Posts Tagged ‘DNA’

by Lindsey Valich

Explorers have dreamt for centuries of a Fountain of Youth, with healing waters that rejuvenate the old and extend life indefinitely.

Researchers at the University of Rochester, however, have uncovered more evidence that the key to longevity resides instead in a gene.

In a new paper published in the journal Cell, the researchers—including Vera Gorbunova and Andrei Seluanov, professors of biology; Dirk Bohmann, professor of biomedical genetics; and their team of students and postdoctoral researchers—found that the gene sirtuin 6 (SIRT6) is responsible for more efficient DNA repair in species with longer lifespans. The research illuminates new targets for anti-aging interventions and could help prevent age-related diseases.

Inevitable double-strand breaks

As humans and other mammals grow older, their DNA is increasingly prone to breaks, which can lead to gene rearrangements and mutations—hallmarks of cancer and aging. For that reason, researchers have long hypothesized that DNA repair plays an important role in determining an organism’s lifespan. While behaviors like smoking can exacerbate double-strand breaks (DSBs) in DNA, the breaks themselves are unavoidable. “They are always going to be there, even if you’re super healthy,” says Bohmann. “One of the main causes of DSBs is oxidative damage and, since we need oxygen to breathe, the breaks are inevitable.”

Organisms like mice have a smaller chance of accumulating double-strand breaks in their comparatively short lives, versus organisms with longer lifespans, Bohmann says. “But, if you want to live for 50 years or so, there’s more of a need to put a system into place to fix these breaks.”

The longevity gene

SIRT6 is often called the “longevity gene” because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes—the SIRT6 proteins—are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer. “The SIRT6 protein seems to be the dominant determinant of lifespan,” Bohmann says. “We show that at the cell level, the DNA repair works better, and at the organism level, there is an extended lifespan.”

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein “more active in repairing DNA and better at enzyme functions,” Gorbunova says. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6.

Species with even more robust SIRT6?

Although it appears that human SIRT6 is already optimized to function, “we have other species that are even longer lived than humans,” Seluanov says. Next steps in the research involve analyzing whether species that have longer lifespans than humans—like the bowhead whale, which can live more than 200 years—have evolved even more robust SIRT6 genes.

The ultimate goal is to prevent age-related diseases in humans, Gorbunova says. “If diseases happen because of DNA that becomes disorganized with age, we can use research like this to target interventions that can delay cancer and other degenerative diseases.”

https://phys.org/news/2019-04-longevity-gene-responsible-efficient-dna.html

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A new Northwestern University study challenges prevailing understandings of genes as immutable features of biology that are fixed at conception.

Previous research has shown that socioeconomic status (SES) is a powerful determinant of human health and disease, and social inequality is a ubiquitous stressor for human populations globally. Lower educational attainment and/or income predict increased risk for heart disease, diabetes, many cancers and infectious diseases, for example. Furthermore, lower SES is associated with physiological processes that contribute to the development of disease, including chronic inflammation, insulin resistance and cortisol dysregulation.

In this study, researchers found evidence that poverty can become embedded across wide swaths of the genome. They discovered that lower socioeconomic status is associated with levels of DNA methylation (DNAm) — a key epigenetic mark that has the potential to shape gene expression — at more than 2,500 sites, across more than 1,500 genes.

In other words, poverty leaves a mark on nearly 10 percent of the genes in the genome.

Lead author Thomas McDade said this is significant for two reasons.

“First, we have known for a long time that SES is a powerful determinant of health, but the underlying mechanisms through which our bodies ‘remember’ the experiences of poverty are not known,” said McDade, professor of anthropology in the Weinberg College of Arts and Sciences at Northwestern and director of the Laboratory for Human Biology Research.

“Our findings suggest that DNA methylation may play an important role, and the wide scope of the associations between SES and DNAm is consistent with the wide range of biological systems and health outcomes we know to be shaped by SES.”

Secondly, said McDade, also a faculty fellow at Northwestern’s Institute for Policy Research, experiences over the course of development become embodied in the genome, to literally shape its structure and function.

“There is no nature vs. nurture,” he adds.

McDade said he was surprised to find so many associations between socioeconomic status and DNA methylation, across such a large number of genes.

“This pattern highlights a potential mechanism through which poverty can have a lasting impact on a wide range of physiological systems and processes,” he said.

Follow-up studies will be needed to determine the health consequences of differential methylation at the sites the researchers identified, but many of the genes are associated with processes related to immune responses to infection, skeletal development and development of the nervous system.

“These are the areas we’ll be focusing on to determine if DNA methylation is indeed an important mechanism through which socioeconomic status can leave a lasting molecular imprint on the body, with implications for health later in life,” McDade said.

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“Genome-wide analysis of DNA methylation in relation to socioeconomic status during development and early adulthood” published recently in the American Journal of Physical Anthropology.

In addition to McDade, co-authors include Calen P. Ryan, Northwestern; Meaghan J. Jones, University of British Columbia; Morgan K. Hoke, University of Pennsylvania; Judith Borja, University of San Carlos; Gregory E. Miller and Christopher W. Kuzawa of Northwestern; and Michael S. Kobor, University of British Columbia.

https://www.eurekalert.org/pub_releases/2019-04/nu-pla040419.php

Thanks to Kebmodee for bringing this to the It’s Interesting community.

Sydney Brenner was one of the first to view James Watson and Francis Crick’s double helix model of DNA in April 1953. The 26-year-old biologist from South Africa was then a graduate student at the University of Oxford, UK. So enthralled was he by the insights from the structure that he determined on the spot to devote his life to understanding genes.

Iconoclastic and provocative, he became one of the leading biologists of the twentieth century. Brenner shared in the 2002 Nobel Prize in Physiology or Medicine for deciphering the genetics of programmed cell death and animal development, including how the nervous system forms. He was at the forefront of the 1975 Asilomar meeting to discuss the appropriate use of emerging abilities to alter DNA, was a key proponent of the Human Genome Project, and much more. He died on 5 April.

Brenner was born in 1927 in Germiston, South Africa to poor immigrant parents. Bored by school, he preferred to read books borrowed (sometimes permanently) from the public library, or to dabble with a self-assembled chemistry set. His extraordinary intellect — he was reading newspapers by the age of four — did not go unnoticed. His teachers secured an award from the town council to send him to medical school.

Brenner entered the University of the Witwatersrand in Johannesburg at the age of 15 (alongside Aaron Klug, another science-giant-in-training). Here, certain faculty members, notably the anatomist Raymond Dart, and fellow research-oriented medical students enriched his interest in science. On finishing his six-year course, his youth legally precluded him from practising medicine, so he devoted two years to learning cell biology at the bench. His passion for research was such that he rarely set foot on the wards — and he initially failed his final examination in internal medicine.


Sydney Brenner (right) with John Sulston, who both shared the Nobel Prize in Physiology or Medicine with Robert Horvitz in 2002.Credit: Steve Russell/Toronto Star/Getty

In 1952 Brenner won a scholarship to the Department of Physical Chemistry at Oxford. His adviser, Cyril Hinshelwood, wanted to pursue the idea that the environment altered observable characteristics of bacteria. Brenner tried to convince him of the role of genetic mutation. Two years later, with doctorate in hand, Brenner spent the summer of 1954 in the United States visiting labs, including Cold Spring Harbor in New York state. Here he caught up with Watson and Crick again.

Impressed, Crick recruited the young South African to the University of Cambridge, UK, in 1956. In the early 1960s, using just bacteria and bacteriophages, Crick and Brenner deciphered many of the essentials of gene function in a breathtaking series of studies.

Brenner had proved theoretically in the mid-1950s that the genetic code is ‘non-overlapping’ — each nucleotide is part of only one triplet (three nucleotides specify each amino acid in a protein) and successive ‘triplet codons’ are read in order. In 1961, Brenner and Crick confirmed this in the lab. The same year, Brenner, with François Jacob and Matthew Meselson, published their demonstration of the existence of messenger RNA. Over the next two years, often with Crick, Brenner showed how the synthesis of proteins encoded by DNA sequences is terminated.

This intellectual partnership dissolved when Brenner began to focus on whole organisms in the mid-1960s. He finally alighted on Caenorhabditis elegans. Studies of this tiny worm in Brenner’s arm of the legendary Laboratory of Molecular Biology (LMB) in Cambridge led to the Nobel for Brenner, Robert Horvitz and John Sulston.


Maxine Singer, Norton Zinder, Sydney Brenner and Paul Berg (left to right) at the 1975 meeting on recombinant DNA technology in Asilomar, California.Credit: NAS

And his contributions went well beyond the lab. In 1975, with Paul Berg and others, he organized a meeting at Asilomar, California, to draft a position paper on the United States’ use of recombinant DNA technology — introducing genes from one species into another, usually bacteria. Brenner was influential in persuading attendees to treat ethical and societal concerns seriously. He stressed the importance of thoughtful guidelines for deploying the technology to avoid overly restrictive regulation.

He served as director of the LMB for about a decade. Despite describing the experience as the biggest mistake in his life, he took the lab (with its stable of Nobel laureates and distinguished staff) to unprecedented prominence. In 1986, he moved to a new Medical Research Council (MRC) unit of molecular genetics at the city’s Addenbrooke’s Hospital, and began work in the emerging discipline of evolutionary genomics. Brenner also orchestrated Britain’s involvement in the Human Genome Project in the early 1990s.

From the late 1980s, Brenner steered the development of biomedical research in Singapore. Here he masterminded Biopolis, a spectacular conglomerate of chrome and glass buildings dedicated to biomedical research. He also helped to guide the Janelia Farm campus of the Howard Hughes Medical Institute in Ashburn, Virginia, and to restructure molecular biology in Japan.

Brenner dazzled, amused and sometimes offended audiences with his humour, irony and disdain of authority and dogma — prompting someone to describe him as “one of biology’s mischievous children; the witty trickster who delights in stirring things up.” His popular columns in Current Biology (titled ‘Loose Ends’ and, later, ‘False Starts’) in the mid-1990s led some seminar hosts to introduce him as Uncle Syd, a pen name he ultimately adopted.

Sydney was aware of the debt he owed to being in the right place at the right time. He attributed his successes to having to learn scientific independence in a remote part of the world, with few role models and even fewer mentors. He recounted the importance of arriving in Oxford with few scientific biases, and leaving with the conviction that seeing the double helix model one chilly April morning would be a defining moment in his life.

The Brenner laboratories (he often operated more than one) spawned a generation of outstanding protégés, including five Nobel laureates. Those who dedicated their careers to understanding the workings of C. elegans now number in the thousands. Science will be considerably poorer without Sydney. But his name will live forever in the annals of biology.

https://www.nature.com/articles/d41586-019-01192-9

Birds do it, bees do it, even educated fleas do it: No, they don’t fall in love, they sleep. However, exactly why all animals with a nervous system evolved to sleep has been a longstanding scientific mystery. Slumber certainly feels great, but it doesn’t exactly make sense — why should we spend a third of our lives passed out?

In a study published Tuesday in Nature Communications, scientists say they’ve figured out why on the cellular level. The core cellular function of sleep, they explain, is to combat the neuronal DNA damage that accumulates during waking hours. Sleep allows neurons to perform the efficient DNA maintenance that’s essential to a healthy life: Scientists already know that less sleep means greater vulnerability to anxiety, frustration, and ill health, but now they’re closer to understanding exactly why that’s the case.

“We’ve found a causal link between sleep, chromosome dynamics, neuronal activity, and DNA damage and repair with direct physiological relevance to the entire organism,” study lead Lior Appelbaum, Ph.D., said Tuesday. “Sleep gives an opportunity to reduce DNA damage accumulated in the brain during wakefulness.”

Applebaum and his team examined how sleep is linked to nuclear maintenance by examining one of the most frequently used model organisms for genetic and developmental studies: the zebrafish. These transparent zebrafish were genetically engineered so that the chromosomes in their neurons carried colorful chemical tags. While the fish were awake and asleep, the scientists observed the movement of DNA and nuclear proteins inside the fish with a high-resolution microscope, which can be seen in the video above.

They witnessed that when the fish were awake, the chromosomes were relatively inactive, and broken strands of DNA accumulated in the neurons. However, when the fish were asleep the chromosomes became more active, and the DNA damage that had accumulated began to be repaired. Subsequent analysis confirmed that in order to perform nuclear maintenance, single neurons need an animal to go to sleep.

The accumulation of DNA damage, says Appelbaum, is the “price of wakefulness.” During wakefulness, chromosomes are less active, leaving them vulnerable to DNA damage caused by radiation, oxidative stress, and neuronal activity. Sleep kickstarts chromosomal activity and synchronizes nuclear maintenance within individual neurons, allowing the brain to be repaired while it’s not being used to the extent that it is during the day.

“It’s like potholes in the road,” Applebaum says. “Roads accumulate wear and tear, especially during daytime rush hours, and it is most convenient and efficient to fix them at night, when there is light traffic.”

Anecdotally, we know that a good night’s sleep can be restorative. Now it appears that it’s quantifiably restorative for the brain as well, allowing it to naturally mend the damage of the day.

Abstract:

Sleep is essential to all animals with a nervous system. Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but not in two other cell types. Manipulation of sleep, chromosome dynamics, neuronal activity, and DNA double-strand breaks (DSBs) showed that chromosome dynamics are low and the number of DSBs accumulates during wakefulness. In turn, sleep increases chromosome dynamics, which are necessary to reduce the amount of DSBs. These results establish chromosome dynamics as a potential marker to define single sleeping cells, and propose that the restorative function of sleep is nuclear maintenance.

by Mike McRae

Earth might have a dizzying array of life forms, but our biology ultimately remains a solitary data point – we simply don’t have a reference for life based on DNA different from our own. Now, scientists have taken matters into their hands to push the boundaries on what life could be like.

Research funded by NASA and led by the Foundation for Applied Molecular Evolution in the US has led to the creation of an entirely new flavour of the DNA double helix, one that has an additional four nucleotide bases.

It’s being called hachimoji DNA (from the Japanese words for ‘eight letters’) and it includes two new pairs to add to the existing partnerships of adenine (A) paired with thymine (T), and guanine (G) with cytosine (C).

This work to expand on nature’s own genetic recipe might sound a little familiar. The same scientists already successfully squeezed in two new letters in 2011. Only last year yet another version of an extended alphabet, also with six letters, was made to function inside a living organism.

Now, in what might seem like a case of overachievement, researchers have gone back to the drawing board to develop even more non-standard nucleotides.

They have a purpose for doubling the number of codes in the recipe book, though.

“By carefully analysing the roles of shape, size and structure in hachimoji DNA, this work expands our understanding of the types of molecules that might store information in extraterrestrial life on alien worlds,” says chemist Steven Benner.

We already know a lot about the stability and functionality of ‘natural’ DNA under a range of environmental conditions, and are slowly teasing apart possible scenarios describing its evolution from simpler organic materials to living chemistry.

But to really get a good sense of how a genetic system could evolve, we need to test the limits of its underlying chemistry.

Hachimoji DNA certainly allows for that. The new codes, labelled P, B, Z and S, are based on the same kind of nitrogenous molecules as existing ones, categorised as purines and pyrimidines.

Similarly, they link up with hydrogen bonds to form their own base pairs – S bonding with B, and P with Z.

That’s where the similarities fade out. These new ‘letters’ introduce dozens of new chemical parameters to the double helix structure that potentially affect how it zips and twists.

By devising models that predict the molecule’s stability and then observing actual structures made of this ‘alien’ DNA, researchers are better equipped what’s truly important when it comes to the fundamentals of a genetic template.

The researchers constructed hundreds of hachimoji helices made up of different configurations of natural and synthetic bases and then subjected them to a range of conditions to see how well they held up.

While there were a few minor differences in how the new letters behaved, there was no reason to believe hachimoji DNA wouldn’t work well as an information-carrying template that could mutate and evolve.

The team not only showed their synthetic letters could contribute to new codes without swiftly disintegrating, the sequences were also translated into synthetic RNA versions.

Their work falls well short of a second genesis. But a novel DNA format such as this is a step towards determining what living chemistry might – and might not – look like elsewhere in the Universe.

“Life detection is an increasingly important goal of NASA’s planetary science missions, and this new work will help us to develop effective instruments and experiments that will expand the scope of what we look for,” says NASA’s Planetary Science Division’s acting director, Lori Glaze.

Devising new bases that can operate alongside our own DNA also has applications closer to home, not only as a way to reprogram life with a different code base, but in our effort to build new kinds of nanostructures.

The sky really isn’t the limit with synthetic DNA. This is going to take us to the stars and back again.

This research was published in Science.

https://www.sciencealert.com/scientists-made-synthetic-dna-using-8-letters-and-it-could-help-us-find-aliens

By Rafi Letzter

A kid in France transcribed parts of the Hebrew book of Genesis and the Arabic-language Quran, into DNA and injected them into his body — one text into each thigh.

Adrien Locatelli, a 16-year-old high school student, posted a paper Dec. 3 on the preprint server OS, in which he claimed, “It is the first time that someone injects himself macromolecules developed from a text.”

Locatelli, a student at the boarding school Lycée les Eaux Claires in Grenoble, France, told Live Science that he didn’t need any special equipment for his project.

“I just needed to buy saline solution and a syringe because VectorBuilder sent me liquid and ProteoGenix sent me powder,” he told Live Science.

VectorBuilder is a company that creates viruses that can sneak DNA strands into cells for gene-editing purposes. ProteoGenix synthesizes, among other things, custom strands of DNA. Both companies primarily serve scientists, but their products are available to anyone who purchases them.

If you saw the texts that Locatelli injected into his body, they wouldn’t look like much. DNA is just a long molecule that can store information. Mostly, it stores the information living things use to go about their business. But it can be used to store just about any kind of information that can be written down.

Locatelli’s method for translating the texts into DNA was straightforward, if a bit crude. DNA encodes its information using repeating strings of four nucleotides, which scientists have abbreviated as A, G, T and C. Locatelli lined up each letter of the Hebrew and Arabic alphabets (which correspond closely to each other) with a nucleotide, so each nucleotide represented more than one letter. So if you were to write a Hebrew sentence using his scheme, every aleph, vav, yud, nun, tsade, and tav would become a G. Every dalet, khet, ayin, and resh would become a T. And so on.

So, is this a good idea? Locatelli thinks so.

“I did this experiment for the symbol of peace between religions and science,” he said, adding, “I think that for a religious person it can be good to inject himself his religious text.”

Locatelli said he didn’t experience any significant health problems following the procedure, though he reported some “minor inflammation” around the injection site on his left thigh for a few days.

This account of only minimal complications fits with what Sriram Kosuri, a professor of biochemistry at UCLA, told Live Science.

“[The injected texts] are unlikely to do anything except possibly cause an allergic reaction. I also don’t know how likely the rAAV vector would be to make actual virus, given the way he injected. I honestly don’t know enough about the vector he used and how he did it (details are scarce),” he wrote in a message.

https://www.livescience.com/64388-boy-encoded-and-injected-dna-bible-quran.html#?utm_source=ls-newsletter&utm_medium=email&utm_campaign=12252018-ls

largest-ever-study-of-genetic-links-to-depression-and-anxiety-launched-309700

The NIHR and King’s College London are calling for 40,000 people diagnosed with depression or anxiety to enrol online for the Genetic Links to Anxiety and Depression (GLAD) Study and join the NIHR Mental Health Bioresource.

Researchers hope to establish the largest ever database of volunteers who can be called up to take part in research exploring the genetic factors behind the two most common mental health conditions – anxiety and depression.

[youtube=https://youtu.be/wzgvS8gU2Ss\

The GLAD study will make important strides towards better understanding of these disorders and provide a pool of potential participants for future studies, reducing the time-consuming process of recruiting patients for research.

Research has shown 30-40% of the risk for both depression and anxiety is genetic and 60-70% due to environmental factors. Only by having a large, diverse group of people available for studies will researchers be able to determine how genetic and environmental triggers interact to cause anxiety and depression.

Leader of the GLAD study and the NIHR Mental Health BioResource, Dr Gerome Breen of King’s College London, said: “It’s a really exciting time to become involved in mental health research, particularly genetic research which has made incredible strides in recent years – we have so far identified 46 genetic links for depression and anxiety.

“By recruiting 40,000 volunteers willing to be re-contacted for research, the GLAD Study will take us further than ever before. It will allow researchers to solve the big unanswered questions, address how genes and environment act together and help develop new treatment options.”

The GLAD Study, a collaboration between the NIHR BioResource and King’s College London, has been designed to be particularly accessible, with a view to motivating more people to take part in mental health research.

Research psychologist and study lead Professor Thalia Eley, King’s College London, said: “We want to hear from all different backgrounds, cultures, ethnic groups and genders, and we are especially keen to hear from young adults. By including people from all parts of the population, what we learn will be relevant to everyone. This is a unique opportunity to participate in pioneering medical science.”

https://www.nihr.ac.uk/news/nihr-launches-largest-ever-study-of-genetic-links-to-depression-and-anxiety/9201