Daily Archives: July 27, 2022

The identified variant p.(Gln77Ter) is new and absent from the Genome Aggregation Database. It was evidenced that pathogenic variants in BICD2 are extremely rare in the population, predicted to be damaging by most tools, and occur in specific hotspots within key BICD2 functional domains [8]. Furthermore, WES did not identify any variant(s) in any of the OMIM genes with an acknowledged disease association (including VPS13B gene). Although BICD2 is essential for the proper development of the cerebral cortex [5] but there have been no other clinical reports of individuals with loss of-function variants in BICD2 showing lissencephaly and cerebellar hypoplasia. However, lissencephaly and cerebellar hypoplasia are consistent with that observed after BICD2 knockdown in mice showing defects in laminar organization of the cerebral cortex, hippocampus and cerebellar cortex, indicative of radial neuronal migration defects. Cell-specific inactivation of BICD2 in astrocytes and neuronal precursors revealed that radial cerebellar granule cell migration is non-cell-autonomous and intrinsic to cerebellar Bergmann glia cells [9, 10]. Therefore, we considered BICD2 to be a convincing candidate gene in the context of lissencephaly and cerebellar hypoplasia. The absence of homozygous loss of function BICD2 variants in the healthy family members supports the clinical relevance of BICD2.

Recently, biallelic variant c.731T>C p.(Leu244Pro) in BICD2 was described in a girl with abnormal gyral pattern in fronto-temporo-parietal regions [6] (Table1). The girl displayed additionally moderate intellectual disability and Cohen-like features [6]. In comparison, our patient showed congenital microcephaly, profound delay, seizures, lissencephaly and cerebellar hypoplasia. Unlike the patient with Cohen-like features, our patient showed spasticity and developed contracture deformities and did not show neutropenia. Interestingly, a heterozygous missense variant c.2080C>T, p.(Arg694Cys) was reported in two unrelated patients with mild perisylvian polymicrogyria, and mild cerebellar vermis hypoplasia [4]. Moreover, a BICD2 nonsense variation p.(Lys775Ter) was identified in a boy with lissencephaly and subcortical band heterotopia [5]. These heterozygous variants are located within the highly conserved CC3 domain of BICD2 (Table1). Nevertheless, the heterozygous missense variants within the CC1 domain were not associated with abnormalities of cortical development but even showed a milder course of SMALED2A and a higher frequency of foot deformities [8]. Indeed, a larger cohort is required to draw conclusions regarding genotype-phenotype correlations.

Lissencephaly and cerebellar hypoplasia noticed in our patient appeared similar to those with LIS1 variants. This is not surprising as LIS1 interacts with the dynein/dynactin complex and BICD2 to recruit cellular structures [11]. In the mean time, these brain MRI features may overlap with RELN-mutated patients phenotype. However, the cortical migration defect was more severe in our patient than in RELN-mutated patients. In addition, our patient had mild cerebellar hypoplasia unlike RELN-mutated patients who had profoundly hypoplastic and dysplasic cerebellum with no identifiable folia [12].

Our study provides valuable findings into human developmental brain malformations disorders associated with definitive loss-of function variants in BICD2.

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A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia | Journal of Human Genetics - Nature.com

What would it be if we had to pick one piece of information most important for the genetic diagnosis of rare disease patients?

The information required for genetic diagnosis is very diverse, such as the correlation between genes and diseases, the function of genes, important location information that determines gene function, and the frequency of finding genetic mutations.

However, if there is only one important piece of information, it would be the pathogenic genetic mutation information that determined a patient's diagnosis in the past.

Suppose a genome decoding of a patient waiting for diagnosis shows the same genetic mutation as the previously confirmed patient. In that case, this becomes a strong basis for diagnosis as it means that the patient waiting for diagnosis has the same disease as the previously diagnosed patient.

The increase in pathogenic mutation information means that we can secure the basis for interpreting more genetic mutations, which, in turn, means that more rare disease patients can receive an accurate diagnosis.

With the recent innovation of genome decoding technology, we can decode genome information of many patients, which helped us rapidly accumulate pathogenic mutation information.

However, it cannot be said that there is enough information on pathogenic genetic mutations to be able to diagnose rare diseases at a sufficient level.

Then how much more mutation information do we require?

The human genome is composed of three billion DNA. If we count the number of single-nucleotide variants (SNVs) where DNA at each location is converted into a different type of DNA, the number reaches nine billion.

Considering all the various types of genetic mutations, such as DNA disappearing, overlapping, and multiple DNA changes simultaneously, the number of mutations in the human genome is virtually infinite.

However, only about 1.54 million mutations are registered in ClinVar, the largest database of genetic mutations worldwide.

When compared with the nine billion SNV types, we can infer that the pathogenic information of genetic mutations currently known to mankind is insufficient.

To overcome this situation, the global clinical genetics community has established a public database with ClinVar. It collects information on the pathogenicity of genetic mutations of patients obtained through genetic testing.

If we share the genetic mutation information of the patient we have diagnosed, we can diagnose rare patients with the same mutation worldwide.

If we share the diagnosis of patients with rare diseases, everyone benefits together, and the diagnosis rate of patients with rare diseases increases.

Hospitals and major global genetic diagnosis companies are actively sharing this genetic mutation information.

In terms of numbers, companies share the most genetic mutation information. The top 8 companies, including Invitae, a U.S. company, have shared 1 million cases, GeneDx 310,000 cases, and Color Health with 70,000 cases, accounting for 72 percent of ClinVars genetic mutations database.

In Korea, 23 institutions shared 3,533 mutation data to ClinVar, with 3billion accounting for 87 percent of all reported mutations from Korea with 3,074 cases.

There are many reasons why diagnostic companies actively share pathogenic genetic mutation information, which is an asset to the company.

However, after recognizing the limitation that a single institution cannot secure the necessary and sufficient number of genetic mutation information for the diagnosis of genetic diseases, companies are voluntarily sharing data to fulfill their mission and responsibility as a diagnosis company if it means they can accurately diagnose even a single patient.

Governments worldwide invest huge amounts of money to secure patient genetic mutation information through large-scale genome research projects and disclose them for public use.

Korea has currently secured the data of 15,000 patients with rare diseases through a national bio big data pilot project. In addition, the government is planning to disclose pathogenic genetic mutation information so it can be used for public purposes.

The genetic mutation information accumulated on a large scale by the government, business, and academia is not only used as evidence data for direct patient diagnosis. Still, it is also used as learning and test data for artificial intelligence models for pathogenicity prediction.

In addition, it can be utilized in interpreting genetic mutations for which there is no basis and as a resource to improve rare genetic disease diagnosis technology in various forms.

When everyone makes some sacrifices and helps each other, the entire ecosystem can prosper to a greater extent.

The cooperation of global governments, companies, and academia to disclose genetic variation information was possible because they prioritized the public good of diagnosing and treating patients with rare genetic diseases.

Companies that disclose genetic mutations that have sacrificed their potential profit-making data for the public good are rewarded with improved market credibility and growth.

In the future, I look forward to the active data sharing between the government, academia, and companies for diagnosing and treating rare genetic diseases and using this virtuous cycle to establish a growing ecosystem.

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[3billion's Rare Disease Story] United we stand strong: Genetic diagnosis that evolves through information sharing - KBR

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the Company and collaborators have identified mutations in the INHBE gene associated with protection against abdominal obesity and metabolic syndrome a condition impacting more than 20 percent of adults worldwide. The discovery leveraged sequencing data from more than 360,000 individuals in UK Biobank, and was published in the 13th issue of Nature Communications. The published data show that rare mutations in the liver-expressed INHBE gene are associated with lower waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Findings support the potential of INHBE to be evaluated as a novel therapeutic target for the treatment of cardiometabolic disease. The Company plans to pursue a development candidate for INHBE and its gene product, Activin E, leveraging its liver IKARIA platform.

We are thrilled that our investment in genetic databases like UK Biobank is proving to be fruitful in identifying novel targets in highly prevalent diseases with continued unmet need, said Paul Nioi, Ph.D., Vice President, Discovery and Translational Research, and the Leader of Alnylams Human Genetics Group. There is a well-established causal link between increased waist-to-hip ratio and a persons risk of cardiometabolic conditions. By exploring the genetic determinants of waist-to-hip ratio in this study, important insights into the mechanisms that contribute to body fat distribution were uncovered helping identify potential therapeutic targets for abdominal obesity, like INHBE. The results of this exome-wide analysis suggest that targeting INHBE is predicted to have broad beneficial effects on all facets of metabolic syndrome with potential reductions in the risk of type 2 diabetes and coronary heart disease. We are currently testing this hypothesis, with the goal of pursuing a development candidate targeting INHBE in the near future.

We are delighted to see that the uniquely detailed data within UK Biobank - generously donated by our half a million participants - is accelerating research into important health conditions. Thanks to the collaboration with leading life sciences companies in the UK Biobank Exome Sequencing Consortium, the UK Biobank resource is helping to rapidly identify new therapeutic targets for abdominal obesity, said Professor Naomi Allen, UK Biobank Chief Scientist.

Using whole exome-sequencing data from UK Biobank, Alnylam and collaborators mined for gene variants associated with lower WHRadjBMI in more than 360,000 individuals of European ancestry, revealing loss of function in INHBE as a novel genetic factor contributing to a healthier fat distribution. Rare predicted loss of function (pLOF) variants in INHBE, were carried by one in 587 individuals and were associated with lower abdominal fat. In vitro characterization of the most common INHBE pLOF variant in the study, indicated an approximately 90% reduction in secreted activin E levels. Further analysis of INHBE pLOF carriers revealed a favorable metabolic profile, including decreased triglycerides, increased high-density lipoprotein cholesterol, and decreased fasting glucose. There were no associations suggesting adverse effects of INHBE pLOF, and carriers of these variants did not show evidence of excess mortality. The study also detected associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution.

About UK Biobank

UK Biobank is a large-scale biomedical database and research resource, containing in-depth genetic and health information from half a million UK participants. The database, which is regularly augmented with additional data, is globally accessible to approved researchers and scientists undertaking vital research into the most common and life-threatening diseases. UK Biobanks research resource is a major contributor to the advancement of modern medicine and treatment and has enabled several scientific discoveries that improve human health.

The UK Biobank Exome Sequencing Consortium (UKB-ESC)

In 2018, Alnylam and partners Regeneron, AbbVie, AstraZeneca, Biogen, and Pfizer announced an agreement with UK Biobank to form the UK Biobank Exome Sequencing Consortium (UKB-ESC), a pre-competitive consortium that aims to sequence the whole exomes of 500,000 volunteer participants in the biomedical resource. The goal of the consortium, which represents the largest ever effort to use genome sequencing to map the DNA of a group of people, is to uncover insights that allow researchers to pinpoint new drug targets at the core of human disease in order to develop effective treatments for patients. To date, the UKB-ESC has made whole-exome sequencing data from 450,000 participants available to the global health community for research purposes and will continue to make all sequenced data available at no cost under the terms of the UKB-ESC charter and the founding principles of UK Biobank.

About Cardiometabolic Disease

Cardiometabolic diseases are the number one cause of death in the world; these include but are not limited to cardiovascular disease, obesity, diabetes mellitus, and non-alcoholic fatty liver disease. An estimated 47 million people in the U.S. alone are living with some form of cardiometabolic disease. Despite the availability of many well-established treatments for cardiometabolic diseases, the substantial mortality associated with this group of diseases underscores the high unmet medical need for new therapeutic options, including those directed to novel disease-modifying targets, and with potential to address poor medication adherence.

About IKARIA Platform

Alnylams IKARIA platform takes advantage of more than two decades of experience in developing RNAi therapeutics. IKARIA enables an extended duration of activity in preclinical studies, with potential for annual dosing in humans, and has design features which provide exquisite specificity, further widening the potential therapeutic index, with enhanced target reduction levels.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of todays medicines by potently silencing messenger RNA (mRNA) the genetic precursors that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylams commercial RNAi therapeutic products are ONPATTRO (patisiran), GIVLAARI (givosiran), OXLUMO (lumasiran), AMVUTTRA (vutrisiran), and Leqvio (inclisiran) being developed and commercialized by Alnylams partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its Alnylam P5x25 strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit http://www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylams views with respect to pursuing INHBE as a therapeutic target for cardiometabolic disease and its goal to identify a development candidate targeting INHBE in the near future, Alnylams aspiration to become a leading biotech company, and the planned achievement of its Alnylam P5x25 strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylams business, results of operations and financial condition and the effectiveness or timeliness of Alnylams efforts to mitigate the impact of the pandemic; the potential impact of the recent leadership transition on Alnylams ability to attract and retain talent and to successfully execute on its Alnylam P5x25 strategy; Alnylam's ability to discover and develop novel drug candidates, including a development candidate targeting INHBE, and delivery approaches, and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates; actions or advice of regulatory agencies and Alnylams ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling its approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylams ability to successfully expand the indication for OXLUMO, ONPATTRO and AMVUTTRA in the future; Alnylam's ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylams ability to maintain strategic business collaborations; Alnylam's dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of current and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the Risk Factors filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in its other SEC filings. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

See the article here:
Alnylam Uncovers Genetic Mutations in INHBE That Protect Against Abdominal Obesity - Business Wire

James Noonan

James Noonan, who has made critical and novel contributions to the fields of human evolutionary genetics and neurodevelopment, was recently appointed the Albert E. Kent Professor of Genetics and Professor of Neuroscience, effective immediately.

Noonan received his B.S. in biology and English literature from the State University of New York at Binghamton in 1997, and his Ph.D. in genetics from Stanford University School of Medicine in 2004. He completed a postdoctoral fellowship in the Genomics Division at Lawrence Berkeley National Laboratory from 2004 to 2007. In 2007, he was recruited to Yale as assistant professor and was promoted to associate professor in 2013, and professor in 2021. He has a secondary appointment in Yales Department of Neuroscience.

Noonans research program is focused on deciphering the role of gene regulatory changes in the evolution of uniquely human traits. This work addresses a central hypothesis in human evolution, proposed more than 40 years ago: that changes in the level, timing, and location of gene expression account for biological differences between humans and other primates. Noonan has discovered thousands of human-specific genetic changes that alter gene expression and regulation, and by pioneering novel genetic models, his lab has begun to reveal how human-specific regulatory changes alter developmental traits. His work has provided key insights into the genetic origins of human biological uniqueness and has driven the rise of a new field: human evolutionary developmental biology.

Noonans seminal research discovered two classes of gene regulatory elements implicated in human evolution. The first are Human Accelerated Regions (HARs), which encode transcriptional enhances which are highly conserved across species and show many human-specific sequence changes (Science 2006, Science 2008). Using humanized mouse models, he has shown that HARs alter developmental gene expression and drive the evolution of novel phenotypes. As an example, he recently showed that one HAR altered expression of a transcription factor that has a role in limb development, possibly contributing to changes in skeletal patterning in human limb evolution (Nature Communications, 2022). These findings provide mechanistic insight into how HARs modified gene expression in human evolution. Using massively parallel assays, he has also comprehensively characterized the effect of thousands of human-specific sequence changes in HARs on their activity during neurodevelopment (Proceedings of the National Academy of Sciences, 2021)

He also identified thousands of human-specific changes in enhancer activity by direct analysis of developing human and nonhuman tissues. These loci, termed Human Gain Enhancers (HGEs), have gained activity in the developing human limb (Cell, 2013) and cerebral cortex (Science, 2015). These studies identified the biological pathways in limb and cortical development likely altered by human-specific regulatory changes, providing the basis for understanding their effects using genetic and experimental models.

Noonan has also contributed substantially to the educational programs of Yale School of Medicine, revolutionizing its graduate training landscape and empowering experimental genetics research across many labs at Yale. He designed the first course in genomics in the medical school more than 12 years ago, serving hundreds of students and faculty with the skills required to excel at the frontier of modern biomedical science. His training efforts have helped to set the standards of genomic research at Yale and ensured that the university remains a world leader in genomics.

Continue reading here:
Noonan appointed Kent Professor of Genetics and Professor of Neuroscience - Yale News

The biotech sector can offer unique opportunities and strong returns to investors willing to stomach the volatility heightened by the current economic environment.

Shares of Verve Therapeutics (VERV) traded up 22% last Tuesday after the companys recent announcement that it dosed its first human patient with an investigational in vivo base-editing medicine, VERVE-101, as a potential treatment for heterozygous familial hypercholesterolemia, according to recent commentary from ARK Invest.

The treatment from the Cambridge, Massachusetts-headquartered company could offer an alternative for hypercholesterolemia patients who have difficulty managing the side effects of statins and other therapeutic options. Founded by world-renowned experts in cardiovascular medicine, human genetics, and gene editing, Verve Therapeutics develops transformative once-and-done therapies for coronary heart disease, according to ARK.

Shares of Verve Therapeutics are up over 83% over a one-month period, according to YCharts. Over a five-day period, shares are down over 7%, but they are rebounding and up nearly 1% in mid-day trading on Tuesday.

Investors can get exposure to Verve Therapeutics with the ARK Genomic Revolution ETF (ARKG A-). ARKG is an actively managed equity strategy that aims to provide exposure to DNA sequencing technology, gene editing, CRISPR, therapeutics, agricultural biology, and molecular diagnostics.

Companies within ARKG are focused on and are expected to substantially benefit from extending and enhancing the quality of human and other life by incorporating technological and scientific developments and advancements in genomics into their businesses, according to the firm.

The funds top holdings as of July 26 include Exact Sciences Corp. (EXAS, 7.42%), Teladoc Health Inc. (TDOC, 5.56%), Ionis Pharmaceuticals Inc. (IONS, 5.30%), CRISPR Therapeutics AG (CRSP, 4.78%), and Signify Health Inc. Class A (SGFY, 4.70%), according to the funds website.

ARKG typically holds between 40 and 60 securities and charges an expense ratio of 75 basis points.

For more news, information, and strategy, visit our Disruptive Technology Channel.

Excerpt from:
Verve Therapeutics Shares Up 84%; ARKG Offers Exposure - ETFdb.com

Prehistoric people in Europe were consuming milk thousands of years before humans evolved the genetic trait allowing us to digest the milk sugar lactose as adults, finds a new study. The research, published in Nature, mapped pre-historic patterns of milk use over the last 9,000 years, offering new insights into milk consumption and the evolution of lactose tolerance.

Until now, it was widely assumed that lactose tolerance emerged because it allowed people to consume more milk and dairy products. But this new research, led by scientists from the University of Bristol and University College London (UCL) alongside collaborators from 20 other countries, shows that famine and exposure to infectious disease best explains the evolution of our ability to consume milk and other non-fermented dairy products.

While most European adults today can drink milk without discomfort, two thirds of adults in the world today, and almost all adults 5,000 years ago, can face problems if they drink too much milk. This is because milk contains lactose, and if we dont digest this unique sugar, it will travel to our large intestine where it can cause cramps, diarrhoea, and flatulence; known as lactose intolerance. However, this new research suggests that in the UK today these effects are rare.

Professor George Davey Smith, Director of the MRC Integrative Epidemiology Unit at the University of Bristol and a co-author of the study, said: To digest lactose we need to produce the enzyme lactase in our gut. Almost all babies produce lactase, but in the majority of people globally that production declines rapidly between weaning and adolescence. However, a genetic trait called lactase persistence has evolved multiple times over the last 10,000 years and spread in various milk-drinking populations in Europe, central and southern Asia, the Middle East and Africa. Today, around one third of adults in the world are lactase persistent.

By mapping patterns of milk use over the last 9,000 years, probing the UK Biobank, and combining ancient DNA, radiocarbon, and archaeological data using new computer modelling techniques, the team were able to show that lactase persistence genetic trait was not common until around1,000BC, nearly4,000years after it was first detected around 4,7004,600 BC.

The lactase persistence genetic variant was pushed to high frequency by some sort of turbocharged natural selection. The problem is, such strong natural selection is hard to explain, added Professor Mark Thomas, Professor of Evolutionary Geneticsand study co-author from University College London.

In order to establish how lactose persistence evolved, Professor Richard Evershed, the studys lead from Bristols School of Chemistry, assembled an unprecedented database of nearly 7,000 organic animal fat residues from 13,181 fragments of pottery from 554 archaeological sites to find out where and when people were consuming milk. His findings showed milk was used extensively in European prehistory, dating from the earliest farming nearly 9,000 years ago, but increased and decreased in different regions at different times.

To understand how this relates to the evolution of lactase persistence, the UCL team, led by Professor Mark Thomas, assembled a database of the presence or absence of the lactase persistence genetic variant using published ancient DNA sequences from more than 1,700 prehistoric European and Asian individuals. They first saw it after around 5,000 years ago. By 3,000 years ago it was at appreciable frequencies and is very common today. Next, his team developed a new statistical approach to examine how well changes in milk use through time explain the natural selection for lactase persistence. Surprisingly, they found no relationship, even though they were able to show they could detect that relationship if it existed, challenging the long-held view the extent of milk use drove lactase persistence evolution.

Professor George Davey Smiths team had been probing the UK Biobank data, comprising genetic and medical data for more than 300,000 living individuals, found only minimal differences in milk drinking behaviour between genetically lactase persistent and non-persistent people. Critically, the large majority of people who were genetically lactase non-persistent experienced no short or long-term negative health effects when they consume milk.

Professor Davey Smith added: Our findings show milk use was widespread in Europe for at least 9,000 years, and healthy humans, even those who are not lactase persistent, could happily consume milk without getting ill. However, drinking milk in lactase non-persistent individuals does lead to a high concentration of lactose in the intestine, which can draw fluid into the colon, and dehydration can result when this is combined with diarrhoeal disease.

Meanwhile, Thomas had been thinking along related lines, but with more of an emphasis on prehistoric famines. He commented: If you are healthy and lactase non-persistent, and you drink lots of milk, you may experience some discomfort, but you not going to die of it. However, if you are severely malnourished and have diarrhoea, then youve got life-threatening problems. When their crops failed, prehistoric people would have been more likely to consume unfermented high-lactose milk exactly when they shouldnt.

To test these ideas, Professor Thomas team applied indicators of past famine and pathogen exposure into their statistical models. Their results clearly supported both explanations the lactase persistence gene variant was under stronger natural selection when there were indications of more famine and more pathogens.

The authors concluded: Our study demonstrates how, in later prehistory, as populations and settlement sizes grew, human health would have been increasingly impacted by poor sanitation and increasing diarrhoeal diseases, especially those of animal origin. Under these conditions consuming milk would have resulted in increasing death rates, with individuals lacking lactase persistence being especially vulnerable. This situation would have been further exacerbated under famine conditions, when disease and malnutrition rates are increased. This would lead to individuals who did not carry a copy of the lactase persistence gene variant being more likely to die before or during their reproductive years, which would push the population prevalence of lactase persistence up.

It seems the same factors that influence human mortality today drove the evolution of this amazing gene through prehistory.

The study was supported by funding from theRoyal Society, theRCUK-Medical Research Council (MRC)andNatural Environment Research Council (NERC), and theEuropean Research Council.

Paper

Dairying, diseases and the evolution of lactase persistence in Europe by R Evershed et al in Nature.

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July: genetic-dairystudy | News and features - University of Bristol

Summary: The discovery of new genetic signatures associated with age-related macular degeneration may lead to better diagnosis and treatment of the currently incurable vision disorder.

Source: Garvan Institute

Better diagnosis and treatment of the incurable eye disease age-related macular degeneration is a step closer, thanks to the discovery of new genetic signatures of the disease.

Scientists from the Garvan Institute of Medical Research, the University of Melbourne, the Menzies Institute for Medical Research at the University of Tasmania and the Center for Eye Research Australia, reprogrammedstem cellsto create models of diseased eye cells, and then analyzed DNA, RNA and proteins to pinpoint thegenetic clues.

Weve tested the way that differences in peoples genes impact the cells involved inage-related macular degeneration. At the smallest scale weve narrowed down specific types of cells to pinpoint the genetic markers of this disease, says joint lead author Professor Joseph Powell, Pillar Director of Cellular Science at Garvan.

This is the basis of precision medicine, where we can then look at what therapeutics might be most effective for a persons genetic profile of disease.

Age-relatedmacular degeneration, or AMD is the progressive deterioration of the maculara region in the center of the retina and towards the back of the eyeleading to possible impairment or loss of central vision. Around one in seven Australians over the age of 50 is affected, and about 15 percent of those aged over 80 havevision lossor blindness.

The underlying causes of the deterioration remain elusive, but genetic andenvironmental factorscontribute. Risk factors include age,family historyand smoking.

The research is published today in the journalNature Communications.

The researchers took skin samples from 79 participants with and without the late stage of AMD, called geographic atrophy. Their skin cells were reprogrammed to revert to stem cells called inducedpluripotent stem cells, and then guided withmolecular signalsto become retinal pigment epithelium cells, which are the cells affected in AMD.

Retinal pigment epithelium cells line the back of the retina and are essential to the health and functioning of the retina. Their degeneration is associated with the death of photoreceptors, which are light-sensing neurons in the retina that transmit visual signals to the brain and are responsible for the loss of vision in AMD.

Analysis of 127,600 cells revealed 439 molecular signatures associated with AMD, with 43 of those being potential new gene variants. Key pathways that were identified were subsequently tested within the cells and revealed differences in the energy-making mitochondria between healthy and AMD cells, rendering mitochondrial proteins as potential targets to prevent or alter the course of AMD.

Further, the molecular signatures can now be used for screening of treatments using patient-specific cells in a dish.

Ultimately, we are interested in matching the genetic profile of a patient to the best drug for that patient. We need to test how they work in cells relevant to the disease, says co-lead of the study Professor Alice Pbay, from the University of Melbourne.

Professor Powell and co-lead authors Professor Pbay, and Professor Alex Hewitt from the Menzies Institute for Medical Research in Tasmania and the Center for Eye Research Australia, have a long-running collaboration to investigate the underlying genetic causes of complex human diseases.

We have been building a program of research where were interested in stem cell studies to model disease at very large scale to do screening for future clinical trials, says Professor Hewitt.

In another recent study, the researchers uncovered genetic signatures of glaucomaa degenerative eye disease causing blindnessusing stem cell models of the retina and optic nerve.

The researchers are also turning their attention to the genetic causes of Parkinsons and cardiovascular diseases.

Author: Press OfficeSource: Garvan InstituteContact: Press Office Garvan InstituteImage: The image is credited to Grace Lidgerwood

Original Research: Open access.Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration by Joseph Powell et al. Nature Communications

Abstract

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression.

Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations.

Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization.

Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy.

This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

Here is the original post:
Genetic Clues to Age-Related Macular Degeneration Revealed - Neuroscience News

The video shows a discussion on genome-editing technique rather than an mRNA procedure. mRNA isnt even mentioned once in the entire video.

Context:

While the world continues to deal with the impact of COVID-19, misleading posts accompanying a 2.17 minutes-long video are doing the rounds over social media spreading misinformation about mRNA COVID-19 vaccines by linking them to a genome-editing technology. One such Facebook post is titled WEF video from 2015 discussing the ability of an mRNA medical procedure to permanently change the genetics of the subject and its offspring. Similar posts include a screengrab of the video and make references to COVID-19 vaccines. What do you think they were really doing with all these covid shots? further asked the post. Such posts aim to instill suspicion and fear in the viewers minds about the technology used in COVID-19 vaccines.

In fact:

The 2.17 minutes-long video being circulated on social media begins with the speaker stating, So this is a precision tool that now allows us to take this protein RNA complex and introduce it into cells or tissues.

It appears that the term RNA has been erroneously misinterpreted as mRNA. In addition, we found an extended version of the video,which is 5.25 minutes-long, on the World Economic Forums official YouTube channel, and the video does not mention mRNA even once.

In the video, University of California professor Jennifer Doudna discusses RNA therapies and DNA editing breakthroughs in 2015 at a World Economic Forum(WEF) event. The CRISPR-Cas9 co-discoverer Doudna describes how the technology can alter DNA and offers the possibility of curing human genetic disorders. Professor Doudna has won the 2020 Nobel Prize in Chemistry along with Professor Emmanuelle Charpentier for discovering the gene-editing technique (CRISPRCas9).In the video, she says that compared to what a word processor does for writing, the technique allows for modifying genomic code in living organisms. Doudna claims that they discovered Cas9, a protein that can be designed to split double-stranded DNA, repair breaks, and correct genetic mutations.

According to Medline Plus, CRISPR-Cas9 is an acronym for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. According to the National Human Genome Research Institute, the genome is the entire set of DNA instructions found in a cell. An individuals genome contains all the information needed for growth and function.

National Cancer Institute defines an mRNA as a particular form of RNA. mRNA molecules transfer the data from the DNA in the cells nucleus to the cytoplasm, where proteins are made. However, the CRISPR-Cas9 system involves guide RNA (gRNA). Furthermore, mRNA is not even mentioned in the original paper published on the subject in Science in 2012.

Medline Plus notes that ethical concerns are often raised when human genomes are edited using tools like CRISPR-Cas9. This DNA editing technology is being investigated for several diseases, including single-gene disorders, in research and clinical trials. Contrary to claims on social media, only particular tissues are affected by the modifications, which are not transferred from generation to generation unless the gene alterations are in the egg, sperm, or embryonic cells. Only in such cases, may the changes be passed on to succeeding generations.

Thus, it is evident that there is no relation between COVID-19 vaccines and genome editing technology as these two technologies are entirely different. Conspiracy theorists have constantly claimed that COVID-19 vaccines were meant to alter human DNA among other bogus claims. These false claims have been repeatedly debunked by Logically and other independent fact-checkers in the past.

The verdict:

The video is about DNA editing techniques and not an mRNA procedure. Some fallacious social media posts linking this technology to COVID-19 vaccines merely show a small portion of the entire video. The authorized mRNA COVID-19 vaccines do not use the gene editing method being explained in the video. Thus, we mark this claim misleading.

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Fact Check: A video from 2015 discusses the ability of an mRNA medical procedure to change the genetics of - The Paradise News