Category Archives: Transhuman News

Genetic Variation Projects

Improved human knowledge of genetic variation is key to our understanding the causes of many diseases. The study of variation in the genome centered historically on PCR amplification of short genomic regions. More recently, new high-throughput technologies have made it viable to use whole genome sequencing for detection of variation.

There are a number of techniques used to select and amplify genomic regions of interest including whole genome or chromosome sampling by random shotgun sequencing, PCR amplification covering contiguous stretches of targeted genomic regions, PCR amplification of targeted gene coding regions and array-based hybridization to immobilized probes covering genomic regions, targeted exonic sequences or the entire exome. Each of these efforts has benefited from the close and historical affiliation with the Department of Molecular and Human Genetics (MHG), as well as other departments and institutions in the Texas Medical Center. The in-depth knowledge generated from these efforts is paving the way toward a new era of genetic research and the promise of genomically-driven personalized medicine.

The BCM-HGSC pioneered the concept of sequencing directed PCR amplification across the exons and splice junctions of potential disease genes. These techniques have been refined into a robust laboratory and informatics pipeline for Sanger sequencing of directed PCR (Medical Re-sequencing) The BCM-HGSC is currently investigating the replacement of PCR amplification with capture chip technology; sequencing for variant discovery is moving to second generation platforms such as Roche/454, AB SOLiD, and Illumina/Solexa.

As part of the 1000 Genomes Project, the BCM-HGSC is playing a defining role in Pilot 3, the targeted sequencing of more than 1000 genes across 1000 individuals. The Center has worked closely with Roche/Nimblegen to develop and design array-based capture chips targeting either the entire human exome or subsets of genes. These sub-regions of the genome are then eluted and used to construct Roche/454 sequencing libraries; sequencing libraries prepared for the other second generation platforms are under development.

The BCM-HGSC has pursued two paths for discovery of sequence and structural variants across defined regions of the human genome. As a part of the International HapMap Project, the BCM-HGSC generated sequence from a pool of 16 human DNAs to identify common single base variants that could then be used to generate subsequent deep genotyping across the initial four ethnic populations. A similar project was carried out using material from individual flow-sorted chromosomes. These data were used to develop our SNP computational identification methods.

The efficiency of this general approach led its application in other species. For example, within the bovine Hereford genome project, we have sampled more than 300,000 sequence reads from six additional bovine breeds. Using the methods that we developed in characterizing human data, we found an average of one SNP every 1.2kb with a remarkably high conversion rate of nearly 95% when tested independently. A similar approach in the honeybee genome project was used to generate variant data from a strain of Africanized bees. Ten thousand markers discovered there are now being used to map the genes responsible for traits associated with aggression.

The second path involved the generation of overlapping PCR amplicons across ten defined 500 kb regions (as defined by the first phase of the ENCODE project from 48 individuals to ascertain all variants across these intervals. This large project allowed the development of many of the protocols and informatics tools that we are using today.

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Human Genetics | BCM-HGSC

The department of Human Genetics considers its teaching responsibilities top priority. Good education in genetics is essential for medical students, medical specialists, general practitioners, and future scientists. We have a clear responsibility to society, as a personal DNA profile will become as ordinary as a determination of your hemoglobin levels. Since the interpretation of this huge amount of complex genetic data will ultimately be done by (medical) specialists and should be understandable for (family) doctors in primary care, our goal is to provide high-quality education of basic genetics for all healthcare professionals.

The department participates in the curricula of Medical Sciences, Biomedical Sciences,Biology, Dentistry, as well as in the Masters program Molecular Mechanisms of Disease. Specific courses that are organized include Medical Genomics, Human Genetics, Genomics and Statistics andGenetic and Metabolic Diseases. In total, more than 50 lecturers contribute their expertise to more than 25 courses, accentuating the central position that the field of genetics holds in life sciences.

For more information, you can contact dr. Arjan de Brouwer, teaching coordinator of the department of Human Genetics.

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Human Genetics - Radboudumc

DetailsLast Updated: Monday, 20 September 2021 09:52

The mission of the Department of Genetics is to promote excellence in education and research in the areas of model organism genetics, human genetics, computational genetics, bioinformatics, and genomics. The Department is situated on the Busch Campus of Rutgers University in Piscataway, NJ. There are more than 30 faculty members in the Department, with laboratories located in the Nelson Biological Laboratories, the Life Sciences Building, and the Waksman Institute.

The Department oversees an undergraduate major in genetics within the Division of Life Science (DLS) and the Schools of Arts and Sciences (SAS), and the Genetic Counseling Master's Program.

The Department is affiliated with the Human Genetics Institute of New Jersey (HGINJ), which houses core microscopy and imaging facilities and offers state-of-the-art custom genomic solutions through its association with Infinity BiologiX (IBX). IBX provides comprehensive services in bioprocessing, genomics, sample analytics and biostorage to the global scientific community.

Considering Med School or Dental School? Genetics is a great major for either career. The Rutgers HPO provides the recent admission statistics by department here.

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Welcome to the Department of Genetics

Sep 30, 2021 10:00 AM

A nationwide team of researchers, led by scientists at University of Utah Health and The Rockefeller University, has determined how a genetic mutation found in mice and monkeys interferes with viruses such as HIV and Ebola. They say the finding could eventually lead to the development of medical interventions in humans

The gene, called retroCHMP3, encodes an altered protein that disrupts the ability of certain viruses to exit an infected cell and prevents it from going on to infect other cells.

Normally, some viruses encase themselves in cell membranes and then make an exit by budding off from the host cell. RetroCHMP3 delays that process long enough that the virus can no longer escape.

This was an unexpected discovery, says Nels Elde, Ph.D., senior author of the study and an evolutionary geneticist in the Department of Human Genetics at U of U Health. We were surprised that slowing down our cell biology just a little bit throws virus replication off its game.

The study appears online Sept. 30 in advance of the Oct. 14 issue of Cell.

RetroCHMP3 originated as a duplicated copy of a gene called charged multivesicular body protein 3, or CHMP3. While some monkeys, mice, and other animals have retroCHMP3 or other variants, humans only have the original CHMP3.

In humans and other creatures, CHMP3 is well known for playing a key part of a role in cellular processes that are vital for maintaining cellular membrane integrity, intercellular signaling, and cell division.

HIV and certain other viruses hijack this pathway to bud off from the cellular membrane and infect other cells. Based on their research, Elde and his colleagues suspected that the duplications of CHMP3 they discovered in primates and mice blocked this from happening as protection against viruses like HIV and other viral diseases.

Building on this notion, Elde and other scientists began exploring whether variants of retroCHMP3 might work as an antiviral. In laboratory experiments conducted elsewhere, a shorter, altered version of human CHMP3 successfully prevented HIV from budding off cells. But there was a glitch: the modified protein also disrupted important cellular functions, causing the cells to die.

Unlike the other researchers, Elde and his colleagues at U of U Health had naturally occurring variants of CHMP3 from other animals in hand. So, working in collaboration with researchers Sanford Simon at The Rockefeller University, along with Phuong Tieu Schmitt and Anthony Schmitt at Pennsylvania State University, they tried a different approach.

Using genetic tools, they coaxed human cells to produce the version of retroCHMP3 found in squirrel monkeys. Then, they infected the cells with HIV and found that the virus had difficulty budding off from the cells, essentially stopping them in their tracks. And this occurred without disrupting metabolic signaling or related cellular functions that can cause cell death.

Were excited about the work because we showed some time ago that many different enveloped viruses use this pathway, called the ESCRT pathway, to escape cells, says Wes Sundquist, Ph.D., a co-corresponding author of the study and chair of the Department of Biochemistry at the University of Utah. We always thought that this might be a point at which cells could defend themselves against such viruses, but we didnt see how that could happen without interfering with other very important cellular functions.

From an evolutionary perspective, Elde believes this represents a new type of immunity that can arise quickly to protect against short-lived threats.

We thought the ESCRT pathway was an Achilles heel that viruses like HIV and Ebola could always exploit as they bud off and infect new cells, Elde says. RetroCHMP3 flipped the script, making the viruses vulnerable. Moving forward, we hope to learn from this lesson and use it to counter viral diseases.

More specifically, that lesson raises the possibility that an intervention that slows down the process may be inconsequential for the host, but provide us with a new anti-retroviral, says Sanford Simon, Ph.D, a study co-author and a professor of Cellular Biophysics at The Rockefeller University.

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In addition to Drs. Elde and Sundquist, University of Utah and University of Utah Health scientists Lara Rheinemann, Diane Miller Downhour, Gaelle Mercenne, Kristen Davenport, Christina Necessary, and John McCullough contributed to this study.

The study, RetroCHMP3 Blocks Budding of Enveloped Viruses Without Blocking Cytokinesis, appears in the October 14, 2021 issue of Cell. This research was supported by the National Institutes of Health, United States Department of Agriculture, the Burroughs Wellcome Fund, and a Pew Charitable Trusts Innovation Fund Award.

Research News Human Genetics Infectious Diseases HIV Ebola

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Gene Found in Monkeys and Mice Could Work as a New Type of Antiviral to Block HIV, Ebola, and Other Deadly Viruses in Humans - University of Utah...

DR. WALLACE: Im a 16-year-old girl and I met this guy online recently who I found interesting. He showed me a picture of himself and hes really cute. But my friends have been warning me that he might not be the guy in the picture. How can I be sure that its really him? He keeps telling me only the minimum about himself and wont tell me what school he goes to or what city he lives in. I dont get why hes so evasive about such basic questions.

Should I continue to trust him so that we can have a successful online friendship? To be even safer, I could make a promise to myself that Ill never go anywhere to meet him in person. What do you think? I find him interesting, via email

I FIND HIM INTERESTING: No matter how long you have been talking to this guy or how friendly he has been, he is still a stranger and, as you pointed out, he might very well not be the boy in the picture.

It can be extremely dangerous if you decide to continue to engage regularly with this person. This could be a 50-year-old man with untoward intentions for all you know.

I implore you to stop this communication immediately as nothing good will come from it, and there could well be many serious risks to your safety involved. Some warning signs from this guy have already been divulged, as youve outlined via his elusive communications.

Stop communicating with him immediately and focus your attention on boys who are definitely your own age at your school or in your social circles in the real world not the virtual one.

DR. WALLACE: Im 12 years old and I have red hair, brown eyes and pale skin with some freckles sprinkled all around. I am the only boy in our family and I have three older sisters.

Whats weird is that I dont look like any of my sisters or my parents at all! They all have blue eyes, blonde hair and olive-colored skin. Im convinced that at some point I was adopted, but I have no proof other than my looks. How can I find out where I really came from? Likely adopted, via email

LIKELY ADOPTED: Have you asked your parents if you were adopted? It would be acceptable for you to ask this question at an appropriate time when youre alone with them. But dont be surprised if youre not adopted.

Human genetics are set up so that recessive genes are involved, and certain individuals have traits that relatives and ancestors a few generations back may have had, too. Not everyone looks like their parents or siblings even though their DNA confirms the family connection to a 100% certainty.

Have you seen your birth certificate or asked to see a copy of it? Please start first with your parents to hear their full story about how you came into their lives. I trust they will be open and honest with you.

As you get older, you can also consider options that can help you verify your ancestry with a DNA test and various genealogy studies as well.

Dr. Robert Wallace welcomes questions from readers. Although he is unable to reply to all of them individually, he will answer as many as possible in this column. Email him at rwallace@thegreatestgift.com.

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Teen should stop online chat with new guy - Cumberland Times-News

By Allison Proffitt

September 28, 2021 | At the beginning of September, the National Institutes of Health launched the Impact of Genomic Variation on Function (IGVF) consortium, a new initiative of NIHs National Human Genome Research Institute (NHGRI). Now, NHGRI has named the first 25 awards across 30 U.S. research sites totaling approximately $185 million over five years.

Researchers have identified millions of human genomic variants that differ across the world, including thousands of disease-associated ones. The IGVF consortium plans to identify which variants in the genome are relevant for health and disease by integrating experimental methods with advanced computer models.

The programs goals are systematic perturbation of the genome to assess the impact of genomic variation on genome function and phenotype, high-resolution identification of where and when genes and regulatory elements function, advancement of network-level understanding of the influence of genetic variation and genome function on phenotype, development and testing of innovative predictive models of the impact of genomic variation on genome function, generation of a resource centered on a catalog of variant impacts and including data, tools, and models that will be shared with the broader research community, and enabling others to perform related studies using these approaches.

Biomedical researchers have recently made remarkable advances in the experimental and computational methods available for elucidating genome function, said Carolyn Hutter, Ph.D., director of the NHGRI Division of Genome Sciences, in a press release. The IGVF consortium will include world leaders in these areas, and together they will leverage these advances to tackle an incredibly challenging and important series of questions related to how genomic variation influences biological function.

The current IGVF consortium includes labs in five areas: Functional Characterization Centers, Regulatory Network Projects, Mapping Centers, Data and Administrative Coordinating Centers, and Predictive Modeling Projects.

The 30 U.S. sites that make up those areas include UC San Francisco; University of Washington; Stanford University; Dana-Farber Cancer Institute; University of Texas Southwestern Medical Center; University of North Carolina, Chapel Hill; Childrens Hospital Boston; Massachusetts General Hospital; Brigham and Womens Hospital; Duke University; Broad Institute; UC Irvine; California Institute of Technology; University of Michigan; Harvard School of Public Health; Northeastern University; University of Wisconsin; University of Massachusetts Medical School; University of Texas MD Anderson Cancer Center; University of Pennsylvania; University of Pittsburgh; Johns Hopkins University School of Medicine; Sloan Kettering Institute for Cancer Research; UC San Diego; UC Los Angeles; Yale University; Washington University, Saint Louis; and Northwestern University.

For the full breakdown of which groups are working in which areas, see the list online.

In an interview with ASHG News, Stephanie Morris, a Program Director in NHGRIs Division of Genome Sciences, outlined how the consortiums results will be integrated into healthcare and research going forward. Today, clinicians rely on statistical correlations that link genomic variation to disease, which have proven valuable. However, of the tens of thousands of disease-associated variants, researchers have only specifically identified a small number of these variants. The consortium will study and characterize thousands of genomic variants and determine which of these directly impact health and disease, which will greatly expand the evidence available to clinicians, Morris told ASHG News.

First Projects Kick Off

Some groups have already publicized their intended research projects. The University of California San Diego School of Medicine researchers will receive $6.4 million in grant funding to study how external signals and genetic variations influence the behavior of one cell type in particular: insulin-producing beta cells in the pancreas.

We plan to develop a roadmap of genetic variations, relevant in beta cells, to predict changes in insulin outputimportant information that may better enable us to prevent and treat diabetes, said team lead Maike Sander, MD, professor and director of the Pediatric Diabetes Research Center at UC San Diego School of Medicine, in a press release.

Washington University School of Medicine in St. Louis has received a $7 million grant as part of the consortium and will serve as the data and administrative coordinating center for the multicenter project.

All information generated by the consortium will be made freely available to the research community via a web portal that will be built from the WashU Epigenome Browser, a tool developed by Ting Wangs team that allows researchers around the world to search and browse genomic data. Because there are thousands of genomic variants associated with disease, and it is not possible to manipulate each variant individually and in each biological setting, consortium researchers also will develop computational modeling approaches to predict the impact of variants on genome function.

Duke University is the recipient of two grants totaling nearly $12 million as part of the consortium. An $8.6 million award will fund the Duke Characterization Center, led by Charlie Gersbach, Greg Crawford and Tim Reddy. The goal of the Duke IGVF Functional Characterization Center is to systematically perturb large numbers of regulatory elements and study their function across different biological contexts. Its a critical next step to more fully understand how the genome works, Crawford told Duke Cancer Institute News.

A second $3.2 million award will fund the Duke Predictive Modeling Center, led by Andrew Allen, David Page, and Sayan Mukherjee. They will take the raw data generated in the Functional Characterization Centers and transform it into consumable information that predicts the effect of variation on function. This work will be focused into three parts. First, they will simulate the data being developed in the Functional Characterization Centers and develop a simulation framework that can replicate the data. The team will also develop new graphical, model-based machine learning approaches that predict the functional effect of noncoding variation on function in diverse cell types. And finally, the team will use population genetics to look for genetic elements in the population that affect function.

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NIH Distributes $185M for Impact of Genomic Variation on Function (IGVF) Consortium - Bio-IT World

Bringing science to the practice of psychiatry has been the personal goal of Sheldon H. Preskorn, MDthe Educator of the Year.

Psychiatric TimesTM was honored and delighted to present Sheldon H. Preskorn, MD, as Educator of the Year at this years Annual Psychiatric TimesTM World CME Conference. An academic psychiatrist, a researcher, an educator, and a mentorPreskorn is, as John J. Miller, MD, described a pioneer in the field of psychopharmacology.

Preskorn shared with attendees the unexpected beginning of his more than 40-years-and-running career in psychiatry. On his TV, he watched a video of Jose Delgado being able to stop a ball, charging in his tracks. To Preskorn, that meant that the brain was related to behaviorand he wanted to learn more.

Amongst his many honors and awards, Preskorn is known for spending the 1980s establishing the value of the therapeutic drug monitoring of tricyclic antidepressants and understanding toxicity. Additionally, in the 1990s, he helped explain the liver cytochrome P450 enzyme system.

My personal goal has been, and remains, bringing science to the practice of psychiatry, Preskorn shared.

During the session, he pointed out the overlap between diagnoses and science in signs and symptoms of borderline personality, bipolar disorder, major depression. He claimed it is not the symptoms that distinguish these disorders, but rather the stability of the symptoms themselves.1

Psychiatry has been mainly stuck at the level of syndromic diagnoses, but we are making inroads and have over the last 50 years into pathophysiology and etiology, he stated.

Additionally, Preskorn thinks of his therapeutic drug monitoring focus as toxicity-centric rather than efficacy-centric. The reason? We've had a better signal to noise ratio in trying to understand toxicity of the drugs and the avoidance of that than we did with antidepressant efficacy. As a matter of fact, in another article that I published, I showed that it's really almost impossible given the signal to noise problem in clinical trials of antidepressants to show any relationship between our blood levels and clinical benefit.

Preskorn also shared an equation of his creation. According to him, 3 variables determine clinical response: sites of action (affinity, intrinsic activity); drug concentration and its site(s) of action (absorption, distribution, metabolism, elimination); and underlying biology of the patient (genetics, age, disease, environment).2

We are born different, said Preskorn. Age, how we vary over our lifespan, disease (which is acquired through pathophysiological processes), and then the environment here referring to the internal environment. That is what underlies drug-drug interactions, where a drug enters the environment of the body and interacts with another drug, either pharmacodynamically, which is the first variable, or pharmacokinetically, which is the second variable in this equation.

Preskorn closed his speech, smiling, with a promise for the future: Its been a great pleasure for me to have shared these few minutes with you and to talk about the developments over the last 40 years. But as I would say: You aint seen nothing yet.

References

1. Preskorn SH, Baker B. The overlap of DSM-IV syndromes: potential implications for the practice of polypsychopharmacology, psychiatric drug development and the human genome project. J Psychiatr Pract. 2002;8(3):170-177.

2. Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Professional Communications, Inc; 1996.

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Pioneering Psychopharmacology: Educator of the Year Award - Psychiatric Times