among others, low levels of FMRP and increased FMR1 mRNA were evident in these patients. This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS.48 In a clinic-based ascertained group of patients with FXS of both gender, a significant difference was found between FXS with ASD and low levels of FMRP when comparing concentrations of the protein in patients with FXS without ASD.29 They found that the mean full scale IQ and adaptive skills composite scores were significantly lower in males than in females (p = 0.016 and p = 0.001, respectively, MannWhitney). Additionally, all individuals with moderate or severe ID were males. Not surprisingly, ASD was present more frequently in males with FXS (46% vs 20% females). This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations is essential to take into consideration not only sex but size and methylation mosaicism.29

There is a small proportion of FXS patients without expansions in the CGG-repeat tract. In this group, the condition is caused by missense or nonsense mutations,5,16 or deletions in FMR1.1,6 Patients with these mutations have similar physical, cognitive and behavioral characteristics to FXS patients. With the increasing availability of diagnostic methods based on next-generation sequencing and comparative genomic hybridization, a higher rate of diagnosis of mutations causing FMR1 function loss is expected. This will allow a clear delimitation of the phenotype caused by the loss of the protein in the absence of CGG tract expansions.

For many monogenic diseases it is known that, besides the allelic variance, the effect of modifier genes has an important role in incomplete penetrance and variable expressivity. The identification of modifier genes that affect the phenotype in monogenic diseases has many challenges that complicate their description. A genetic variant can modify the effect in the phenotype of another variant in many ways, including epistasis and genetic interactions.49,50

In studies using FXS murine models, important new evidence was acquired in order to establish the importance of potential modifier genes and their impact on FXS phenotype development. The knockout mouse model for FXS was generated in the last decade of the XX century. Fmr1 KO mice had learning deficits, abnormal synaptic connections, seizures, hyperactivity and macroorchidism.51,52 When describing the mouse phenotype in detail, it was evident that abnormal phenotypic characteristics depend, at least in some proportion, on their genetic background.53

During the identification of modifier genes in the FXS phenotype, a large proportion of the research has aimed towards the susceptibility to developing certain clinical behavioral characteristics, such as aggression, ASD and seizures.34,5459 All of the studies use a similar methodological design: they arrange groups of people with or without a specific phenotypic trait and establish the frequency of specific variants in modifier gene candidates.

The possibility that Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype in FXS patients has also been investigated. The replacement of a methionine for a valine in the 66th position of the BDNF protein interferes with normal intracellular traffic and BDNF dependent secretory activity in cortical neurons.60 This polymorphism has been related to cerebral anatomy alterations61 and neuropsychiatric disorders.62,63 In a sample of 27 males with FXS from Finland, it was found that all the patients with epilepsy (15%) had the Met66 allele, whereas the prevalence of this allele is 20% in the normal population. Research suggests that the Met66 allele in BDNF interacting with FM in FMR1 may partially explain the higher incidence of seizures in patients with FXS.56 In a more recent study with a higher number of males with FXS (77 patients), the results were not replicated and there was no association between seizures and Val66Met polymorphism.58 These results show the importance of validating studies about modifier genes in different populations.

In research about genes that affect mood and aggression, such as the serotonin transporter (5-HTTLPR), the monoamine oxidase A (MAOA-VNTR) and COMT, conflicting results were found. All of those genes are involved in regulatory pathways for different neurotransmitters, and their variants have been associated with the development of behavioral phenotypes in different contexts other than FXS. In one group of 50 males with FXS, the relationship of 5-HTTLPR and MAOA-VNTR polymorphisms with the frequency/severity of aggressive/destructive, self-injurious and stereotypic behaviors was studied. It was found that the high-transcribing long (L/L) genotype in 5-HTTLPR was related with a higher frequency of aggressive/destructive and stereotypic behavior, while patients with the short (S/S) genotype had less aggression. The MAOA-VNTR genotype had no effect on behavior.55 On the other hand, in a study of 64 males with FXS where the COMT gene was also included, the results of the previous study were not replicated. There was no association between behavioral characteristics and either 5-HTTL PR (serotonin) or MAOA genotypes. Nevertheless, the A/A genotype in COMT that modifies dopamine levels was associated with greater interest and pleasure in the environment, and with less risk of property destruction, stereotyped behavior and compulsive behavior.54 The authors of the study suggest that the non-reproducibility of the results regarding MAOA-VNTR can be explained by differences in the prevalence of aggressive and stereotyped behavior among the studied populations or by differences in the measurements used to characterize each behavior.

The importance of identifying potential modifier genes was explored in a clinical trial. The researchers investigated the relation between polymorphisms in several genes and the response of sertraline in 51 children. They found that BDNF, MAOA, 5-HTTLPR, Cytochrome P450 2C19 and 2D6 polymorphisms had significant correlations with treatment response.64

Currently the knowledge about molecular causes of the variable phenotype in patients with FXS include characteristics associated with the FMR1 gene itself and to secondary, modifying gene effects.

Regarding FMR1, when the diagnosis is established, the type of mutation causing FXS is identified: CGG repeat tract expansion vs pathological variant causing loss of function in FMR1.

When the CGG is identified, is it expected that about half of the patients have size or methylation mosaicism or both.29 The presence of any of those mosaicisms determines the expression or not of FMR1 mRNA and FMRP. The quantity of FMRP is directly related with IQ.34,37,39 While the presence of size mosaicism is related with better intellectual functioning and less maladaptive behavior,29,42 elevated concentrations of FMR1 mRNA in patients with FM have been associated with a higher risk of developing FXTAS45,46,48 and with the severity of behavioral symptoms.47

The search for modifier genes affecting the phenotype has been carried out using the candidate genes strategy. Because high impact clinical manifestations in FXS are related with neurologic phenotypes, the studied candidate genes are involved in CNS development and the appearance of seizures (BNDF)56,6062 and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y COMT).54,55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.

Scientific and clinical evidence about molecular causes of variable expressivity in FXS is growing quickly. It is evident that aspects of the mutation type in FMR1 and the behavior of the CGG repeat tract are relevant in the presentation of the condition. Research about modifier genes is still emerging. There are important limitations such as sample size and comparability of different studies, mainly due to smaller groups of selected patients and the use of different tools for measuring the phenotypes.

Independent cohorts of patients with FXS across different continents have shown evidence that mosaicism, FMR1 mRNA or FMRP quantification are associated with the severity of the phenotype. However, this information cannot currently be used effectively in the integral management of patients. When intervention strategies become available in order to prevent the development of FXTAS, or when certain molecules can regulate levels of FMRP expression to measure FMR1 mRNA and FMRP, they could be crucial for selecting patients and identifying the best therapeutic intervention.

In clinical trials there is an important window of opportunity. Identifying mosaicism, measuring transcription/translation activity of FMR1 and stratifying patients by modifier genotypes29,65 will permit the identification of subgroups of patients with greater potential to respond to specific treatments.

The authors report no conflicts of interest in this work.

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