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  • richardmitnick 7:33 am on July 20, 2016 Permalink | Reply
    Tags: , , Genetics,   

    From Princeton: “Role for enhancers in bursts of gene activity (Cell)” 

    Princeton University
    Princeton University

    July 19, 2016
    Marisa Sanders for the Office of the Dean for Research

    A new study by researchers at Princeton University suggests that sporadic bursts of gene activity may be important features of genetic regulation rather than just occasional mishaps. The researchers found that snippets of DNA called enhancers can boost the frequency of bursts, suggesting that these bursts play a role in gene control.

    The researchers analyzed videos of Drosophila fly embryos undergoing DNA transcription, the first step in the activation of genes to make proteins. In a study published on July 14 in the journal Cell, the researchers found that placing enhancers in different positions relative to their target genes resulted in dramatic changes in the frequency of the bursts.

    “The importance of transcriptional bursts is controversial,” said Michael Levine, Princeton’s Anthony B. Evnin ’62 Professor in Genomics and director of the Lewis-Sigler Institute for Integrative Genomics. “While our study doesn’t prove that all genes undergo transcriptional bursting, we did find that every gene we looked at showed bursting, and these are the critical genes that define what the embryo is going to become. If we see bursting here, the odds are we are going to see it elsewhere.”

    The transcription of DNA occurs when an enzyme known as RNA polymerase converts the DNA code into a corresponding RNA code, which is later translated into a protein. Researchers were puzzled to find about ten years ago that transcription can be sporadic and variable rather than smooth and continuous.

    In the current study, Takashi Fukaya, a postdoctoral research fellow, and Bomyi Lim, a postdoctoral research associate, both working with Levine, explored the role of enhancers on transcriptional bursting. Enhancers are recognized by DNA-binding proteins to augment or diminish transcription rates, but the exact mechanisms are poorly understood.

    Until recently, visualizing transcription in living embryos was impossible due to limits in the sensitivity and resolution of light microscopes. A new method developed three years ago has now made that possible. The technique, developed by two separate research groups, one at Princeton led by Thomas Gregor, associate professor of physics and the Lewis-Sigler Institute for Integrative Genomics, and the other led by Nathalie Dostatni at the Curie Institute in Paris, involves placing fluorescent tags on RNA molecules to make them visible under the microscope.

    The researchers used this live-imaging technique to study fly embryos at a key stage in their development, approximately two hours after the onset of embryonic life where the genes undergo fast and furious transcription for about one hour. During this period, the researchers observed a significant ramping up of bursting, in which the RNA polymerase enzymes cranked out a newly transcribed segment of RNA every 10 or 15 seconds over a period of perhaps 4 or 5 minutes per burst. The genes then relaxed for a few minutes, followed by another episode of bursting.

    The team then looked at whether the location of the enhancer – either upstream from the gene or downstream – influenced the amount of bursting. In two different experiments, Fukaya placed the enhancer either upstream of the gene’s promoter, or downstream of the gene and saw that the different enhancer positions resulted in distinct responses. When the researchers positioned the enhancer downstream of the gene, they observed periodic bursts of transcription. However when they positioned the enhancer upstream of the gene, the researchers saw some fluctuations but no discrete bursts. They found that the closer the enhancer is to the promoter, the more frequent the bursting.

    To confirm their observations, Lim applied further data analysis methods to tally the amount of bursting that they saw in the videos. The team found that the frequency of the bursts was related to the strength of the enhancer in upregulating gene expression. Strong enhancers produced more bursts than weak enhancers. The team also showed that inserting a segment of DNA called an insulator reduced the number of bursts and dampened gene expression.

    In a second series of experiments, Fukaya showed that a single enhancer can activate simultaneously two genes that are located some distance apart on the genome and have separate promoters. It was originally thought that such an enhancer would facilitate bursting at one promoter at a time—that is, it would arrive at a promoter, linger, produce a burst, and come off. Then, it would randomly select one of the two genes for another round of bursting. However, what was instead observed was bursting occurring simultaneously at both genes.

    “We were surprised by this result,” Levine said. “Back to the drawing board! This means that traditional models for enhancer-promoter looping interactions are just not quite correct,” Levine said. “It may be that the promoters can move to the enhancer due to the formation of chromosomal loops. That is the next area to explore in the future.”

    The study was funded by grants from the National Institutes of Health (U01EB021239 and GM46638).

    Access the paper here:

    Takashi Fukaya, Bomyi Lim & Michael Levine. Enhancer Control of Transcriptional Bursting, Cell (2016), Published July 14. EPub ahead of print June 9. http://dx.doi.org/10.1016/j.cell.2016.05.025

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 9:46 am on June 16, 2016 Permalink | Reply
    Tags: , , Genetic engineering transforms tobacco plant into an antimalaria drug factory, Genetics, Tobacco   

    From AAAS: “Genetic engineering transforms tobacco plant into an antimalaria drug factory” 

    AAAS

    AAAS

    Jun. 15, 2016
    Robert F. Service

    1
    DanBrandenburg/iStockphoto

    Tobacco, the plant responsible for the most preventable deaths worldwide, may soon become the primary weapon against one of the world’s deadliest diseases. Researchers have engineered tobacco plants to produce the chemical precursor to artemisinin, the best antimalarial drug on the market. Artemisinin is naturally made in tiny amounts by a small brownish plant called Artemisia annua. But several years ago researchers transplanted the drugmaking genes into yeast, allowing them to collect the compound from a microbial brew. The fermentation process is still relatively expensive, however. So researchers decided to transplant the suite of genes needed to synthesize artesinic acid into tobacco, an inexpensive, high-volume crop (pictured) that’s already grown worldwide, as they report this week in eLife. The team calculates that harvesting artemisinic acid from a plot of land 200 square kilometers—less area than a city the size of Boston—would provide enough artemisinin to meet the entire worldwide demand. Down the road, the authors suggest that tobacco plants may serve as factories for producing other complex drugs.

    See the full article here .

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 8:09 am on June 14, 2016 Permalink | Reply
    Tags: , , , Genetics,   

    From NC State: “What Is CRISPR? And How Can it Be Used to Turn Genes ‘Off’?” 

    NC State bloc

    North Carolina State University

    1

    June 13, 2016
    Matt Shipman

    CRISPR systems have been a hot research topic since they were shown to have utility as genetic engineering tools in 2012. And they’re often explained in a way that most folks can understand. But those explanations often overlook key details – like the fact that scientists are still in the process of discovering the fundamental rules of how these systems work.

    For example, here’s a simplified explanation: CRISPR-Cas systems protect bacteria from invaders such as viruses. They do this by creating small strands of RNA that match DNA sequences specific to a given invader. When those CRISPR RNAs find a match, they unleash Cas proteins that chop up the invader’s DNA, preventing it from replicating.

    But of course it’s more complex than that. For example, there are six different types of CRISPR systems (that we know of). One of the most widely-studied CRISPR systems is CRISPR-Cas9, which is a Type II CRISPR system.

    But the most common CRISPR systems in nature are Type I. And new research from NC State is shedding light on some of the fundamental rules that govern Type I CRISPR systems – such as how long that CRISPR RNA can be, and how changing the length of the CRISPR RNA affects the behavior of the system.

    To learn more, we talked to Chase Beisel and Michelle Luo, who recently published a paper on the work in Nucleic Acids Research, in collaboration with two groups at Montana State University. Beisel is an assistant professor of chemical and biomolecular engineering at NC State; Luo is a Ph.D. student in Beisel’s lab.

    The Abstract: Why are Type I CRISPR systems of particular interest?
    Michelle Luo1
    Michelle Luo

    Michelle Luo: As you mentioned, Type I systems are the most common type of CRISPR-Cas systems. They account for over half of known systems. This is of particular interest as we look into co-opting an organism’s own system for other purposes. While CRISPR-Cas9 is undeniably a revolutionary genetic tool, it relies on importing this foreign Cas9 protein into an organism. This is a non-trivial task. However, if you use an organism’s own CRISPR-Cas proteins, as shown in our earlier work, you can avoid the challenges of expressing a non-natural protein. Because Type I systems are so prevalent, they offer a promising route to explore how a natural CRISPR-Cas system can be exploited for other means.

    The Abstract: In your recent work, you were evaluating how and whether you could modify the RNA in Type I CRISPR systems. Specifically, you were looking at whether you could modify the length of RNA in Type I CRISPR systems. Why would you want to change the length of the RNA?

    Luo: Two years ago, a number of papers were published detailing the crystal structures of Type I protein complexes that bind and help degrade target DNA. These publications hinted at the CRISPR RNA serving as a scaffold to assemble the different proteins in the complex. In other words, the RNA serves as a framework for these proteins to grab onto. Thus, we hypothesized that if we changed the length of the CRISPR RNA, we could change the size and composition of the Type I protein complex, and possibly the complex’s behavior.

    The Abstract: How, or why, might expanding the protein complexes used in DNA recognition be useful?
    Chase Beisel2
    Chase Beisel

    Chase Beisel: Going into the project, we didn’t know if the longer RNAs would allow the complex to even assemble, let alone function properly. We were surprised to find that the longer RNAs still formed a stable complex that could bind and direct the cutting of DNA. Because this complex is larger and recognizes a longer target sequence, we originally envisioned that the complex could be used for more specific DNA editing or for controlling gene expression.

    The Abstract: When I think of CRISPR, I think of a system that either leaves DNA alone or cuts it up. What do you mean when you say that changing the length of the RNA is more effective at gene repression?

    Luo: Your summary is on point. Normally, CRISPR-Cas systems survey the DNA landscape, and if they detects a target, they will cut up the DNA with tiny molecular scissors. If the target is not identified, the DNA will be left alone. Our earlier work demonstrated that we can prevent the cutting of the DNA by removing the scissors from the equation. We do this by deleting the cas3 gene from the genomic Type I locus. Now, instead of cutting the DNA, the CRISPR-Cas system simply binds the DNA. If we direct these modified systems to a gene, it will block the expression of that gene. Our most recent work shows that changing the length of the RNA can affect how strongly that silencing occurs. For certain regions, the longer the CRISPR RNA, the stronger the repression.

    The Abstract: Does that make the CRISPR system more specific? I.e., does it allow the system to be more targeted in terms of the DNA it “attacks”?

    Beisel: We wondered the same thing. We did in fact explore how longer RNAs impact specificity as part of the publication, although the results were mixed. On one hand, more of the RNA was involved in base pairing, where more base pairing would necessarily mean greater specificity. On the other hand, we found the longer RNAs were accommodating to mismatches with the target sequence, suggesting weaker specificity. In the end, more experiments will be needed to explore the question of specificity and how it impacts any downstream uses of Type I systems.

    The Abstract: How might that gene repression function be used? Are there any potential applications?

    Luo: Absolutely! This is particularly promising for metabolic engineering. If you want to make a microbial factory to produce a valuable product of interest, such as a biofuel, you have to alter the metabolism of an organism. This requires overexpressing genes that lead to production and turning off genes that compete with production. Our system allows researchers to turn off genes in a way that is potent, site-specific, reversible, and multiplexed. Our latest discovery suggests that you can fine-tune the extent of CRISPR-based gene repression simply by altering the length of the CRISPR RNA. That’s what our recent paper in Nucleic Acids Research is about.

    The Abstract: What are the future directions for this research?

    Beisel: Aside from the applications Michelle mentioned, we’re interested in why nature only uses RNA of a fixed length, given that longer RNAs make perfectly functional complexes. We’re also interested in whether this phenomenon applies across the many different flavors of Type I systems, from those that use far fewer proteins in the complex to those found in organisms living at extreme temperatures.

    See the full article here .

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    NC State was founded with a purpose: to create economic, societal and intellectual prosperity for the people of North Carolina and the country. We began as a land-grant institution teaching the agricultural and mechanical arts. Today, we’re a pre-eminent research enterprise that excels in science, technology, engineering, math, design, the humanities and social sciences, textiles and veterinary medicine.

    NC State students, faculty and staff take problems in hand and work with industry, government and nonprofit partners to solve them. Our 34,000-plus high-performing students apply what they learn in the real world by conducting research, working in internships and co-ops, and performing acts of world-changing service. That experiential education ensures they leave here ready to lead the workforce, confident in the knowledge that NC State consistently rates as one of the best values in higher education.

     
  • richardmitnick 10:09 am on June 10, 2016 Permalink | Reply
    Tags: , Genetics, How honeybees do without males,   

    From phys.org: “How honeybees do without males” 

    physdotorg
    phys.org

    June 9, 2016

    1
    An isolated population of honeybees, the Cape bees, living in South Africa has evolved a strategy to reproduce without males. A research team from Uppsala University has sequenced the entire genomes of a sample of Cape bees and compared them with other populations of honeybees to find out the genetic mechanisms behind their asexual reproduction. Credit: Mike Allsopp

    Most animals reproduce sexually, which means that both males and females are required for the species to survive. Normally, the honeybee is no exception to this rule: the female queen bee produces new offspring by laying eggs that have been fertilised by sperm from male drones. However, one isolated population of honeybees living in the southern Cape of Africa has evolved a strategy to do without males.

    In the Cape bee, female worker bees are able to reproduce asexually: they lay eggs that are essentially fertilised by their own DNA, which develop into new worker bees. Such bees are also able to invade the nests of other bees and continue to reproduce in this fashion, eventually taking over the foreign nests, a behaviour called social parasitism.

    The explanation for this unique behaviour is unknown, however a research team from UU has come closer to uncovering the genetic mechanisms behind it. The team sequenced the entire genomes of a sample of Cape bees and compared them with other populations of honeybees that reproduce normally. They found striking differences at several genes, which can explain both the abnormal type of egg production that leads to reproduction without males, and the unique social parasitism behaviour.

    “The question of why this population of honeybees in South Africa has evolved to reproduce asexually is still a mystery. But understanding the genes involved brings us closer to understanding it. This study will help us to understand how genes control biological processes like cell division and behaviour. Furthermore understanding why populations sometimes reproduce asexually may help us to understand the evolutionary advantage of sex, which is a major conundrum for evolutionary biologists, says Matthew Webster”, researcher at the Department of Medical Biochemistry and Microbiology at Uppsala University.

    See the full article here .

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    About Phys.org in 100 Words

    Phys.org™ (formerly Physorg.com) is a leading web-based science, research and technology news service which covers a full range of topics. These include physics, earth science, medicine, nanotechnology, electronics, space, biology, chemistry, computer sciences, engineering, mathematics and other sciences and technologies. Launched in 2004, Phys.org’s readership has grown steadily to include 1.75 million scientists, researchers, and engineers every month. Phys.org publishes approximately 100 quality articles every day, offering some of the most comprehensive coverage of sci-tech developments world-wide. Quancast 2009 includes Phys.org in its list of the Global Top 2,000 Websites. Phys.org community members enjoy access to many personalized features such as social networking, a personal home page set-up, RSS/XML feeds, article comments and ranking, the ability to save favorite articles, a daily newsletter, and other options.

     
  • richardmitnick 3:35 pm on June 8, 2016 Permalink | Reply
    Tags: , Genetics, Nicole L. Achee, ,   

    From Notre Dame: Women in Science “Entomologist Nicole L. Achee helps write gene drives report” 

    Notre Dame bloc

    Notre Dame University

    June 08, 2016
    William G. Gilroy

    1
    Nicole Achee

    University of Notre Dame medical entomologist Nicole L. Achee is a member of a committee convened to summarize the scientific discoveries related to gene drives and considerations for their responsible use. The National Institutes of Health (NIH) and the Foundation for the National Institutes of Health asked the National Academies of Sciences, Engineering and Medicine to convene the committee. The committee report, titled “Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty and Aligning Research with Public Values,” was released Wednesday (June 8).

    Gene drives are systems (either existing in nature or human-made) that transfer genetic material from a parent organism to its offspring through sexual reproduction. The result of a gene drive is the preferential increase of a specific trait from one generation to the next, which therefore can spread throughout the population.

    “For example, a gene drive system could change the ability of a female mosquito to ‘smell’ a human and therefore succeed in ‘finding’ a person to bite,” Achee said. “Inheritance of this trait could potentially cause a reduction in that mosquito’s population over time because blood is needed by the females to develop eggs.”

    The report is intended to be used as a tool by the general public and professionals alike who are either interested in gene drives or directly involved with their evaluation, development and use. It is based on six core themes: values, science, phased testing, risk assessment, public engagement and governance of gene drives.

    Gene drive systems are being proposed to solve a number of problems. These include challenges in public health, agriculture and conservation.

    “Most research on gene drive systems to date has been focused on generating a basic understanding of their function and mechanisms for controlling or altering organisms that transmit infectious diseases to humans, such as mosquitoes that carry parasites causing malaria,” Achee said. “Other applications of gene drive systems range from the control of weeds that compete with cash crops to management of invasive species that threaten biodiversity of ecosystems.”

    Achee’s research focuses on preventing and controlling human diseases caused by arthropods, such as mosquitoes. She is research associate professor in Notre Dame’s Department of Biological Sciences and a faculty member of the University’s Eck Institute for Global Health. The National Academies of Science invited her to participate in the study based on her expertise in mosquito ecology, international field-based research and global health.

    See the full article here .

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    Notre Dame Campus

    The University of Notre Dame du Lac (or simply Notre Dame /ˌnoʊtərˈdeɪm/ NOH-tər-DAYM) is a Catholic research university located near South Bend, Indiana, in the United States. In French, Notre Dame du Lac means “Our Lady of the Lake” and refers to the university’s patron saint, the Virgin Mary.

    The school was founded by Father Edward Sorin, CSC, who was also its first president. Today, many Holy Cross priests continue to work for the university, including as its president. It was established as an all-male institution on November 26, 1842, on land donated by the Bishop of Vincennes. The university first enrolled women undergraduates in 1972. As of 2013 about 48 percent of the student body was female.[6] Notre Dame’s Catholic character is reflected in its explicit commitment to the Catholic faith, numerous ministries funded by the school, and the architecture around campus. The university is consistently ranked one of the top universities in the United States and as a major global university.

    The university today is organized into five colleges and one professional school, and its graduate program has 15 master’s and 26 doctoral degree programs.[7][8] Over 80% of the university’s 8,000 undergraduates live on campus in one of 29 single-sex residence halls, each of which fields teams for more than a dozen intramural sports, and the university counts approximately 120,000 alumni.[9]

    The university is globally recognized for its Notre Dame School of Architecture, a faculty that teaches (pre-modernist) traditional and classical architecture and urban planning (e.g. following the principles of New Urbanism and New Classical Architecture).[10] It also awards the renowned annual Driehaus Architecture Prize.

     
  • richardmitnick 7:06 am on June 3, 2016 Permalink | Reply
    Tags: , Genetics, ,   

    From Scope at Stanford: “Genetics of sea creatures: One researcher uses her science training to help the environment” Women in Science 

    Stanford University Name
    Stanford University

    1

    June 2, 2016
    Jennifer Huber

    2
    Lauren Liddell, Photo courtesy of Lauren Liddell

    Lauren Liddell, PhD, developed a passion for genetics early at a girls science day at her Michigan middle school, when she extracted the DNA of a banana.

    Nearly two decades later, Liddell now works as a postdoctoral research fellow in genetics at the School of Medicine. Unlike most of her colleagues who study human health, Liddell is applying her molecular genetics expertise to one of the most critical environmental challenges that we face today: climate change. I recently spoke with Liddell about her research and her participation in the Rising Environmental Leadership Program, a year-round program that helps graduate students and postdoctoral fellows hone their leadership and communications skills.

    How did you end up studying sea anemones at Stanford?

    As a freshly minted PhD studying molecular genetics, I approached John Pringle, PhD, about working as a postdoc in his lab… Several years ago, John’s passion for scuba diving and overall curiosity led him to shift his research to tackle environmental problems. Specifically, we’re trying to understand sea anemone-algae symbiosis, in the hopes of discovering things that may be useful for coral conservation.

    Coral reefs are a poster child for climate change right now, because coral is dying — about 35 percent of the Great Barrier Reef off the coast of Australia is already dead or dying through a process called bleaching. Bleaching is caused by the loss of the symbiotic algae that live in the guts of coral. Normally, the gut algae collect energy from the sun and turn it into food that supports the life of the coral host. As ocean temperatures rise and the ocean acidifies, the algae leave the coral host and the coral starves and bleaches — bleached coral reefs are basically the skeletons.

    So we use sea anemones in the lab to study coral, similar to how scientists use mice to study human processes. We’re studying Aiptasia sea anemones as a model for coral reef bleaching, because sea anemones are easier to work with in the lab and they have the same gut algae, Symbiodinium, as coral reefs. We want to understand what goes wrong with symbiosis when ocean temperatures and acidity increase.

    What have you found?

    We’re trying various genetic methods to identify the genes that are important for this symbiosis. We’re also investigating how some corals are able to survive bleaching, whereas others die off. We have two main strains of sea anemones and multiple “flavors” of Symbiodinium algae that we use to test how the different environmental stressors, like heat and acidity, affect symbiosis.

    Surprisingly, we’ve found that the Hawaiian sea anemone is less tolerant to heat stress than the Floridian strain. And even more exciting, we’ve found that the Symbiodinium “flavor” can affect the ability of the sea anemone host to resist heat.

    What was the Rising Environmental Leadership Program like?

    The Rising Environmental Leadership Program (RELP) is an exciting program for people who are passionate about making a real impact on society. The program included a week-long boot camp in Washington D.C., where we met with Congress, nonprofit organizations like the Nature Conservancy, and governmental agencies like the Environmental Protection Agency and the Department of Energy… We really got to see firsthand how science research directly informs science policy.

    What do you want to do next?

    Originally, I wanted to be a liberal arts professor, because I love teaching and getting people excited about science. But moving to the Bay Area really opened my eyes to many other opportunities to make an impact. For instance, companies like 23andMe can help people understand their genetics and what that means for their health.

    I’m currently looking for careers in biotech. Once I’ve gained some business skills though, I plan to apply for an AAAS Science and Technology Policy Fellowship to get more firsthand experience with policymaking. My RELP experience made it blatantly clear that we need to train the politicians about science, so they can make informed decisions that impact our future.

    See the full article here .

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    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

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  • richardmitnick 12:39 pm on May 30, 2016 Permalink | Reply
    Tags: , Genetics, Is Intelligence Hereditary?,   

    From SA: “Is Intelligence Hereditary?” 

    Scientific American

    Scientific American

    May 1, 2016 [This just appeared in social media.]
    Robert Plomin

    Genes make a substantial difference, but they are not the whole story.

    1
    Credit: Getty Images/iStockphoto/Thinkstock Images

    Scientists have investigated this question for more than a century, and the answer is clear: the differences between people on intelligence tests are substantially the result of genetic differences.

    But let’s unpack that sentence. We are talking about average differences among people and not about individuals. Any one person’s intelligence might be blown off course from its genetic potential by, for example, an illness in childhood. By genetic, we mean differences passed from one generation to the next via DNA. But we all share 99.5 percent of our three billion DNA base pairs, so only 15 million DNA differences separate us genetically. And we should note that intelligence tests include diverse examinations of cognitive ability and skills learned in school. Intelligence, more appropriately called general cognitive ability, reflects someone’s performance across a broad range of varying tests.

    Genes make a substantial difference, but they are not the whole story. They account for about half of all differences in intelligence among people, so half is not caused by genetic differences, which provides strong support for the importance of environmental factors. This estimate of 50 percent reflects the results of twin, adoption and DNA studies. From them, we know, for example, that later in life, children adopted away from their biological parents at birth are just as similar to their biological parents as are children reared by their biological parents. Similarly, we know that adoptive parents and their adopted children do not typically resemble one another in intelligence.

    Researchers are now looking for the genes that contribute to intelligence. In the past few years we have learned that many, perhaps thousands, of genes of small effect are involved. Recent studies of hundreds of thousands of individuals have found genes that explain about 5 percent of the differences among people in intelligence. This is a good start, but it is still a long way from 50 percent.

    Another particularly interesting recent finding is that the genetic influence on measured intelligence appears to increase over time, from about 20 percent in infancy to 40 percent in childhood to 60 percent in adulthood. One possible explanation may be that children seek experiences that correlate with, and so fully develop, their genetic propensities.

    The ability to predict cognitive potential from DNA could prove tremendously useful. Scientists might use DNA to try to map out the developmental pathways linking genes, intelligence, the brain and the mind. In terms of practical implications, we have known for decades about hundreds of rare single-gene and chromosomal disorders, such as Down syndrome, that result in intellectual disability. Finding additional genes that contribute to intellectual disability could help us perhaps prevent or at least ameliorate these cognitive challenges.

    See the full article here .

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    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

     
  • richardmitnick 8:45 am on May 19, 2016 Permalink | Reply
    Tags: , Genetics, Mapping gene networks to better understand disease, , Swiss Institute of Bioinformatics (SIB), University of Lausanne   

    From Science Node: “Mapping gene networks to better understand disease” 

    Science Node bloc
    Science Node

    18 May, 2016
    Phoebe Baldwin

    1
    Lung cancer cells invade surrounding tissues. Image courtesy Scott Wilkinson and Adam Marcus.

    The risk of a person developing a complex disease such as cancer is influenced by their genes. Advances in genome-sequencing technologies have enabled researchers to compare the genetic variations between people with a given condition, and people without. However, the mechanisms by which these genetic variations impact upon disease processes remain largely unknown.

    Research spearheaded by the University of Lausanne and the Swiss Institute of Bioinformatics (SIB) used innovative software to construct gene network maps that will increase understanding of how diseases start and progress. The findings were recently published* in Nature Methods.

    The researchers used data from the Functional Annotation of the Mammalian Genome (FANTOM) consortium. They examined almost 400 different human cell and tissue types — the most ever analyzed at one time — to determine the networks in which genes interact for a given disorder. To analyze this data they developed a new software tool called Magnum, which they have made freely downloadable.

    Using Magnum, the team was able to map networks of interacting genes with unprecedented resolution. Then, using genetic associations from public data, the researchers were able to relate the genes to 37 different psychiatric, neurodegenerative, and immune-related diseases.

    Their results showed that genes that are associated with a given disorder tend to cluster in groups. In this way they are connected in networks, and specifically in networks of tissues that are relevant for that disease.

    “What I hoped we would see was enrichment in neural tissues for psychiatric diseases and so forth, as has been observed in other studies that looked at gene expression,” says project leader Daniel Marbach. “Our results turned out so fine-grained, that even within the different neural tissues or immune cells, the most relevant ones came up. That was surprising to everybody.”

    In cases of schizophrenia, for example, the strongest clustering of disease-associated genes was observed in networks of brain tissues and in structures that are known to be targeted by current medical treatments.

    The network-based approach is promising because of this clustering of genes in relevant tissues. Each network acts as a ‘control system’ for the cells or tissues by outlining hundreds of thousands of regulatory interactions among genes.

    “We propagate information in these networks about diseases,” says Marbach. “If we have one diseased gene that interacts with another gene, then that other gene has an increased likelihood of being involved in the same disease process.”

    Studies like this could drive progress toward better diagnostic tests and targeted treatments that will be more successful and have fewer side effects. Observing individual genes and groups of interacting genes further could give a better understanding of disease processes and mechanisms.

    “In the future we would like to identify specific pathways or disease mechanisms in these tissues,” says Marbach. “It was good to see the known biology repeated in a new way, and add new hypotheses for some diseases that another cell type or tissue may be involved.”

    *Science paper:
    Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases

    See the full article here .

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    “We report on all aspects of distributed computing technology, such as grids and clouds. We also regularly feature articles on distributed computing-enabled research in a large variety of disciplines, including physics, biology, sociology, earth sciences, archaeology, medicine, disaster management, crime, and art. (Note that we do not cover stories that are purely about commercial technology.)

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  • richardmitnick 4:40 pm on May 10, 2016 Permalink | Reply
    Tags: , Genetics, , New approach to genetic analysis yields markers linked to complex diseases   

    From MIT: “New approach to genetic analysis yields markers linked to complex diseases” 

    MIT News
    MIT News
    MIT Widget

    May 10, 2016
    Anne Trafton

    1
    “This approach overcomes a major hurdle in the human genetics field and addresses an important question surrounding the hidden heritability of many complex traits,” Laurie Boyer says. Image: Christine Daniloff/MIT

    Study identifies new gene variants that may be targets for treating arrhythmia.

    Many diseases, such as cancer, diabetes, and schizophrenia, tend to be passed down through families. After researchers sequenced the human genome about 15 years ago, they had high hopes that this trove of information would reveal the genes that underlie these strongly heritable diseases.

    However, around 2010, scientists began to realize that this wasn’t panning out. For one, there just weren’t enough patients: In order to unearth a statistically significant genetic marker, researchers would need groups of patients much larger than what they had been able to assemble so far. Furthermore, many of the variants that these studies turned up were found outside the regions of DNA that encode proteins, making it much more difficult to figure out how they might cause disease.

    A new study* from MIT addresses both of those problems. By combining information on gene-disease associations with maps of chemical modifications known as epigenomic marks, which control what genes are turned on, the researchers were able to identify additional genetic contributors to a heritable cardiac disorder that makes people more susceptible to heart failure.

    “This approach overcomes a major hurdle in the human genetics field and addresses an important question surrounding the hidden heritability of many complex traits,” says Laurie Boyer, the Irwin and Helen Sizer Career Development Associate Professor of Biology and Biological Engineering at MIT and one of the senior authors of the study.

    This strategy could also shed light on many other inherited diseases, the researchers say.

    “The exciting part is that we’ve applied this to one trait in one tissue, but we can apply this now to basically every disease,” says Xinchen Wang, an MIT graduate student and the paper’s lead author. “The new direction for us now is to target some of the bigger diseases like cholesterol-related heart disease and Alzheimer’s.”

    Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute, is also a senior author of the paper, which appears in the May 10 issue of the journal eLife.

    Finding patterns

    Since the human genome project was completed, scientists have compared the genetic make-up of thousands of people, in search of genetic differences associated with particular diseases. These studies, known as genome-wide association studies (GWAS), have revealed genetic markers linked with type 2 diabetes, Parkinson’s disease, obesity, and Crohn’s disease, among others.

    However, in order for a variant to be considered significant, it must meet stringent statistical criteria based on how frequently it appears in patients and how much of an effect it has on the disease. Until now, the only way to yield more significant “hits” for a given variant would be to double or triple the number of people in the studies, which is difficult and expensive.

    The MIT team took an alternative approach, which was to try to identify variants that don’t occur often enough to reach genome-wide significance in the smaller studies but still have an impact on a particular disease.

    “Below this genome-wide significance threshold lies a large number of markers that perhaps we should be paying attention to,” Kellis says. “If we can successfully prioritize new disease genes in these subthreshold loci, we can have a head start in developing new therapeutics that target these genes.”

    To test the usefulness of this strategy, the researchers focused on a cardiac trait known as the QT interval, which is a measure of how long it takes for electrical impulses to flow through the heart as it contracts. Variations in this interval are a risk factor for arrhythmia and heart failure, which is one of the leading causes of death in the United States.

    Genome-wide association studies had already yielded about 60 genetic markers linked with variations in QT interval length. The MIT team created a computer algorithm that first analyzes these known markers to discover common epigenomic properties among them, and then uses these properties to pick out subthreshold genetic markers with similar properties that make these markers likely contributors to the disease trait.

    This analysis revealed that many of the known, significant genetic variants were located in parts of the genome known as enhancers, which control gene activity from a distance. Enhancers where these variants were found were also active specifically in heart tissue, tended to be located in DNA regions that are more likely to be regulatory, and were found in regions that are similar across primate species.

    The researchers then analyzed the variants that were only weakly associated with QT interval and found approximately 60 additional locations that shared most of these properties, potentially doubling the number of candidate regions previously identified using genetic evidence alone.

    Next, the researchers sought to predict the target genes that these genetic variants affect. To do so, they analyzed models of the three-dimensional structure of chromosomes to predict the long-distance contacts between enhancer regions harboring subthreshold variants and their potential target genes. They selected about two dozen of those genes for further study, and from their own experiments combined with an analysis of previous gene knockout studies, they found that many of the predicted new target genes did have an effect on the heart’s ability to conduct electrical impulses.

    “This is the smoking gun we were looking for,” Kellis says. “We now have genetic evidence from humans, epigenomic evidence from heart cells, and experimental data from mice, together showing that the genetic differences in subthreshold enhancers influence heart function.”

    Skipping ahead

    Boyer’s lab now plans to apply this approach to learning more about congenital heart defects.

    “We know very little about the genetic etiology of congenital heart defects. Every 15 minutes a baby is born with a congenital heart defect, and it’s a devastating set of defects,” she says. “We could now go back to some of these genomic and epigenomic studies to improve our understanding of the biology of these different defects.”

    This approach developed by the MIT team is general and should allow researchers working on many traits to identify genetic markers that are invisible when using genome-wide association studies alone. This can speed up the development of new therapies, especially for rare diseases, where gathering sufficiently large groups of patients can be very difficult and sometimes impossible.

    “Instead of waiting for years until subthreshold variants are elucidated with genetics, we can skip ahead and begin characterizing the prioritized regions and genes immediately,” Boyer says.

    “We expect that an expanded set of candidate drug targets can shorten the path to new therapeutics by decades for many devastating disorders, and help translate these insights into tangible improvements in human health,” Kellis says.

    The research was funded by the National Institutes of Health and the National Health, Lung, and Blood Institute Bench to Bassinet Program.

    Other institutions contributing to this study include Massachusetts General Hospital, and the Hubrecht Institute and the University of Groningen, both in the Netherlands.

    *Science paper:
    Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures in eLife

    See the full article here .

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  • richardmitnick 8:20 am on March 31, 2016 Permalink | Reply
    Tags: , , Genetics,   

    From AAAS: “Cause of rare immune disease identified” 

    AAAS

    AAAS

    Mar. 30, 2016
    Mitch Leslie

    1
    A newly discovered disease found in a Belgian family may cause illness by inappropriately activating the inflammasome, a cellular structure that triggers inflammation. Chris Bickel/Science

    The Belgian family had puzzled doctors for more than a decade. Beginning when they were children, some members were prone to bouts of fever that could last for months. Their muscles and joints ached, their blood vessels were inflamed, and their skin erupted with sores that ranged from severe acne to abscesses and ulcers. One patient’s heart was so badly damaged that he needed a transplant at the age of 20.

    Now, researchers have figured out why the family members became ill, revealing that they suffer from a previously undiscovered genetic disease that unleashes a protein that normally helps protect us from microbes. Armed with the findings, doctors might be able to recognize other people with similar symptoms who have gone undiagnosed and offer treatment. In addition, the researchers say, the results might provide insight into more common diseases such as inflammatory bowel disease, where inflammation is out of control.

    “The paper beautifully works out the biochemistry” of how the mutation that causes the new disease alters a key immune protein, says geneticist Daniel Kastner of the National Human Genome Research Institute in Bethesda, Maryland, who wasn’t connected to the research.

    Scientists have already identified several rare but painful diseases in which the immune system triggers inappropriate inflammation in various parts of the body. These conditions differ from autoimmune diseases like rheumatoid arthritis and type I diabetes because a different branch of the immune system, which includes the body’s first responders to foreign invaders, malfunctions. Some of the Belgian family’s symptoms resembled the symptoms of one of these so-called autoinflammatory diseases, familial Mediterranean fever (FMF), but they were much worse. In FMF, for instance, fever lasts for a few days, not months.

    FMF results from mutations in the gene for pyrin, a protein inside many immune cells that detects infections by certain microbes. One attempt to track down the genetic flaw in the Belgian sufferers suggested that they could carry a defect in the same gene, but researchers dismissed the possibility because their symptoms were so different from those in people with FMF, says immunologist Seth Masters of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia, a co-author on the new paper. “It really didn’t look like the same disease.”

    Yet when Masters and colleagues sequenced the DNA of the Belgian family, they found a mutation in the gene for pyrin. It’s in a different location than in most people with FMF, the team reports today in Science Translational Medicine. After searching disease databases and hearing from other doctors who had patients with the similar symptoms, the researchers identified three other families in Lebanon, France, and the United Kingdom that had the same mutation. They’ve named the resulting disease pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).

    Although the same gene is mutated in people with FMF, the type and severity of the symptoms confirm that PAAND is a unique disease, Kastner says. “It’s not FMF. Period.” It’s rare for different mutations in the same gene to cause distinct diseases, but PAAND and FMF are not the only examples, says medical geneticist Wayne Grody of the University of California, Los Angeles (UCLA), who wasn’t connected to the study. He notes, for instance, that mutations in the CFTR gene can trigger the potentially lethal disease cystic fibrosis or a milder illness that results in male infertility.

    Masters and colleagues further determined how the mutation in PAAND patients causes pyrin to go awry. When pyrin senses toxins released by some kinds of bacteria, it spurs formation of a structure called the inflammasome that in turn triggers inflammation. To prevent pyrin from switching on prematurely, cells typically shield it with another protein until they are in trouble. But the scientists found that this shield falls off the version of pyrin that the Belgian family produced, resulting in an overactive molecule. “In effect you take away the brake,” says co-author Adrian Liston, an immunologist at the University of Leuven in Belgium.

    What makes the paper stand out, says Grody, is the team’s thorough investigation. “They really have a mechanism—we don’t have anything like that to explain FMF,” he says. The work also points to a potential treatment, a drug that blocks an inflammation-promoting molecule that was abundant in the patients. When the researchers treated one member of the Belgian family with the drug, “all the signs of disease disappeared within a couple of weeks,” Liston says. “It was really quite remarkable.” The scientists now plan to launch a clinical trial of the drug in more PAAND patients. Masters and Liston say that the results could also help researchers better understand the role of inflammation in non–auto-inflammatory illnesses, including Alzheimer’s disease and inflammatory bowel disease.

    The study might provide more immediate benefits for some people as well. FMF is relatively common for an autoinflammatory disease, but even in the Mediterranean region only about one in 200 to one in 1000 people suffer from it. Although PAAND isn’t likely to be prevalent, researchers think that more patients are waiting for a diagnosis. Large numbers of people with the disease could live in populous countries such as India and China, Masters says. Grody and his colleagues at the FMF clinic at UCLA will be on the lookout for new cases. “I’m certain there are other families out there,” he says.

    Research Article
    Inflammation

    Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

    Science team:

    Seth L. Masters1,2,*, Vasiliki Lagou3,4,5,†, Isabelle Jéru6,7,8,†, Paul J. Baker1,2,†, Lien Van Eyck4,5, David A. Parry9, Dylan Lawless10, Dominic De Nardo1,2, Josselyn E. Garcia-Perez4,5, Laura F. Dagley1,2,11, Caroline L. Holley12, James Dooley4,5, Fiona Moghaddas1,2, Emanuela Pasciuto4,5, Pierre-Yves Jeandel13, Raf Sciot14,15, Dena Lyras16, Andrew I. Webb2,11, Sandra E. Nicholson1,2, Lien De Somer15, Erika van Nieuwenhove4,5,15, Julia Ruuth-Praz7,8, Bruno Copin8, Emmanuelle Cochet8, Myrna Medlej-Hashim17, Andre Megarbane18, Kate Schroder12, Sinisa Savic19,20, An Goris3, Serge Amselem6,7,8, Carine Wouters4,15,*,‡ and Adrian Liston4,5,*,‡

    Affiliations:

    1Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
    2Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
    3Department of Neurosciences, KU Leuven, Leuven 3000, Belgium.
    4Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
    5Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
    6INSERM, UMR S933, Paris F-75012, France.
    7Université Pierre et Marie Curie–Paris, UMR S933, Paris F-75012, France.
    8Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d’Embryologie médicales, Paris F-75012, France.
    9Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh LS7 4SA, UK.
    10Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Wellcome Trust Brenner Building, Saint James’s University Hospital, Leeds LS7 4SA, UK.
    11Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
    12Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
    13Département de Médecine Interne, Hôpital Archet 1, Université Nice Sophia-Antipolis, 06202 Nice, France.
    14Department of Pathology, KU Leuven, Leuven 3000, Belgium.
    15University Hospitals Leuven, Leuven 3000, Belgium.
    16Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia.
    17Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Beirut 1102 2801, Lebanon.
    18Al-Jawhara Center, Arabian Gulf University, Manama 26671, Bahrain.
    19Department of Allergy and Clinical Immunology, Saint James’s University Hospital, Leeds LS9 7TF, UK.
    20National Institute for Health Research–Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, Saint James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK.

    ↵*Corresponding author. E-mail: masters@wehi.edu.au (S.L.M.); carine.wouters@uzleuven.be (C.W.); adrian.liston@vib.be (A.L.)

    ↵† These authors contributed equally as second authors.

    ↵‡ These authors contributed equally as co-last authors.

    See the full article here .

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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