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18 Things You Should Know About Genetics

This is an animated film that presents fundamental background information about genetics, as well as offering some quirky but interesting facts about DNA, genes and genetics. It was created to be an upbeat, fun educational short film to initiate and draw interest to this sometimes daunting and seemingly complex subject matter.

The Origin of Genes

Disorders resulting from mutation in Mitochondrial DNA (mtDNA)



mtDNA Mutation


Cancer:

        Mitochondrial DNA is prone to somatic mutations, which are a type of non-inherited mutation. Somatic mutations occur in the DNA of certain cells during a person's lifetime and typically are not passed to future generations. There is limited evidence linking somatic mutations in mtDNA with certain cancer types, including breast, colon, stomach, liver and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).

       It is possible that somatic mutations in mtDNA increase the production of potentially harmful molecules called reactive oxygen species. MtDNA is particularly vulnerable to the effect of these molecules and has a limited ability to repair itself. As a result, reactive oxygen species easily damages mtDNA, causing a buildup of additional somatic mutations. Researchers are investigating how these mutations could be related to uncontrolled cell division and growth of cancerous tumours.

Cyclic Vomiting Syndrome:

Cyclic vomiting syndrome may be related to genetic changes in mitochondrial DNA. Some of these changes alter single DNA building blocks (nucleotides), whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Defects in energy production may lead to symptoms during periods when the body requires more energy, such as when the immune system is fighting an infection. However, it remains unclear how changes in mitochondrial function are related to recurrent episodes of nausea and vomiting

Kearns-Sayre syndrome:
Most people with Kearns-Sayre syndrome have a single, large deletion of mitochondrial DNA. The deletions range from 1,000 to 10,000 nucleotides, and the most common deletion is 4,997 nucleotides. Kearns-Sayre syndrome primarily affects the eyes, causing weakness of the eye muscles (ophthalmoplegia) and breakdown of the light-sensing tissue at the back of the eye (retinopathy). The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation, causing a decrease in cellular energy production. Researchers have not determined how these deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy.

Leigh syndrome Mutations in one of several different mitochondrial genes can cause Leigh syndrome, which is a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.
Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation. For example, the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6, provides instructions for a protein that makes up one part of complex V, an important enzyme in oxidative phosphorylation that generates the majority of the cell's energy (ATP) in the mitochondria. The other genes provide instructions for making transfer RNA molecules, which are essential for protein production within mitochondria. Many of these proteins play an important role in oxidative phosphorylation. The mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation. Although the mechanism is unclear, it is thought that impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome.

More on mtDNA Mutation Disorders: http://ghr.nlm.nih.gov/chromosome/MT

Vamsi Mootha - Bio-Data Cruncher

While surfing the internet not long ago, a Harvard biologist stumbled upon a pile of research data including unpublished leftovers from an unresolved genetic study. It wasn't unusual: Data like that can be found all over the web.

33 Year-old Indian-American professor Vamsi Mootha using a unique computational method, mined the data and indentified a gene underlying a rare but fatal pediatric disorder called "Leigh Syndrome, French-Canadian" variant or LSFC. Astonishingly, he did it in a single weekend.

For the diabetes study, Mootha applied computational approaches similar to those used on the pediatric study to both found reaserch and data his team generated independently. As a result, he located a set of three genes that revs up the energy-producing ability of muscle cells and might lessen diabetes' harmful effects. Again, the finding was notable not only because of its potential consequence, but also because Mootha has found a way to sort the hay in the genetic haystack to discover the proverbial needle.

Each human cell contains all of the body's approximately 23,000 genes. But not every gene in every cell is active; some are silent. It's the repertoire of active genes that makes a muscle cell different than a liver cell or skin cell. In a diseased cell, the program is altered. The correct genes are activated too much or not enough.

A relatively new technology, called microarrays, enables interrogation of every gene to determine how active it is. Rather than just look at a slice of diseased cell tissue under a microscope, scientists can see how many of the 23,000 genes are switched on or off and to what degree. Multiply all that data by all the patients in research studies such as Mootha encountered, and the result is an intimidating mass of numbers to crunch and assess.

"Vamsi got a hold of the data from the internet, but he said you can't compare gene by gene. You'd be doing so many comparisons, you aren't going to find anything statistically significant," said Alan Attie, a University of Wisconsin biochemistry professor.

"Vamsi re-curated the list of genes, making about 120 categories by functional group," such as genes that make fat or carbohydrates, or control respiration, etc., Attie said. "It turned out that the mitochondrial respiration group showed a big difference. But looking at the individual gene level, there would have been only modest differences."

Mootha and collaborators had found that the master regulator of gene expression for genes in the mitochondria were different between diabetics and non-diabetics. Though Mootha, whose undergraduate degree is in mathematics, calls his approach "relatively simple computation," National Institutes of Health research physiologist Robert Balaban disagrees.

"Vamsi is not attempting to reduce the problem to its simplest elements, but to accept the complexity of biology and develop the tools we will use over the next several decades to unravel the interactions that naturally occur," he said.

One of those tools is a software program that a graduate student is developing, based on Mootha's algorithms, which other scientific researchers can use to profile diseases.

Mootha's diabetes discovery was significant for both the disease and other researchers trying to mine masses of data, but his passion is investigating mitochondrial mutations linked to rarer diseases such as LSFC (.pdf).

That's how he envisions employing his windfall. "$500,000 is really not enough money to fund a large, modern genomics lab, but it might be enough to jump-start a research program focused on developing therapies for rare mitochondrial disorders," Mootha said.

"Big pharma will not develop drugs to combat these disorders anytime soon since the market is so small, so the onus is on private institutions and academic labs to develop new therapeutics."

Source: http://www.wired.com/medtech/health/news/2004/10/65474

Harvard Medical School, Broad Institute team works to better understand Mitochondria

Why do nearly 1 million people taking cholesterol-lowering statins often experience muscle cramps? Why is it that in the rare case when a diabetic takes medication for intestinal worms, his glucose levels improve? Is there any scientific basis for the purported health effects of green tea?

A new chemical tool kit provides the first clinical explanation for these and other physiological mysteries. The answers, it turns out, all boil down to mitochondria, those tiny organelles floating around in cellular cytoplasm, often described as the cell’s battery packs.

A research team led by Harvard Medical School (HMS) assistant professor and Broad Institute associate member Vamsi Mootha has developed a tool kit that isolates five primary aspects of mitochondrial function and analyzes how individual drugs affect each of these areas. These results were published online Feb. 24 in Nature Biotechnology.

Over the past few decades, mitochondria have increasingly been understood as a key determinant of cellular health. On the other hand, mitochondrial dysfunction can lead to many neurodegenerative conditions as well as metabolic diseases such as diabetes. Because mitochondria are responsible for turning the food we eat into the energy that drives our bodies, these and other connections are logical. Nevertheless, there has not yet been a systematic method for thoroughly interrogating all facets of mitochondrial activity.

“Historically, most studies on mitochondria were done by isolating them from their normal environment,” says Mootha, who is also a member of the Center for Human Genetic Research at Massachusetts General Hospital. “We wanted to analyze mitochondria in the context of intact cells, which would then give us a picture of how mitochondria relate to their natural surroundings. To do this we created a screening compendium that could then be mined with computation.”

In order to thoroughly analyze these organelles, Mootha and his team zeroed in on five basic features of mitochondria activity, looking at how a library of 2,500 chemical compounds affected mitochondrial toxic byproducts (like all “chemical factories” mitochondria produce their own toxic waste), energy levels, speed with which substances pass through these organelles, membrane voltage, and expression of key mitochondrial and nuclear genes. (Mitochondria contain their own genome, consisting of approximately 37 genes in humans.)

“It’s just like taking your car in for an engine diagnostic,” explains Mootha. “The mechanic will probe the battery, the exhaust system, the fan belt, etc., and as a result will then produce a read-out for the entire system. That’s analogous to what we’ve done.”

As a result of these investigations, Mootha and his group produced three major findings.

First, the team discovered a pathway by which the mitochondria and the cell’s nuclear genome communicate with each other. They found this by discovering that certain drugs actually break communication between these two genomes. By reverse engineering the drugs’ toxic effects, they may be able to reconstruct normal function.

Second, the team looked at a class of the cholesterol-lowering drugs called statins. Roughly 100 million Americans take statins, and among that group, about 1 million experience muscle cramping and aches. Previous studies suggested that mitochondria were involved, but clinical evidence remained conflicting. Mootha and his colleagues found that three out of the six statins (Fluvastatin, Lovastatin, and Simvastatin) interfered with mitochondria energy levels, as did the blood-pressure drug Propranolol. When combined, the effect was worse.

“It’s likely that a fair number of patients with heart disease are on one of these three statins as well as Propranolol,” says Mootha, “Our cellular studies predict that these patients might be at a higher risk for developing the muscle cramps. Obviously, this is only a hypothesis, but now this is easily testable.”

The third and arguably most clinically relevant finding builds on a paper Mootha co-authored in 2003, a paper that demonstrated how type 2 diabetes was linked to a decrease in the expression of mitochondrial genes. A subsequent and unrelated paper showed a relationship between type 2 diabetes and an increase in mitochondrial toxic byproducts. Mootha’s group decided to query their tool kit to see if there were any drugs that affected both of these functions, drugs that could boost gene expression while reducing mitochondrial waste.

Indeed, they found six compounds that did just that, five of which were known to perturb the cell’s cytoskeleton, that is, the scaffolding that gives a cell its structure.

“Our data shows that when we disrupt the cytoskeleton of the cell, that sends a message to boost the mitochondria, turning on gene expression and dropping the toxic byproducts,” says Mootha. “The connection between the cytoskeleton and mitochondrial gene expression has never been shown before and could be very important to basic cell biology.”

Of the five drugs that did this, one, called Deoxysappanone, is found in green tea and is known to have anti-diabetic effects. Another, called Mebendazole, is used for treating intestinal worm infections. This connection gives a rationale to case reports in which diabetics treated with Mebendazole have described improvements in their glucose levels while on the drug.

The researchers intend to further investigate some of the basic biological questions that this study has raised, foremost being the relationship between the cytoskeleton and mitochondria. They also plan on using this tool kit to develop strategies for restoring normal mitochondrial function in certain metabolic and neurodegenerative conditions where it has broken down.

This research was funded by grants from the American Diabetes Association and the Richard and Susan Smith Family Foundation.

Source: http://news.harvard.edu/gazette/story/2008/02/hms-broad-institute-team-works-to-better-understand-mitochondria/

Mitochondrial DNA (mtDNA)

Human Mitochondrial DNA:

What is mtDNA all about?

Mitochondiral DNA (mtDNA) is located in cell organelles called Mitochondira, structures within Eukaryotic cells that convert the chemical energy from food into a form that cells can use, ATP. Most other DNA present in Eukaryotic organisms is found in the cell nucleus. mtDNA can be regarded as the smallest chromosome, and was the first significant part of Human Genome to be sequenced. In most species, including humans, mtDNA is inherited solely from the mother. The DNA sequence of mtDNA has been determined from a large number of organisms and individual (including some organisms that are extinct), and the comparison of those DNA Sequences represents a mainstay in Phylogenetics, in that it allows biologist to elucidate the evolutionary relationships among species. It also permits an examination of the relatedness of populations, and so has become important in Anthropology and Field Biology.

Mitochondrial Inheritance
In most multicellular organisms, mtDNA is inherited from mother (maternally inherited). Mechanisms for this includes simple dilution (an egg contains 100,000 to 1,000,000 mtDNA molecules, whereas a sperm contains only 100 to 1000), degradation of sperm mtDNA in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental) pattern of mtDNA inheritance is found in most animals, most plants and in fungi as well.

Female Inheritance
 In sexual reproduction, mitochondria are normally inherited exclusively from the mother. The mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, the most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells. Sometomes the tail is lost during fertilization.

In 1999 it was reported that parental sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo. Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling. Ubiquitin can be attached to protein and label them for destruction. The ubiquitin tag directs protein to proteasome, which is a large protein complex in the cell that degrades and recycles unneeded proteins. This discovery won the Nobel Prize for Chemistry in 2004. Ubiquitin Tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms. Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins.

Peter Sutovsky Et. el [1], published a Nature Journal "Development: Ubiquitin Tag for Sperm Mitochondria" (25 November 1999). Like other mammals, humans inherit mitochondria from mother only, even though the sperm contributes nearly one hundred mitochondria to the fertilized egg. In support of the idea that this strictly maternal inheritance of mtDNA arises from selective destruction of sperm mtDNA. The journal shows the sperm mtDNA inside fertilized Cow and Monkey eggs are tagged by the recycling marker protein ubiquitin. This imprint is a death sentence that is written during spermatogenesis and executed after the sperm mitochondria encounter the egg's cytoplasmic destruction machinery.

The fact that mtDNA is maternally inherited enables researchers to trace maternal lineage far back in time (Y-Chromosome DNA, paternally inherited, is used in an analogous way to trace the Antage Lineage). This is accomplished in humans by sequencing one or more of the Hypervariable Control Regions (HVR1 or HVR2) of the mtDNA, as with a genealogical DNA Test. HVR1 consists of about 440 base pairs. These 440 base pairs are then compared to the control regions of the other individual to determine maternal lineage.
Because mtDNA is not highly conserved and has a rapid mutation rate, it is useful for studying the evolutionary relationships - phylogeny - of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined. Since mtDNA is transmitted from mother to child (both male and female), it can be useful tool in geneological research into a person's maternal line.



References:
[1] Peter Sutovsky, Ricardo D. Moreno, João Ramalho-Santos, Tanja Dominko, Calvin Simerly & Gerald Schatten. "Development: Ubiquitin Tag for Sperm Mitochondria". Link: http://www.nature.com/nature/journal/v402/n6760/full/402371a0.html

Significance of Mitochondria

Mitochondria are rod-shaped organelles that can be considered the power generators of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy "currency" of the cell that powers the cell's metabolic activities. This process is called aerobic respiration and is the reason animals breathe oxygen. Without mitochondria (singular, mitochondrion), higher animals would likely not exist because their cells would only be able to obtain energy from anaerobic respiration (in the absence of oxygen), a process much less efficient than aerobic respiration. In fact, mitochondria enable cells to produce 15 times more ATP than they could otherwise, and complex animals, like humans, need large amounts of energy in order to survive.

Mitochondria, often referred to as the powerhouse of the cell. These organelles are found in virtually all of our body’s cells and are responsible for generating the bulk of cellular ATP.  In addition, the organelle plays a central role in apoptosis, ion homeostasis, intermediary metabolism, and biosynthesis.  Studies during the past 25 years have demonstrated a clear role of the mitochondrion in rare, inborn errors of metabolism.  More recent studies have implicated mitochondrial dysfunction in a variety of common human diseases, such as diabetes, neurodegeneration, and the aging process itself.

Dr. Vamsi Mootha in Mootha Labs

Contrary to popular belief, the mitochondrion is incredibly dynamic.  Its protein composition and functional properties vary across cell types, remodel during development, and respond to external stimuli.  Mitochondria contain their own genome (referred to as mtDNA) which encode a mere 13 proteins.  All the other estimated 1000+ proteins are encoded in the nuclear genome and imported into this cellular compartment.

Mootha's Laboratory uses new tools of genomics in combination with biochemical physiology to systematically explore mitochondrial function in health and in disease.  They focus on rare, monogenic syndromes as well as common diseases.  The long-term goal of the lab is to develop predictive models of mitochondrial physiology that can aid in the diagnosis and treatment of a broad range of human diseases. Hats off to Dr. Vamsi Mootha.

Read more about Mitochondria in "Molecular Expressions - Cell Biology and Mircoscopy Structure and Function of Cells and Viruses"
Follow the link: http://micro.magnet.fsu.edu/cells/mitochondria/mitochondria.html

Probing Mitochondrial Physiology - Forefront of a new Science

Vamsi Mootha is an associate member of the Broad Institute. He is developing experimental and computational strategies to integrate genomic, proteomic, and physiological data to accelerate human disease gene discovery. He has applied these strategies to the successful identification of genes underlying rare, inherited metabolic syndromes, and more recently, has been extending these efforts to more common diseases, such as type 2 diabetes. He utilizes a multidisciplinary approach that includes mathematics, computer science, biochemistry, and genetics.

Vamsi's research program is primarily focused on the mitochondrion, the "powerhouse of the cell," and its role in human diseases. Work previously published by Vamsi and colleagues at the Broad demonstrated that mitochondria are less active in the muscles of diabetics and those at risk for developing diabetes. Recently, Vamsi and colleagues identified three genes that form a regulatory circuit in controlling the activity of mitochondria in a given cell. This gene circuit is a promising drug target for type 2 diabetes.

A 2004 recipient of the Macarthur genius award, Vamsi is associate professor of systems biology at Harvard Medical School and associate professor of medicine in the Center for Human Genetics at Massachusetts General Hospital.

Vamsi received his undergraduate degrees in mathematical and computational science at Stanford University, where he graduated Phi Beta Kappa with highest honors. He received his M.D. in 1998 at Harvard Medical School in the Harvard-MIT Division of Health Sciences and Technology, where his thesis work was focused on mitochondrial physiology. He subsequently completed his internship and residency in internal medicine at Brigham and Women's Hospital in 2001, after which he completed postdoctoral fellowship training at the Whitehead Institute/MIT Center for Genome Research.

ABCC9 Gene - Sleep Control

Scientists have identified the gene responsible for controlling the length of time for which an individual sleeps and why some have their own internal alarm clock.

Karla Allebrandt and her team from the Ludwig Maximilians University of Munich identified a gene called ABCC9 that can reduce the length of time we sleep.

The discovery is expected to explain why light sleepers, such as Margaret Thatcher, are able to get by on just four hours shut-eye a night.

The Europe-wide study of 4,000 people from seven different EU countries saw the volunteers fill out a questionnaire assessing their sleep habits. The researchers then analysed their answers, as well as participants’ genes. They discovered that people who had two copies of one common variant of ABCC9 slept for “significantly shorter” periods than people with two copies of another version.

Having already established that the ABCC9 gene was also present in fruitflies, the team were able to modify it in the animal and shorten the length of time for which it slept.

“Apparently the relationships of sleep duration with other conditions such as heart disease and diabetes can be in part explained by an underlying common molecular mechanism,” the Daily Mail quoted Allebrandt as saying.

“The ABCC9 gene is evolutionarily ancient, as a similar gene is present in fruitflies. Fruitflies also exhibit sleep-like behaviour.

“When we blocked the function of the ABCC9 homolog in the fly nervous system, the duration of nocturnal sleep was shortened,” she added.