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Jan302008

Genetic material under a magnifying glass
Genetic material under a magnifying glass

The genetic alphabet contains four letters. Although our cells can readily decipher our genetic molecules, it isn’t so easy for us to read a DNA sequence in the laboratory. Scientists require complex, highly sophisticated analytical techniques to crack individual DNA codes. Volker Deckert and his team at the Institute for Analytical Sciences (ISAS) in Dortmund have recently developed a method that could provide a way to directly sequence DNA. Their process is based on a combination of Raman spectroscopy and atomic force microscopy. As reported in the journal Angewandte Chemie, Deckert and Elena Bailo have successfully analyzed DNA’s closest relative, RNA.

Direct sequencing means that the letters of the genetic code are read directly, as if with a magnifying glass. A DNA or RNA strand has a diameter of only two nanometers, so the magnification must be correspondingly powerful. Deckert’s team uses an atomic force microscope to achieve this degree of magnification. Steered by the microscope, a tiny, silvered glass tip moves over the RNA strand. A laser beam focused on the tip excites the section of the strand being examined and starts it vibrating. The spectrum of the scattered light (Raman spectrum) gives very precise information about the molecular structure of the segment. Each genetic “letter”, that is, each of the nucleic acids, vibrates differently and thus has a characteristic spectral “fingerprint”.

The direct resolution of individual bases has not been attainable, but is also not necessary. The tip only has to be moved over the RNA strand at intervals corresponding to about the base-to-base distance. Even if the measured data then consist of overlapped spectra from several neighboring bases, the information can be used to derive the sequence of the RNA.

If this method, known as tip-enhanced Raman spectroscopy (TERS), can be extended to DNA, it could revolutionize the decoding of genetic information. Previous methods for sequencing DNA are highly complex, work indirectly, and require a large sample of genetic material. In contrast, the TERS technique developed by Deckert directly “reads” the code without chemical agents or detours. It also requires only a single strand of DNA. “DNA sequencing could become very simple,” says Deckert, “like reading a barcode at the supermarket.”

Admin · 265 views · 9 comments
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Jan302008

Turning on adult stem cells may help repair bone
Turning on adult stem cells may help repair bone

The use of a drug to activate stem cells that differentiate into bone appears to cause regeneration of bone tissue and be may be a potential treatment strategy for osteoporosis, according to a report in the February 2008 Journal of Clinical Investigation. The study – led by researchers from Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute (HSCI) – found that treatment with a medication used to treat bone marrow cancer improved bone density in a mouse model of osteoporosis, apparently through its effect on the mesenchymal stem cells (MSCs) that differentiate into several types of tissues.

“Stem cell therapies are often thought of as putting new cells into the body, but this study suggests that medications can turn on existing stem cells that reside in the body’s tissues, acting as regenerative medicines to enhance the body’s own repair mechanisms,” says David Scadden, MD, director of the MGH Center for Regenerative Medicine and HSCI co-director. “Drugs that direct immature cells to become a particular cell type, like in this study, could potentially be very useful.”

The study was designed to examine whether the drug bortezamib (Bzb), which can alleviate bone destruction associated with the cancer multiple myeloma, could also regenerate bone damaged by non-cancerous conditions. In their first experiments, the researchers showed that treating mice with Bzb increased several factors associated with bone formation. Similar results were seen when cultured MSCs were treated with Bzb, but not when the drug was applied to cells that were committed to become particular cell types. Found in the bone marrow, MSCs have the potential to develop into the bone-building osteoblasts and several other types of cells – including cartilage, fat, skin and muscle.

Subsequent experiments supported the hypothesis that Bzb increases osteoblast activity and bone formation by acting on MSCs but not on more differentiated osteoblast precursors. Use of Bzb to treat a mouse model of menopausal osteoporosis produced significant improvements in bone formation and density. Since current treatments for osteoporosis – which target differentiated cells like osteoblasts and the osteoclasts that break down bone – have limitations, the ability to direct differentiation of MSCs could be a promising approach to treating osteoporosis and cancer-associated bone loss, the researchers note.

“If the paradigm displayed in this study holds true for other tissues, we may have options for repairing and regenerating sites affected by injury or disease with medications – that would be pretty exciting.” says Scadden, who is the Gerald and Darlene Jordan Professor of Medicine at Harvard Medical School.

Admin · 160 views · 1 comment
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Jan302008

Stress Response In The Brain Relies On A Blood-thinning Protein
Stress Response In The Brain Relies On A Blood-thinning Protein

A stressed-out mouse tends to be a bit timid, tentative, even fearful. For that matter, so does a stressed-out human. Our ability to learn from frightening situations is part of what helps us avoid them in the future. When that learning process goes awry, it can lead to depression and a decreased ability to recognize dangerous situations. Now, research by Rockefeller scientists has pinned down a protein in the hippocampus — a part of the brain that controls memory, learning and fear — that’s essential for maintaining this stress response.

The protein tPA (tissue plasminogen activator) is best known for its ability to dissolve blood clots. But more and more studies are showing that it also plays a role in neural plasticity in the brain. Sidney Strickland, head of the Laboratory of Neurobiology and Genetics, and postdoc Erin Norris have taken the research a step further to see whether tPA has anything to do with how stress affects memory, learning ability and anxiety.

Prior research from the Strickland lab had shown that mice lacking tPA also seem to lack fear, a behavior largely dictated by a part of the brain called the amygdala. To determine whether tPA also affects behavior controlled by the hippocampus, Norris and Strickland compared normal mice to tPA-deficient ones. Then they divvied the mice up further: Half of each group they left alone, and the rest they exposed to six hours of painless restraint stress. Once the groups were complete, the researchers placed each mouse — wild-type, stressed wild-type, tPA-deficient and stressed tPA-deficient — into a small chamber, where the rodents were exposed to a sound paired with a small electric shock. The next day they returned the mice to the chamber, but this time left them alone.

All of the non-stressed as well as the stressed wild-type mice appeared to have learned from experience, showing their fear of the chamber in the form of freezing behavior. In comparison, the mice lacking tPA had significantly reduced freezing responses. “So they were either less fearful of their situation, or they just didn’t remember — they didn’t learn from their training,” Norris says. “We could say that if you don’t have tPA and you are in a stressful situation, you don’t have synaptic plasticity changes in the hippocampus.” The wild-type mice were capable of learning because tPA could induce changes in their brains’ neural synapses.

Norris and Strickland believe that the underlying mechanism for this has to do with a receptor that normally resides at the cell membrane but changes its location during stress. They found that, in mice lacking tPA, the receptor stayed anchored at the membrane even during stress. And without the receptor’s change in position, there could be no stress response. Norris has since begun investigating whether tPA could also be an important factor in depression, since stress has been shown to lead to this disorder in humans.

Admin · 162 views · 1 comment
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Jan302008

Smile! You've Been Averaged


Smile! You've Been Averaged



smile


If airports used today's face-recognition technology to ID passengers, they would be wrong a lot of the time. But researchers have found a way to improve the technique: By replacing the standard photo on a person's ID with an image generated by combining several shots of the individual, a team from the University of Glasgow in the U.K. dramatically boosted the technique's accuracy.
Even human beings sometimes have difficulty recognizing people from their photographs, especially if the focus is blurry or the lighting poor. But as a face becomes more familiar, the brain improves at matching it to a photo. To explain this phenomenon, psychologists Rob Jenkins and A. Mike Burton came up with a model of how the mind constructs an image of a face from repeat encounters, distilling the essence of its features into a reliable mental representation. The researchers wondered if applying the model to a face-recognition system would improve its performance.

That's exactly what they found when they tested the idea using a system that a few airports are trying out for small-scale recognition tasks, such as identifying airline crew members. The system is also used by a Web site containing a database of celebrity pictures at which visitors can upload personal photos to find out which celebrities they most resemble. To evaluate the baseline performance of the system, the researchers probed it with 20 different pictures of 25 famous men who were represented in the Web site's database. On average, the system correctly identified the celebrity (by returning a photo of the same celebrity from its own database) 54% of the time.

Using a computer program, the researchers then produced an "average" image for each of the 25 celebrities by merging each person's set of 20 pictures, which had been taken over several decades under various light conditions. When they fed the averages into the system, it recognized the faces with 100% accuracy. The researchers then put the technique to a more difficult test: They constructed the average using only those images of a celebrity that the system had failed to recognize during the baseline performance test. This new average image was recognized correctly 80% of the time. The researchers report their results in this week's issue of Science.

How does it work? "Different photos of the same person can look very different depending on the ambient conditions at the time the picture was taken, the facial expression, and a number of other factors," Jenkins explains. "By averaging these pictures, we're essentially blocking out all that extraneous information." The advantage of the technique is that it would be easy to implement; just swap the standard photos on passports and driver's licenses with an average image. That way, when the airport camera snaps a picture of a passenger, a computer will be able to check whether that photo matches the ID more accurately.

Face-recognition experts say the technique is worth exploring but needs to be tried on larger data sets. "This is too small a test set to make the claim that 100% accuracy has now been achieved," says Anil Jain, a computer science professor at Michigan State University in East Lansing.

Admin · 238 views · 3 comments
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Jan292008

Viruses for a healthy pregnancy
Viruses for a healthy pregnancy

Sequences of DNA in the human genome that originated from ancient viral infections have some surprising effects on our bodies and are even essential for a healthy pregnancy, according to an article in the February issue of Microbiology Today.

Retrovirus infections represent the most intimate host-pathogen relationship. The virus inserts a copy of its genome into the DNA of the host cell, resulting in an irreversible, stable and sometimes lifelong infection. If a sperm or egg cell is infected, the virus DNA can be passed down generations, permanently fixed in the germ line. As a result, an endogenous retrovirus (ERV) can exist for millions of years.

“Over the course of evolution, retroviruses have invaded the germ-line of our ancestors on numerous occasions. Now, human ERVs (HERVs) make up around 8% of our genome,” say Dr David Griffiths from the Moredun Research Institute and Cécile Voisset from the Faculté de Médecine et des Sciences de la Santé in France.

Although there are no viruses similar to these ancient pathogens currently infecting humans, there are some related viruses in animals. For a retrovirus to become part of the host genome it is usually inactivated by mutation or silencing so it does not express any proteins. An epidemic of neoplastic disease in Australian koalas is giving researchers the rare opportunity to study this process.

“Recent work has provided some tantalizing evidence supporting the roles of HERVs in normal physiology and also in disease,” says Dr Griffiths, “they can be seen as bona fide human genes.” Some HERVs may be crucial for a healthy pregnancy, whereas others have been linked to diseases like MS and cancer.

“It is only recently that the abundance of HERVs has been recognised and we are learning that they can have significant functions,” says Dr Griffiths.

Admin · 153 views · 1 comment
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Jan292008

Microbes as climate engineers
Microbes as climate engineers

We might think we control the climate but unless we harness the powers of our microbial co-habitants on this planet we might be fighting a losing battle, according to an article in the February 2008 issue of Microbiology Today.

Humans are continually altering the atmosphere. “Arrogant organisms that we are, it is easy to view this as something entirely novel in Earth’s history,” says Dr Dave Reay from the University of Edinburgh. “In truth of course, micro-organisms have been at it for billions of years.”

Humans affect the atmosphere indirectly by their activities. Most human-induced methane comes from livestock, rice fields and landfill: in all of these places, microbes are actually responsible for producing the methane, 150 million tonnes a year. Microbes in wetlands produce an additional 100 million tonnes and those that live inside termites release 20 million tonnes of methane annually.

90 billion tonnes of carbon a year is absorbed from the atmosphere by the oceans, and almost as much is released; microbes play a key role in both. On land, a combination of primary production, respiration and microbial decomposition leads to the uptake of 120 billion tonnes of carbon every year and the release of 119 billion tonnes.

“The impact of these microbially-controlled cycles on future climate warming is potentially huge,” says Dr Reay. By better understanding these processes we could take more carbon out of the atmosphere using microbes on land and in the sea. Methane-eating bacteria can be used to catch methane that is released from landfill, Cyanobacteria could provide hydrogen fuel, and plankton have already become a feedstock for some biofuels.

“Microbes will continue as climate engineers long after humans have burned that final barrel of oil. Whether they help us to avoid dangerous climate change in the 21st century or push us even faster towards it depends on just how well we understand them.”

Admin · 125 views · 1 comment
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Jan292008

Search for the 'on' switches may reveal genetic role in development and disease
Search for the 'on' switches may reveal genetic role in development and disease

DURHAM, N.C. -- A new resource that identifies regions of the human genome that regulate gene expression may help scientists learn about and develop treatments for a number of human diseases, according to researchers at Duke’s Institute for Genome Sciences & Policy (IGSP).

“The majority of DNA in our bodies is packaged, or tightly structured,” said Gregory Crawford, Ph.D., a researcher in the IGSP and one of the senior investigators on this study. “Our goal was to identify the areas of DNA across the entire genome that are not packaged, because we know those are the regions that are important in regulating gene activity.”

The researchers published their findings in the January 25, 2008 issue of the journal Cell. The study was funded by the Duke IGSP and the National Human Genome Research Institute.

They combined two known processes to look at regulatory regions across the whole human genome, Crawford said.

“We used an enzyme called DNase that has been known for decades to preferentially identify unpackaged regions of DNA,” he said. “In this study, we identified all unpackaged regions within the entire genome using two extremely efficient methodologies: microarrays and sequencing.”

Microarrays are glass slides on which scientists can simultaneously look at millions of short pieces of DNA. New sequencing technologies are able to determine the genetic code of millions of DNA fragments. Together, these tools generated guides to understanding the location of the unpackaged regions, and the researchers compared the results found using each method and found high levels of agreement.

By combining the two methods, the researchers were able to scan the entire genome efficiently.

“Scientists have used similar methods to look at tiny portions of the genome in the past, but ours is the first technology to really allow researchers to look at the whole genome, so we can see all of the areas where gene regulation occurs,” said Terrence Furey, Ph.D., a researcher in the IGSP and co-senior investigator on this study. “Identifying these sites may help us understand the biological basis for gene regulation expression patterns in different cell types. We'll also compare patterns within and across species, in response to external stimuli and in diseased tissues.”

The researchers said they looked at normal cells for this study because in order to understand anything about disease or the aging processes, it's important to first understand what a normal cell looks like.

“Perhaps in the future, this data resource could help researchers learn to turn a harmful gene off or increase the expression of helpful ones,” Furey said.

Admin · 97 views · 1 comment
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Jan292008

Evolutionary battle scars' identify enhanced antiviral activity
Evolutionary battle scars' identify enhanced antiviral activity

Rapid evolution of a protein produced by an immunity gene is associated with increased antiviral activity in humans, a finding that suggests evolutionary biology and virology together can accelerate the discovery of viral-defense mechanisms, according to researchers at Fred Hutchinson Cancer Research Center in Seattle, Washington.

These findings, published January 25 in the open-access journal PLoS Genetics, present a striking example by which evolutionary studies can directly lead to biomedically important discoveries in the field of infectious diseases.

The immunity gene, called ZAP, is a key player in a newly discovered branch of antiviral defenses in mammals referred to as “intrinsic immunity.” Host proteins like ZAP can target intracellular stages of the viral life cycle to inhibit viral activity. The ZAP gene, first discovered in rats, thwarts a variety of divergent viruses, from retroviruses (like HIV) to alphaviruses (like Sindbis) to filoviruses (like Ebola).

Researchers believe ZAP functions by virtue of its RNA-binding abilities, which recognize specific sequences of the virus and target their viral RNA for destruction. Host-virus interactions are a classic example of genetic conflict in which both entities try to gain an evolutionary advantage over the other. This “back-and-forth” evolution is predicted to result in rapid changes of both host and viral proteins, which results in an evolutionary signature of positive selection, especially at the direct interaction interface.

“This suggests that we might be able to deduce host-virus conflicts purely by looking at rapidly evolving protein segments,” said Dr. Julie Kerns, postdoctoral researcher and the lead author of the study, which was conducted in collaboration with Drs. Harmit Singh Malik and Michael Emerman, respectively from the Basic Sciences and Human Biology Divisions of the Center.

The researchers found that there has been very little sequence evolution in the RNA-binding domain, which suggests that human ZAP may be similar to the rat gene in its viral RNA-binding specificity. However, surprisingly, the rapid evolution characteristic of “intrinsic immunity” genes was concentrated in a protein domain that was not even present in the originally discovered rat gene.

The authors found that humans encode two protein versions, or isoforms, from a single ZAP gene: a shorter version similar to the original rat gene and a longer version that possesses a rapidly evolving poly (ADP-ribose) polymerase (PARP)-like domain. In virological assays, the longer human ZAP protein isoform has higher antiviral activity. Thus, positive selection correctly predicted the more potent antiviral isoform of this protein.

The authors further suggest that ZAP is locked in a conflict with alphaviruses. The discovery of a potential human gene that can restrict alphaviral infection is particularly timely as the mosquito-borne alphavirus, Chikungunya, was responsible for a large epidemic in parts of Southeast Asia in 2006 and is now threatening to invade parts of Europe. The researchers believe this finding has important implications for the understanding of intrinsic immunity against viruses, and could potentially serve as a guide in the development of antiviral therapeutics.

“We think that a particular alphaviral protein may be playing an evolutionary ‘cat-and-mouse’ game with the ZAP gene,” Malik said. “Identifying this protein could lead to novel ways to tackle diseases caused by alphaviruses.”

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Jan292008

Evolution of human genome's 'guardian' gives people unique protections from DNA damage
Evolution of human genome's 'guardian' gives people unique protections from DNA damage

Study underscores need for careful analysis of human disease studies in mouse models
CINCINNATI – Human evolution has created enhancements in key genes connected to the p53 regulatory network – the so-called guardian of the genome – by creating additional safeguards in human genes to boost the network’s ability to guard against DNA damage that could cause cancer or a variety of genetic diseases, an international team of scientists led by Cincinnati Children’s Hospital Medical Center writes in the Jan. 22 Proceedings of the National Academy of Sciences. Because genetically engineered mouse models are increasingly powerful tools in understanding the risks and mechanisms of human diseases – and rodents do not have the same evolution-based safeguards in p53 function as humans – the study also underscores the need for additional considerations in the interpretation of research using rodent models.

“Our findings are especially important because rodents are often used as model organisms to investigate the genetic origins of diseases that affect humans, such as cancer investigators evaluating the impact of DNA-damaging agents,” said Anil Jegga, DVM, a researcher in the Division of Biomedical Informatics at Cincinnati Children’s. “Rodent models remain important to our understanding of disease processes, although our study suggests the need to address experimentally the differences in p53 regulatory pathways between humans and rodent models.”

In the study, Jegga and his colleagues used comparative functional genomics to look systematically at small DNA sequences associated with the promoters, or enhancers, of specific genes that carry out orders from p53. These promoter elements act like antennae – responding to activated p53 by boosting target gene expression and function inside a cell’s nucleus. By comparing these response elements across nearly 50 different binding sites of genes in the p53 network, and looking specifically at genes that repair DNA damage in 14 species (from zebra fish to humans), researchers were able to reveal critical evolutionary changes in their function. The 14 species represented an estimated 500 million years of evolutionary separation, helping investigators determine how the function of p53 response elements was conserved or changed as different species developed. Dr. Jegga said researchers were surprised to find the acquisition of functional response for certain genes involved in DNA metabolism or repair to be mostly unique in humans. While the functional ability of some genes is shared with chimpanzees and rhesus monkeys, researchers said DNA metabolism and repair function it is not shared at all with rodents.

In humans, when DNA damage is detected, the p53 network seems to have gained additional capabilities that allow it to slow cell growth, initiate repairs or, if needed, apoptotic cell death. Apoptotic, or programmed cell death capability in the p53 network, is thought to be evolutionarily conserved throughout the development of vertebrate species and was probably established after the divergence of vertebrates and non-vertebrates. DNA metabolism and repair capabilities controlled by p53 may have emerged more recently in evolutionary history to create primate-specific response characteristics, the researchers explained.

“The fact that DNA metabolism and repair genes have undergone this kind of evolution in humans may reflect an increased need for coordinated control of molecular repair activities during DNA replication to allow for the maintenance of genomic integrity during complex differentiation, growth, and aging,” said Bruce Aronow, Ph.D., co-director of Computational Medicine at Cincinnati Children’s and a study co-author.

“That different strategies to guard our chromosome structures and DNA sequences against damage are subject to evolutionary adaptation is also suggested by other knowledge we have,” Dr. Aronow explained. “For example, compared to rodents humans have much shorter telomeres, which are regions of highly repetitive DNA at the end of chromosomes that help shield against damage. Shorter telomeres can make people more susceptible to chromosomal damage and increase our risk of developing malignant tumors. When genes replicate, the process does not copy the very ends of the gene, so telomeres act like caps on the ends of shoelaces, helping preserve DNA structure and preventing genetic unraveling and loss of genetic information.”

A clue to p53 functional differences may be found in sunlight. Exposure to the ultra-violet rays in sunlight activates the DNA-damage responses of the repair gene (Ddb2) in humans, but the same gene does not function in rodents. Some studies have suggested that rodents may have a reduced need for genetic protection from sunlight because they are nocturnal and have a fur shield.

“Although the full implications of these evolutionary points remain far from clear, our work demonstrates that there has been both refinement and evolution of gene networks controlled by p53,” Dr. Aronow said. “Exciting work is underway by research groups within the National Cancer Institute’s Mouse Models of Human Cancer Consortium to develop mice that are genetically engineered to test the combined effects of altering p53 and telomerase, the enzyme that controls the length and stability of repeating DNA sequences in the telomere region. Mouse models will continue to become progressively more powerful tools for studying human cancer and additional information about the p53 network will help us refine our interpretation of pre-clinical research that may lead to improved cancer prevention for at-risk and normal individuals.”

In conducting their analysis of p53 target genes, the international research team used comparative DNA sequence analysis and functional tests of highly engineered yeast and mouse cell culture assays to examine 47 established p53 response elements in 14 vertebrate and non-vertebrate species. The study included researchers from the National Institute for Cancer Research (Molecular Mutagenesis Unit, Department of Translational Oncology) in Genoa, Italy, and the Laboratory of Molecular Genetics Chromosome Stability Group of the National Institute of Environmental Health Sciences (National Institutes of Health).

“The findings reveal a new piece of the p53 puzzle and help us to understand how genes became part of the network,” suggests In the study, Michael A. Resnick, Ph.D., who initiated the study and is Head of the Chromosome Biology Group at NIEHS. Resnick and his team have been characterizing the functions of p53, a well-known suppressor of tumors They have created systems in mouse, human and yeast cells that address contributions of normal and tumor mutant p53 in regulation of genes, as well as the responsiveness of various kinds of promoter elements. The functional models, concepts and rules developed in Resnick's lab, previously described in the Proceedings in terms of a hand playing a piano, provided a conceptual base for launching the study and provide building blocks being used by scientists as they try to determine the diversity between humans in their potential responses to environmental stressors. The functional studies of various p53’s with common and unusual promoter elements have relied upon the novel systems developed in mammalian cells by Daniel Menendez, Ph.D., a Research Fellow at NIEHS, and in yeast by Alberto Inga, Ph.D., a former NIEHS Research Fellow, now with his own lab at the National Institute for Cancer Research in Italy that formed the basis for much of the study.

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Jan292008

In silico modeling helps predict severity of mitochondrial disease
In silico modeling helps predict severity of mitochondrial disease

A team of researchers in Australia, the United Kingdom and the United States has revealed how mitochondrial diseases are passed from the mother to the next generation in a mouse model system. The study, which was published on-line in Nature Genetics*, shows for the first time how mitochondrial diseases that cause muscle weakness, diabetes, stroke, heart failure and epilepsy are passed from mother to offspring.

Mitochondria are the “engines” present in each cell that produce adenosine triphosphate (ATP), the key energy currency that drives metabolism. Mitochondria also have their own DNA (mitochondrial or mtDNA) that encodes a small but essential number of proteins required for energy production in cells. Mitochondria, and the mtDNA that they contain, are inherited solely from the mother, as the paternal mtDNA present in the sperm are destroyed after the egg is fertilized. In almost all diseases caused by mutant mtDNA, the patient’s cells will contain a mixture of mutant and normal mtDNA. The proportion of mutant mtDNA in most cases determines the severity of the disease.

The inheritance of these diseases does not follow the rules of Mendelian genetics. Instead, there are large random shifts at the mtDNA mutation level between mother and offspring. This study explains how these large random shifts occur within the first three weeks of embryo formation, through the combined use of computational modeling and a mouse model system.

Dr. David Samuels, assistant professor at the Virginia Bioinformatics Institute (VBI), commented: “The computational model used in this investigation simulates the biological process directly and allows scientists to examine the early stages of embryo formation and development. Clinicians can therefore take a close look at the replication of mitochondrial DNA and the dynamics of cell division in mouse embryos before and after implantation in the uterus.” He added: “Computational modeling and cutting-edge lab work were both essential for this study. The experiments gave us new information that we had to have to build the simulation, and the simulation was used as a tool to analyze the data from the experiment.”

Dr. Patrick Chinnery, Wellcome Senior Fellow in Clinical Science and professor of neurogenetics at the University of Newcastle in the United Kingdom, remarked: “Mitochondrial disease can have devastating effects on a family, and the chance of having affected children is a cause of major stress. By defining the main biological mechanism, we hope in the long term to develop counseling guidelines that will help patients and their families make more informed decisions.”

The computational model reveals how mtDNA is divided into different embryonic cells before and after implantation and how the replicating mtDNA molecules are subsequently separated between the dividing germ cells that make up the embryo. The model accounts for the marked reduction in the number of mtDNA molecules that are transmitted from mother to offspring, the so-called “mitochondrial genetic bottleneck.” It is thought that this genetic bottleneck has evolved over time to remove deleterious mitochondrial mutations from the population. These mutations are either lost during transmission or, if transferred, give rise to offspring with a low chance of survival.

Although the current study investigates the transmission of mitochondrial DNA in mice, the computational model is also applicable to human data. Mitochondrial diseases are thought to affect as many as one person in 5000. The research offers the hope that clinicians will be able to predict a child’s risk of developing maternally inherited mitochondrial diseases that cause muscle weakness, diabetes, stroke, heart failure and epilepsy.

Admin · 108 views · 1 comment
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