Daily Archives: December 17, 2014

Amount of mitochondrial DNA predicts frailty, mortality in humans

Posted: December 17, 2014 at 3:44 pm

December 17, 2014

Mitochondrial DNA from the snake adrenal gland, where the mitochondrion is adjacent to a highly ordered array of endoplasmic reticulum (bottom left). Credit: John Long

Chuck Bednar for redOrbit.com Your Universe Online

The amount of mitochondrial DNA (mtDNA) found in a persons blood could be used to predict his or her overall risk of frailty and death from any cause 10 to 15 years before the first symptoms appear, researchers from The Johns Hopkins University say in a new study.

Mitochondrial DNA, the cellular organelles that help convert food into chemical energy for cells, can be used to enhance our scientific understanding of aging, the study authors explained. Their findings, which were published online earlier this month in the Journal of Molecular Medicine, could be used to develop a new test to identify at-risk individuals.

Dr. Dan Arking, an associate professor of genetic medicine at the university, said that he and his colleagues dont know enough yet to say whether the relationship is one of correlation or causation, but either way, mitochondrial DNA could be a very useful biomarker in the field of aging. It could be used to identify people who could benefit health-wise from lifestyle changes.

Unlike other cell structures, mitochondria (which are also known as power houses since they are responsible for generating the majority of a cells energy) contain their own DNA separate from those enclosed in the nucleus. Their DNA comes in the form of between two and 10 small, circular chromosomes which code for 37 genes necessary for mitochondrial function.

Previous research from Dr. Arkings laboratory has found a link between genetic differences in mtDNA and the reduced muscle strength and increased frailty experienced by older men and women. In medical terms, frailty refers to a highly recognizable set of aging symptoms, including weakness, decreased energy, reduced activity and weight loss, the study authors added.

In order to further study this correlation, the investigative team analyzed the amount of mtDNA in blood samples collected for a pair of large studies that began during the late 1980s. They monitored the health of individuals for up to 20 years and calculated the amount of mtDNA each sampled contained relative to the amount of nuclear DNA.

Dr. Arking and his colleagues then reviewed measures of frailty and health status gathered on the studies participants over time. They found that, on average, study participants that met the criteria for frailty had nine percent less mtDNA than nonfrail participants. Furthermore, white participants in the bottom one-fifth of the study population in terms of mtDNA were 31 percent more likely to be clinically frail than participants in the top one-fifth.

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Thousands of foreign criminals' DNA samples have been deleted because of legal loophole

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Scandal revealed in annual report by Britain's biometrics watchdog One burglary suspect's samples deleted despite 13 years' jail elsewhere It is thanks to European judges who ruled keeping details were unlawful

By Ian Drury, Home Affairs Correspondent for the Daily Mail

Published: 18:31 EST, 16 December 2014 | Updated: 18:37 EST, 16 December 2014

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DNA samples from thousands of foreign criminals have been deleted from British databases due to a legal loophole.

Police are not allowed to store swabs or fingerprints from offenders who were convicted abroad, it emerged yesterday.

The scandal was revealed in the annual report from Britains independent biometrics watchdog. In one case, police had to delete samples from a burglary suspect after he was arrested in the UK, even though he had served 13 years for similar offences elsewhere in Europe.

Scandal: DNA samples from thousands of foreign criminals have been deleted in Britain (file photo)

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Can the Subaltern Genome Code? Rethinking race, science, and subjectivity – Ruha Benjamin – Video

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Can the Subaltern Genome Code? Rethinking race, science, and subjectivity - Ruha Benjamin
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Download Ancestors in Our Genome The New Science of Human Evolution PDF – Video

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AncestryDNA Reconstructs Partial Genome of Person Living 200 Years Ago – Video

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AncestryDNA Reconstructs Partial Genome of Person Living 200 Years Ago
Imagine if you could go back in time and see your ancestors. Would you see a part of yourself in one of them? Genetics is starting to answer questions about what a long ago ancestor may have...

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New method identifies genome-wide off-target cleavage sites of CRISPR-Cas nucleases

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PUBLIC RELEASE DATE:

16-Dec-2014

Contact: Sue McGreevey smcgreevey@partners.org 617-724-2764 Massachusetts General Hospital @MassGeneralNews

Massachusetts General Hospital (MGH) investigators have developed a method of detecting, across the entire genome of human cells, unwanted DNA breaks induced by use of the popular gene-editing tools called CRISPR-Cas RNA-guided nucleases (RGNs). Members of the same team that first described these off-target effects in human cells describe their new platform, called Genome-wide Unbiased Indentification of DSBs Evaluated by Sequencing (GUIDE-seq), in a report being published online in Nature Biotechnology.

"GUIDE-seq is the first genome-wide method of sensitively detecting off-target DNA breaks induced by CRISPR-Cas nucleases that does not start with the assumption that these off-target sites resemble the targeted sites," says J. Keith Joung, MD, PhD, associate chief for Research in the MGH Department of Pathology and senior author of the report. "This capability, which did not exist before, is critically important for the evaluation of any clinical use of CRISPR-Cas RGNs."

Used to cut through a double strand of DNA in order to introduce genetic changes, CRISPR-Cas RGNs combine a bacterial gene-cutting enzyme called Cas9 with a short RNA segment that matches and binds to the target DNA sequence. In a 2013 Nature Biotechnology paper, Joung and his colleagues reported finding that CRISPR-Cas RGNs could also induce double-strand breaks (DSBs) at sites with significant differences from the target site, including mismatches of as many as five nucleotides. Since such off-target mutations could potentially lead to adverse effects, including cancer, the ability to identify and eventually minimize unwanted DSBs would be essential to the safe clinical use of these RGNs, the authors note.

The method they developed involves use of short, double-stranded oligonucleotides that are taken up by DSBs in a cell's DNA, acting as markers of off-target breaks caused by the use of CRISPR-Cas. Those tags allow the identification and subsequent sequencing of those genomic regions, pinpointing the location of off-target mutations. Experiments with GUIDE-seq showed it was sensitive enough to detect off-target sites at which CRISPR RGNs induced unwanted mutations of a gene that occur with a frequency of as little as 0.1 percent in a population of cells. These experiments also revealed that, since many such mutations took place at sites quite dissimilar from the targeted site, no easy rules would predict the number or location of off-target DSBs.

Two existing tools designed to predict off-target mutations by analysis of the target sequence were much less effective than GUIDE-seq in predicting confirmed off-target sites and also misidentified sites that did not prove to have been cut by the enzyme. Comparing GUIDE-seq with a tool called ChIP-seq - which identifies sites where proteins bind to a DNA strand - confirmed that ChIP-seq does not provide a robust method for identifying CRISPR-Cas-induced DSBs.

GUIDE-seq was also able to identify breakpoint hotspots in control cell lines that were not induced to express the CRISPR RGNs. "Various papers have described fragile genomic sites in human cells before," Joung notes, "but this method may be the first to identify these sites without the addition of drugs that enhance the occurrence of such breaks. We also were surprised to find those breaks occurred largely at different sites in the two cell lines used in this study. The ability to capture these RGN-independent breaks suggests that GUIDE-seq could be a useful tool for studying and monitoring DNA repair in living cells."

In addition, GUIDE-seq was able to verify that an MGH-developed approach for improving the accuracy of CRISPR-Cas by shortening the guiding RNA segment reduced the number of DSBs throughout the genome. Joung also expects that GUIDE-seq will be useful in identifying off-target breaks induced by other gene-editing tools. Along with pursuing that possibility, he notes the importance of investigating the incidence and detection of off-target mutations in human cells not altered to create cell lines - a process that transforms them into immortalized cancer cells. Understanding the range and number of off-target mutations in untransformed cells will give a better picture of how CRISPR-Cas RGNs and other tools would function in clinical applications.

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Microbiome may have shaped early human populations

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16-Dec-2014

Contact: David Salisbury david.salisbury@vanderbilt.edu 615-343-6803 Vanderbilt University @vanderbiltu

We humans have an exceptional age structure compared to other animals: Our children remain dependent on their parents for an unusually long period and our elderly live an extremely long time after they have stopped procreating.

Could the microscopic fellow travelers that consider the human body to be their home - collectively known as the microbiome - have played an active role in shaping and maintaining this unusual aspect of human nature?

That is the speculative proposition advanced by Martin Blaser, professor of medicine and microbiology at NYU's Langone Medical Center, and supported by mathematical models produced by Glenn Webb, professor of mathematics at Vanderbilt University. They present their argument in a paper titled, "Host demise as a beneficial function of indigenous microbiota in human hosts," published online today in mBio, the journal of the American Society for Microbiology.

Scientists have known for a long time that every species of plant and animal acts as host for a distinctive collection of microorganisms. The human microbiome consists of about 100 trillion microbial cells, outnumbering the much larger human cells by about 10 to 1. Until recently they thought that the influence these microscopic communities have on their hosts was extremely limited. But recent research has found that their influence extends well beyond aiding digestion and producing bodily odors; they also aid brain development, reproduction and defense against infection. Taken together, the new evidence has led to the hologenomic theory of evolution, which proposes that the object of Darwin's natural selection is not just the individual organism as he proposed, but the organism plus its associated microbial community.

Blaser got the idea for the impact of microbes on human age structure from his lifetime research on Helicobacter pylori, a bacterium found in the stomach of more than 50 percent of the world's population.

H. pylori co-exists peacefully in people's stomachs for most of their lives. It even has some beneficial effects. In 1996, for example, Blaser discovered that it may help regulate levels of stomach acid. However, H. pylori is also a major cause of stomach cancer, a risk that increases with age.

"I began thinking that a real symbiont is an organism that keeps you alive when you are young and kills you when you are old. That's not particularly good for you, but it's good for the species," Blaser said.

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Commensal bacteria were critical shapers of early human populations

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PUBLIC RELEASE DATE:

16-Dec-2014

Contact: Garth Hogan ghogan@asmusa.org American Society for Microbiology @ASMnewsroom

WASHINGTON, DC--December 16, 2014--Using mathematical modeling, researchers at New York and Vanderbilt universities have shown that commensal bacteria that cause problems later in life most likely played a key role in stabilizing early human populations. The finding, published in mBio, the online open-access journal of the American Society for Microbiology, offers an explanation as to why humans co-evolved with microbes that can cause or contribute to cancer, inflammation, and degenerative diseases of aging.

The work sprung from a fundamental question in biology about senescence, or aging past the point of reproduction. "Nature has a central problem--it must have a way to remove old individuals, whether fish or trees or people," says Martin Blaser, microbiologist at New York University Langone Medical Center in New York City. "Resources are always limited. And young guys are ultimately competing with older ones."

In most species, individuals die shortly after the reproductive phase. But humans are weird--we have an extra long senescence phase. Blaser began to think about the problem from the symbiotic microbe's point of view and he came up with a hypothesis: "The great symbionts keep us alive when we are young, then after reproductive age, they start to kill us." They are part of the biological clock of aging.

In other words, he hypothesized that evolution selected for microbes that keep the whole community of hosts healthy, even if that comes with a cost to an individual host's health.

Modeling of early human population dynamics could tell him if he was on the right track. Blaser worked together with his collaborator Glenn Webb, professor of mathematics at Vanderbilt University in Nashville, to define a mathematical model of an early human population, giving it characteristics similar to a time 500-100,000 years ago, when the human population consisted of sparse, isolated communities.

Webb came up with a non-linear differential equation to describe the variables involved, their rates of change over time, and the relationship between those rates. "It can reveal something that's not quite appreciated or intuitive, because it sorts out relationships changing in time," even with many variables, such as age-dependent fertility rates and mortality rates, changing simultaneously, explains Webb.

Using this baseline model, the team could tweak the conditions to see what happened to the population dynamics. For example, they increased the fertility rate from roughly six children per female to a dozen, proposing that this might be one way for populations to overcome the burden of senescence, by boosting juvenile numbers. Instead, they were surprised to see that this created wild oscillations in total population size over time--an unstable scenario.

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