Dr. Anthony Komaroff/Universal Uclick

In last week's column, a reader asked whether she should be tested for genes linked to Alzheimer's disease. Today, I thought I'd give you my view on the larger question: Will studies of our genes change the practice of medicine and improve our lives?

My answer: During my career, progress in human genetics has been greater than virtually anyone imagined. However, human genetics also has turned out to be much more complicated than people imagined. As a result, we have not moved as rapidly as we had hoped in changing medical practice.

I graduated from medical school in the late 1960s. We knew what human genes were made of -- DNA -- and we were beginning to understand how genes work. We had even identified a handful of genes that were linked to specific diseases. We assumed that disease resulted from an abnormality in the structure of a gene.

If I had asked any biologist on the day I graduated, Will we ever know how many genes we have, and the exact structure of each gene? I'll bet the answer would have been: Not in my lifetime, or my children's lifetime.

They would have been wrong. Today we do know those answers. Indeed, some diseases are caused by an abnormality in the structure of genes. In fact, sometimes it is very simple: one particular change at one particular spot in just one particular gene leads to a specific disease. Sickle cell anemia is an example.

Unfortunately, with most diseases it's far from that simple. The first complexity: Most diseases are influenced by the structure of multiple genes, not just one. Examples are diabetes and high blood pressure.

The second complexity: Many diseases are explained not by an abnormal gene structure, but by whether genes are properly turned on or off. Most cancers fall into this category.

What do I mean by that? Every cell in our body has the same set of genes. Yet, a cell in our eye that sees light is different from a cell in our stomach that makes acid. Why? Because different genes are turned on in each type of cell.

Similarly, if a gene with a normal structure is not properly turned on or off, a cell can malfunction -- it can become diseased. Whether a gene is turned on properly is proving to be a more important cause of disease than we once imagined.

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ASK DOCTOR K: Progress in genetics will lead to better diagnosis

Details Published on Tuesday, 25 February 2014 16:53

Hardened plaque discovered on the teeth of 1,000 year old human skeletons has revealed not only their diets but the diseases they faced.HARDENED plaque discovered on the teeth of 1,000-year-old human skeletons has revealed the world's oldest case of gum disease.

Described as a 'microbial Pompeii', the plaque preserved bacteria and microscopic particles of food on the surfaces of teeth, effectively creating a mineral tomb for microbiomes.

And it revealed that our ancestors had gum disease that was caused by the same bacteria that plagues modern man, despite major changes in diet and hygiene.

They found that the ancient human oral microbiome already contained the basic genetic machinery for antibiotic resistance over eight centuries before the invention of antibiotics in the 1940s.

DNA testing of the tartar also showed some of the things ancient humans had been eating, such a vegetables, which do not show up in fossil records.

Gum disease is caused by a build-up of plaque on the teeth and is thought to affect over half of adults in the UK.

The teeth were taken from skeletons found at a site in Dalheim, Germany.Plaque is a sticky substance that contains bacteria and when it hardens it forms tartar.

Unlike bone, which rapidly loses much of its molecular information when buried, calculus grows slowly in the mouth and enters the soil in a much more stable state, helping it to preserve biomolecules.

Researchers from the University of York, along with Swiss and Danish colleagues, said studying plaque will be more important than teeth in discovering the lifestyles of our past ancestors.

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Plaque On 1000-Year-Old Human Teeth Could Unlock Secrets Of Medieval Diet And Disease

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Newswise Philadelphia, Feb. 20, 2014 A large international study analyzing genes in tens of thousands of individuals has discovered 11 new genetic signals associated with blood pressure levels. Ten of those signals are in or very near genes encoding proteins that appear to be likely targets for drugs already in existence or in development.

The fact that most of these new gene signals are druggable targets offers the possibility of expedited pharmaceutical development of therapeutics for high blood pressure, a serious risk factor for cardiovascular diseases, said geneticist Brendan J. Keating, D. Phil., of The Center for Applied Genomics at The Childrens Hospital of Philadelphia, co-senior author of the study. Some of the protein targets already are targets of existing drugs for other diseases, while others are the focus of drugs currently in early-phase clinical trials or under preclinical development.

Keating collaborated with two other senior co-authors, Folkert W. Asselbergs, M.D., Ph.D., of University Medical Center Utrecht, the Netherlands, and Patricia B. Munroe, Ph.D., of Queen Mary University, London, U.K. The study appears online today in the American Journal of Human Genetics. Study co-authors were from the U.S., the U.K., the Netherlands, Canada, Germany, Sweden and Ireland.

High blood pressure, or hypertension, a chronic medical condition, is a well-known risk factor for heart disease, stroke, peripheral artery disease and chronic kidney disease. It is a complex condition, affected by many different genes. Because not all patients respond well to current blood pressure medications and other treatments, and other patients require combinations of three or more drugs, there is a substantial unmet need for improved medicines.

In the current study, the researchers performed a discovery analysis of DNA from more than 87,000 individuals of European ancestry. They then assessed their initial findings in a replication test, using an independent set of another 68,000 individuals.

The study team confirmed 27 previously discovered gene signals associated with blood pressure, and discovered 11 novel genetic signals. When the researchers used pharmacological databases to analyze potential targets in the discovered genetic regions, they found that gene products associated with 10 of the genes were predicted to be targets for small-molecule drugs. Two genes, KCNJ11 and NQO1, in fact, are already currently targeted by existing approved drugs. If clinicians can reposition existing drugs to treat some patients with hypertension, this will save significant time in drug development, as they wont be starting development from scratch, said Keating.

Keating added that other gene signals discovered in the study are associated with candidate drugs currently under development within pharmaceutical companies, and it may be possible that they can be repositioned as blood pressure therapeutics.

He stressed that even with possible repositioning, much research remains to be done to determine which drug candidates are effective against hypertension, possibly in personalized treatments based on patients genetic makeup. Keating added that the list of genes affecting blood pressure will likely grow as research continues.

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CHOP Researcher Co-Leads Study Finding Genes that Affect Blood Pressure

February 20, 2014

Image Caption: Beagle, a Cray XE6 supercomputer at Argonne National Laboratory, supports computation, simulation and data analysis for the biomedical research community. Credit: Argonne National Laboratory

Lee Rannals for redOrbit.com Your Universe Online

Researchers writing in the journal Bioinformatics say that genome analysis can be radically accelerated.

Over the years, the cost of sequencing an entire human genome has dropped, but analyzing three billion base pairs of genetic information from a single genome can take months. A team from the University of Chicago is reporting that one of the worlds fastest supercomputers is able to analyze 240 full genomes in about two days.

This is a resource that can change patient management and, over time, add depth to our understanding of the genetic causes of risk and disease, study author Elizabeth McNally, the A. J. Carlson Professor of Medicine and Human Genetics and director of the Cardiovascular Genetics clinic at the University of Chicago Medicine, said in a statement.

Megan Puckelwartz, a graduate student in McNallys laboratory and the studys first author, said the Beagle supercomputer based at Argonne National Laboratory is able to process many genomes simultaneously rather than one at a time.

It converts whole genome sequencing, which has primarily been used as a research tool, into something that is immediately valuable for patient care, Puckelwartz said in a statement.

Scientists have been working on exome sequencing, which focuses on just two percent or less of the genome that codes for proteins. About 86 percent of disease-causing mutations are located in this coding region, but still about 15 percent of significant mutations come from the other coding regions.

Researchers used raw sequencing data from 61 human genomes and analyzed the data on Beagle. They used publicly available software packages and a quarter of the computers total capacity, finding that a supercomputer environment helped with accuracy and speed.

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Using Supercomputers To Speed Up Genome Analysis

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Newswise Although the time and cost of sequencing an entire human genome has plummeted, analyzing the resulting three billion base pairs of genetic information from a single genome can take many months.

In the journal Bioinformatics, however, a University of Chicago-based teamworking with Beagle, one of the worlds fastest supercomputers devoted to life sciencesreports that genome analysis can be radically accelerated. This computer, based at Argonne National Laboratory, is able to analyze 240 full genomes in about two days.

This is a resource that can change patient management and, over time, add depth to our understanding of the genetic causes of risk and disease, said study author Elizabeth McNally, MD, PhD, the A. J. Carlson Professor of Medicine and Human Genetics and director of the Cardiovascular Genetics Clinic at the University of Chicago Medicine.

The supercomputer can process many genomes simultaneously rather than one at a time, said first author Megan Puckelwartz, a graduate student in McNallys laboratory. It converts whole genome sequencing, which has primarily been used as a research tool, into something that is immediately valuable for patient care.

Because the genome is so vast, those involved in clinical genetics have turned to exome sequencing, which focuses on the two percent or less of the genome that codes for proteins. This approach is often useful. An estimated 85 percent of disease-causing mutations are located in coding regions. But the rest, about 15 percent of clinically significant mutations, come from non-coding regions, once referred to as junk DNA but now known to serve important functions. If not for the tremendous data-processing challenges of analysis, whole genome sequencing would be the method of choice.

To test the system, McNallys team used raw sequencing data from 61 human genomes and analyzed that data on Beagle. They used publicly available software packages and one quarter of the computers total capacity. They found that shifting to the supercomputer environment improved accuracy and dramatically accelerated speed.

Improving analysis through both speed and accuracy reduces the price per genome, McNally said. With this approach, the price for analyzing an entire genome is less than the cost of the looking at just a fraction of genome. New technology promises to bring the costs of sequencing down to around $1,000 per genome. Our goal is get the cost of analysis down into that range.

This work vividly demonstrates the benefits of dedicating a powerful supercomputer resource to biomedical research, said co-author Ian Foster, director of the Computation Institute and Arthur Holly Compton Distinguished Service Professor of Computer Science. The methods developed here will be instrumental in relieving the data analysis bottleneck that researchers face as genetic sequencing grows cheaper and faster.

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Entrepreneurial Achievement Award: Bradley Dixon, MD
http://www.cincinnatichildrens.org Entrepreneurial Achievement Award Bradley P. Dixon, MD Division of Nephrology and Hypertension Assistant Professor of Pedi...

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TUESDAY, Feb. 18, 2014 (HealthDay News) -- Cat lovers have long known that the distinctive three-toned calico patterning is almost exclusively found in female felines.

Now, the genetics behind that anomaly may help scientists understand human DNA a little better, too.

That's because calico cats may help explain so-called gene silencing -- flipping the "off switch" on genes, researchers say.

A team at the University of California, San Francisco say the unique orange-white-and-black patchwork fur on these cats is due to the silencing or inactivation of one of their two X chromosomes.

As the researchers explained, cells in female mammals have two copies of the X chromosome -- one from the mother and one from the father. Cells require only one active X chromosome, so the second one is turned off.

Calico cats have an orange-fur-color gene on one of their X chromosomes and a black-fur gene on the other. According to the UCSF team, the random silencing of one of the X chromosomes in each cell results in the calico cats' unique patchwork coat.

Scientists don't know exactly how a cell turns off a chromosome, so the researchers are trying to learn more about how different kinds of genes can be switched on or off without affecting the underlying DNA sequence.

This knowledge could lead to improved understanding, diagnosis and treatment of X-chromosome-related diseases in humans, said the researchers, who are scheduled to present their findings Tuesday at the Biophysical Society's annual meeting in San Francisco.

"Uncovering how only one X chromosome is inactivated will help explain the whole process of 'epigenetic control,' meaning the way changes in gene activity can be inherited without changing the DNA code," Elizabeth Smith, a postdoctoral fellow in the anatomy department at UCSF, said in an American Institute of Physics news release.

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Calico cats may help scientists understand human genetics

Anthony L. Komaroff, M.D. Ask Dr. K

Dr. Komaroff

Dear Dr. K: In yesterday's column, a reader asked whether she should be tested for genes linked to Alzheimer's disease. Today, I thought I'd give you my view on the larger question: Will studies of our genes change the practice of medicine and improve our lives?

My answer: During my career, progress in human genetics has been greater than virtually anyone imagined. However, human genetics also has turned out to be much more complicated than people imagined. As a result, we have not moved as rapidly as we had hoped in changing medical practice.

I graduated from medical school in the late 1960s. We knew what human genes were made of DNA and we were beginning to understand how genes work. We had even identified a handful of genes that were linked to specific diseases. We assumed that disease resulted from an abnormality in the structure of a gene.

If I had asked any biologist on the day I graduated, "Will we ever know how many genes we have, and the exact structure of each gene?" I'll bet the answer would have been: "Not in my lifetime, or my children's lifetime."

They would have been wrong. Today we do know those answers. Indeed, some diseases are caused by an abnormality in the structure of genes. In fact, sometimes it is very simple: one particular change at one particular spot in just one particular gene leads to a specific disease. Sickle cell anemia is an example.

Unfortunately, with most diseases it's far from that simple. The first complexity: Most diseases are influenced by the structure of multiple genes, not just one. Examples are diabetes and high blood pressure.

The second complexity: Many diseases are explained not by an abnormal gene structure, but by whether genes are properly turned on or off. Most cancers fall into this category.

What do I mean by that? Every cell in our body has the same set of genes. Yet, a cell in our eye that sees light is different from a cell in our stomach that makes acid. Why? Because different genes are turned on in each type of cell.

More here:

Ask Dr. K: Gene studies lead to better diagnoses

Scientists have mapped the effects of war, colonization, trade, migration and slavery on the genetic mixing of humans over the bulk of recorded history and created an online interactive atlas of humanity's genetic history.

In a paper published Thursday in the journal Science, researchers detailed the genetic mixing between 95 populations across Europe, Africa, Asia and South America during 100 historical events over the last 4,000 years.

The events covered in the interactive atlas include the expansion of the Mongol empire by Genghis Khan, the Arab slave trade, the so-called Bantu expansion into Southern Africa, and European colonialism.

When people from different groups interbreed, their offspring's DNA becomes a mixture of both admixing groups. Scientists say pieces of this DNA are passed down to following generations, although the size of the segments become smaller and smaller.

By studying the size of the DNA segments in present-day humans, researchers can infer how long ago it was that the admixture occurred.

"Each population has a particular genetic 'palette.'" said study co-author Daniel Falush, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

"Though we can't directly sample DNA from the groups that mixed in the past, we can capture much of the DNA of these original groups as persisting, within a mixed palette of modern-day groups," he said in a prepared statement.

To accomplish this, researchers used a sophisticated statistical method called "Globetrotter" to analyze genome data from 1,490 individuals.

While genetic signals obtained from a single individual might be relatively weak, they strengthen as scientists look at a larger group. As a result, researchers found that their genetic data matched historical events and periods.

One such example involved the legacy of the Mongol empire, researchers said. Traces of Mongol DNA in the Hazara people of Pakistan support historical accounts that the Hazara descended from Mongol warriors.

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Contact: Clare Ryan clare.ryan@ucl.ac.uk 44-020-310-83846 University College London

The interactive map, produced by researchers from Oxford University and UCL (University College London), details the histories of genetic mixing between each of the 95 populations across Europe, Africa, Asia and South America spanning the last four millennia.

The study, published this week in Science, simultaneously identifies, dates and characterises genetic mixing between populations. To do this, the researchers developed sophisticated statistical methods to analyse the DNA of 1490 individuals in 95 populations around the world. The work was chiefly funded by the Wellcome Trust and Royal Society.

'DNA really has the power to tell stories and uncover details of humanity's past.' said Dr Simon Myers of Oxford University's Department of Statistics and Wellcome Trust Centre for Human Genetics, co-senior author of the study.

'Because our approach uses only genetic data, it provides information independent from other sources. Many of our genetic observations match historical events, and we also see evidence of previously unrecorded genetic mixing. For example, the DNA of the Tu people in modern China suggests that in around 1200CE, Europeans similar to modern Greeks mixed with an otherwise Chinese-like population. Plausibly, the source of this European-like DNA might be merchants travelling the nearby Silk Road.'

The powerful technique, christened 'Globetrotter', provides insight into past events such as the genetic legacy of the Mongol Empire. Historical records suggest that the Hazara people of Pakistan are partially descended from Mongol warriors, and this study found clear evidence of Mongol DNA entering the population during the period of the Mongol Empire. Six other populations, from as far west as Turkey, showed similar evidence of genetic mixing with Mongols around the same time.

'What amazes me most is simply how well our technique works,' said Dr Garrett Hellenthal of the UCL Genetics Institute, lead author of the study. 'Although individual mutations carry only weak signals about where a person is from, by adding information across the whole genome we can reconstruct these mixing events. Sometimes individuals sampled from nearby regions can have surprisingly different sources of mixing.

'For example, we identify distinct events happening at different times among groups sampled within Pakistan, with some inheriting DNA from sub-Saharan Africa, perhaps related to the Arab Slave Trade, others from East Asia, and yet another from ancient Europe. Nearly all our populations show mixing events, so they are very common throughout recent history and often involve people migrating over large distances.'

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Interactive map of human genetic history revealed

February 10, 2014

University of Oxford

Seven new genetic regions associated with type 2 diabetes have been identified in the largest study to date of the genetic basis of the disease.

DNA data was brought together from more than 48,000 patients and 139,000 healthy controls from four different ethnic groups. The research was conducted by an international consortium of investigators from 20 countries on four continents, co-led by investigators from Oxford Universitys Wellcome Trust Centre for Human Genetics.

The majority of such genome-wide association studies have been done in populations with European backgrounds. This research is notable for including DNA data from populations of Asian and Hispanic origin as well.

The researchers believe that, as more genetic data increasingly become available from populations of South Asian ancestry and, particularly, African descent, it will be possible to map genes implicated in type 2 diabetes ever more closely.

One of the striking features of these data is how much of the genetic variation that influences diabetes is shared between major ethnic groups, says Wellcome Trust Senior Investigator Professor Mark McCarthy from the University of Oxford. This has allowed us to combine data from more than 50 studies from across the globe to discover new genetic regions affecting risk of diabetes.

He adds: The overlap in signals between populations of European, Asian and Hispanic origin argues that the risk regions we have found to date do not explain the clear differences in the patterns of diabetes between those groups.

Among the regions identified by the international research team are two, near the genes ARL15 and RREB1, that also show strong links to elevated levels of insulin and glucose in the body two key characteristics of type 2 diabetes. This finding provides insights into the ways basic biochemical processes are involved in the risk of type 2 diabetes, the scientists say.

The genome-wide association study looked at more than 3 million DNA variants to identify those that have a measurable impact on risk of type 2 diabetes. By combining DNA data from many tens of thousands of individuals, the consortium was able to detect, for the first time, regions where the effects on diabetes susceptibility are rather subtle.

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Diabetes Genetics Study Brings In Data From Different Ethnic Groups

Lawrence LeBlond for redOrbit.com Your Universe Online

A multi-institutional team of researchers this week published in the journal Science a study identifying, dating and characterizing the genetic mixing between populations around the world. Along with the study, the team released an interactive map detailing the histories of this genetic mixing.

Researchers from Max Planck Institute for Evolutionary Anthropology, Oxford University and University College London developed sophisticated statistical methods to analyze the DNA of nearly 1500 people from 95 different populations around the world and from over the past four millennia. These populations hailed from Europe, Africa, Asia and South and Central America.

The groups work was funded by the Wellcome Trust and Royal Society.

DNA really has the power to tell stories and uncover details of humanitys past, said co-senior study author Dr Simon Myers, of Oxford Universitys Department of Statistics and Wellcome Trust Centre for Human Genetics.

Because our approach uses only genetic data, it provides information independent from other sources. Many of our genetic observations match historical events, and we also see evidence of previously unrecorded genetic mixing. For example, the DNA of the Tu people in modern China suggests that in around 1200CE, Europeans similar to modern Greeks mixed with an otherwise Chinese-like population. Plausibly, the source of this European-like DNA might be merchants travelling the nearby Silk Road, explained Dr Myers in a statement.

Dubbed Globetrotter, this powerful technique provides a good in-depth look at the past. For Instance, the method provided invaluable insight into the genetic legacy of the Mongol Empire. Historically, it is believed that the Hazara people of Pakistan are partially descended from Mongol warriors; the study found clear evidence to back up this belief, discovering that Mongol DNA had in fact entered the Pakistani population during the Mongol Empire. As well, six other neighboring populations showed similar evidence of genetic mixing with the Mongols during this period.

What amazes me most is simply how well our technique works, said study lead author Dr Garrett Hellenthal, of the UCL Genetics Institute. Although individual mutations carry only weak signals about where a person is from, by adding information across the whole genome we can reconstruct these mixing events. Sometimes individuals sampled from nearby regions can have surprisingly different sources of mixing.

For example, we identify distinct events happening at different times among groups sampled within Pakistan, with some inheriting DNA from sub-Saharan Africa, perhaps related to the Arab Slave Trade, others from East Asia, and yet another from ancient Europe. Nearly all our populations show mixing events, so they are very common throughout recent history and often involve people migrating over large distances, said Dr Hellenthal.

The team also identified chunks of DNA shared between individuals from different populations, based on the genome data taken from all 1490 individuals. They found that those populations that shared more ancestry also shared more of these chunks. As well, individual chunks gave the team clues about the underlying ancestry along chromosomes.

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New Interactive Map Reveals Human History Of Genetic Mixing

Sometimes biology is cruel. Sometimes simply a one-letter change in the human genetic code is the difference between health and a deadly disease.

But even though doctors and scientists have long studied the often devastating disorders caused by these tiny changes, replicating these changes in the lab in order to study them in human stem cells has proven challenging. But now, scientists at the UC San Francisco-affiliatedGladstone Institutes have found a way to efficiently edit the human genome one letter at a time not only boosting researchers ability to model human disease, but also paving the way for therapies that cure disease by fixing these so-called bugs in a patients genetic code.

Bruce Conklin, MD

Led by Gladstone investigator and professor in the UCSF School of Medicine,Bruce Conklin, MD, the research team describes in an issue ofNature Methods how they have solved one of science and medicines most pressing problems: how to efficiently and accurately capture rare genetic mutations that cause disease as well as how to fix them. This pioneering technique highlights the type of out-of-the-box thinking that is often critical for scientific success.

Advances in human genetics have led to the discovery of hundreds of genetic changes linked to disease, but until now weve lacked an efficient means of studying them, explained Conklin. To meet this challenge, we must have the capability to engineer the human genome, one letter at a time, with tools that are efficient, robust and accurate. And the method that we outline in our study does just that.

One of the major challenges preventing researchers from efficiently generating and studying these genetic diseases is that they can exist at frequencies as low as one-in-a-thousand, making the task of finding and studying them labor-intensive.

For our method to work, we needed to find a way to efficiently identify a single mutation in a cell among hundreds of normal, healthy cells, explained Gladstone research scientist Yuichiro Miyaoka, PhD, the papers lead author. So we designed a special fluorescent probe that would distinguish the mutated sequence from the original sequences. We were then able to sort through both sets of sequences and detect mutant cells even when they made up as little one in every thousand cells. This is a level of sensitivity more than one hundred times greater than traditional methods.

The team then applied these new methods to induced pluripotent stem cells, or iPS cells. These cells, derived from the skin cells of human patients, have the same genetic makeup including any potential disease-causing mutations as the patient. In this case, the research team first used a highly advanced gene-editing technique called TALENs to introduce a specific mutation into the genome. Some gene-editing techniques, while effective at modifying the genetic code, involve the use of genetic markers that then leave a scar on the newly edited genome. These scars can then affect subsequent generations of cells, complicating future analysis. Although TALENs, and other similarly advanced tools, are able to make a clean, scarless single letter edits, these edits are very rare, so that new technique from the Conklin lab is needed.

Our method provides a novel way to capture and amplify specific mutations that are normally exceedingly rare, saidConklin. Our high-efficiency, high-fidelity method could very well be the basis for the next phase of human genetics research.

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Genome Editing Goes Hi-Fi

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An extra copy of chromosome 21 causes Down's syndrome but there is a dispute over who discovered it.

A disagreement over the discovery of the cause of Downs syndrome has resurfaced in France more than 50 years after the findings were published.

The dispute erupted again at the French Federation of Human Genetics' (FFGH) seventh biennial congress on human and medical genetics in Bordeaux at the end of last month.

Paediatric cardiologist Marthe Gautier, who was involved in the experiments that led to the identification of the extra copy of chromosome 21 the cause of the syndrome was due to relate her role in the discovery when two bailiffs arrived with a court authorization to record the session. The FFGH then decided at the last minute to cancel Gautier's presentation.

The bailiffs were representing the Paris-based Jrme Lejeune Foundation, which finances a large proportion of current Down's syndrome research in France. The foundation does not deny Gautiers contribution to the work leading to the discovery, but it credits the late Lejeune for the discovery itself.

Lejeune, a geneticist, was first author of the key paper reporting1 the finding, published by the French Academy of Sciences in January 1959. Gautier was listed as second author, and Raymond Turpin, a paediatric geneticist and Gautiers and Lejeunes boss at the Trousseau Hospital in Paris, was listed as third author.

The FFGH says that it wanted to honour Gautiers role in the discovery by giving her the floor and awarding her the federation's grand prize. Without questioning Jrme Lejeunes very important contribution to French genetics through the article on trisomy 21 and other work, we simply wanted to make a gesture in recognition of the determinant character of Marthe Gautiers contribution, the federation said in a statement.

But when the bailiffs walked in, we realized the recording might be used in a court case, FFGH treasurer and former president Dominique Bonneau told Nature. Not only do we not have the funds to fight a libel suit, but we felt it was inappropriate to hold the presentation under such strong legal pressure. Gautier received her prize discreetly and nine eminent geneticists signed a statement endorsing the decision to cancel the presentation.

Jean-Marie Le Mn, president of the Jrme Lejeune Foundation, says that the bailiffs were sent because the foundation wanted an official recording of the talk so that there could be no dispute over what was said. We needed to know what was said in case Jrme Lejeunes memory was smeared, he says.

Continued here:

Down's syndrome discovery dispute resurfaces in France

Sometimes biology is cruel. Sometimes simply a one-letter change in the human genetic code is the difference between health and a deadly disease. But even though doctors and scientists have long studied disorders caused by these tiny changes, replicating them to study in human stem cells has proven challenging. But now, scientists at the Gladstone Institutes have found a way to efficiently edit the human genome one letter at a time -- not only boosting researchers' ability to model human disease, but also paving the way for therapies that cure disease by fixing these so-called 'bugs' in a patient's genetic code.

Led by Gladstone Investigator Bruce Conklin, MD, the research team describes in the latest issue of Nature Methods how they have solved one of science and medicine's most pressing problems: how to efficiently and accurately capture rare genetic mutations that cause disease -- as well as how to fix them. This pioneering technique highlights the type of out-of-the-box thinking that is often critical for scientific success.

"Advances in human genetics have led to the discovery of hundreds of genetic changes linked to disease, but until now we've lacked an efficient means of studying them," explained Dr. Conklin. "To meet this challenge, we must have the capability to engineer the human genome, one letter at a time, with tools that are efficient, robust and accurate. And the method that we outline in our study does just that."

One of the major challenges preventing researchers from efficiently generating and studying these genetic diseases is that they can exist at frequencies as low as 1%, making the task of finding and studying them labor-intensive.

"For our method to work, we needed to find a way to efficiently identify a single mutation among hundreds of normal, healthy cells," explained Gladstone Research Scientist Yuichiro Miyaoka, PhD, the paper's lead author. "So we designed a special fluorescent probe that would distinguish the mutated sequence from the original sequences. We were then able to sort through both sets of sequences and detect mutant cells -- even when they made up as little one in every thousand cells. This is a level of sensitivity more than one hundred times greater than traditional methods."

The team then applied these new methods to induced pluripotent stem cells, or iPS cells. These cells, derived from the skin cells of human patients, have the same genetic makeup -- including any potential disease-causing mutations -- as the patient. In this case, the research team first used a highly advanced gene-editing technique called TALENs to introduce a specific mutation into the genome. Some gene-editing techniques, while effective at modifying the genetic code, involve the use of genetic markers that then leave a 'scar' on the newly edited genome. These scars can then affect subsequent generations of cells, complicating future analysis. Athough TALENs, and other similarly advanced tools, are able to make a clean, scarless single letter edits, these edits are very rare, so that new technique from the Conklin lab is needed.

"Our method provides a novel way to capture and amplify specific mutations that are normally exceedingly rare," said Dr. Conklin. "Our high-efficiency, high-fidelity method could very well be the basis for the next phase of human genetics research."

"Now that powerful gene-editing tools, such as TALENs, are readily available, the next step is to streamline their implementation into stem cell research," said Dirk Hockemeyer, PhD, assistant professor of molecular and cellular biology at the University of California, Berkeley, who was not involved in this study. "This process will be greatly facilitated by the method described by Dr. Conklin and colleagues."

"Some of the most devastating diseases we face are caused by the tiniest of genetic changes," added Dr. Conklin. "But we are hopeful that our technique, by treating the human genome like lines of computer code, could one day be used to reverse these harmful mutations, and essentially repair the damaged code."

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Newswise Genetic adaptations for life at high elevations found in residents of the Tibetan plateau likely originated around 30,000 years ago in peoples related to contemporary Sherpa. These genes were passed on to more recent migrants from lower elevations via population mixing, and then amplified by natural selection in the modern Tibetan gene pool, according to a new study by scientists from the University of Chicago and Case Western Reserve University, published in Nature Communications on Feb. 10.

The transfer of beneficial mutations between human populations and selective enrichment of these genes in descendent generations represents a novel mechanism for adaptation to new environments.

The Tibetan genome appears to arise from a mixture of two ancestral gene pools, said Anna Di Rienzo, PhD, professor of human genetics at the University of Chicago and corresponding author of the study. One migrated early to high altitude and adapted to this environment. The other, which migrated more recently from low altitudes, acquired the advantageous alleles from the resident high-altitude population by interbreeding and forming what we refer to today as Tibetans.

High elevations are challenging for humans because of low oxygen levels but Tibetans are well adapted to life above 13,000 feet. Due to physiological traits such as relatively low hemoglobin concentrations at altitude, Tibetans have lower risk of complications, such as thrombosis, compared to short-term visitors from low altitude. Unique to Tibetans are variants of the EGLN1 and EPAS1 genes, key genes in the oxygen homeostasis system at all altitudes. These variants were hypothesized to have evolved around 3,000 years ago, a date which conflicts with much older archaeological evidence of human settlement in Tibet.

To shed light on the evolutionary origins of these gene variants, Di Rienzo and her team, led by first author Choongwon Jeong, graduate student at the University of Chicago, obtained genome-wide data from 69 Nepalese Sherpa, an ethnic group related to Tibetans. These were analyzed together with the genomes of 96 unrelated individuals from high-altitude regions of the Tibetan plateau, worldwide genomes from HapMap3 and the Human Genome Diversity Panel, as well as data from Indian, Central Asian and two Siberian populations, through multiple statistical methods and sophisticated software.

The researchers found that, on a genomic level, modern Tibetans appear to descend from populations related to modern Sherpa and Han Chinese. Tibetans carry a roughly even mixture of two ancestral genomes: one a high-altitude component shared with Sherpa and the other a low-altitude component shared with lowlander East Asians. The low-altitude component is found at low to nonexistent frequencies in modern Sherpa, and the high-altitude component is uncommon in lowlanders. This strongly suggested that the ancestor populations of Tibetans interbred and exchanged genes, a process known as genetic admixture.

Tracing the history of these ancestor groups through genome analysis, the team identified a population size split between Sherpa and lowland East Asians around 20,000 to 40,000 years ago, a range consistent with proposed archaeological, mitochondria DNA and Y chromosome evidence for an initial colonization of the Tibetan plateau around 30,000 years ago.

This is a good example of evolution as a tinkerer, said Cynthia Beall, PhD, professor of anthropology at Case Western Reserve University and co-author on the study. We see other examples of admixtures. Outside of Africa, most of us have Neanderthal genesabout 2 to 5 percent of our genomeand people today have some immune system genes from another ancient group called the Denisovans.

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The Genetic Origins of High-Altitude Adaptations in Tibetans

Table of Contents

The human karyotype | Human chromosomal abnormalities

Human allelic disorders (recessive) | Human allelic disorders (dominant)

Sex-linked traits | Diagnosis of human genetic diseases | Radioactive probes

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There are 44 autosomesand 2 sex chromosomes in the human genome, for a total of 46. Karyotypesare pictures of homologous chromosomes lined up together during Metaphase I of meiosis. The chromosome micrographs are then arranged by size and pasted onto a sheet.

Click here for a larger picture. This picture is from The Primate Cytogenetics Network at ( http://www.selu.com/~bio/cyto/karyotypes/Hominidae/Hominidae.html).

A common abnormality is caused by nondisjunction, the failure of replicated chromosomes to segregate during Anaphase II. A gamete lacking a chromosome cannot produce a viable embryo. Occasionally a gamete with n+1 chromosomes can produce a viable embryo.

In humans, nondisjunction is most often associated with the 21st chromosome, producing a disease known as Down's syndrome (also referred to as trisomy21). Sufferers of Down's syndrome suffer mild to severe mental retardation, short stocky body type, large tongue leading to speech difficulties, and (in those who survive into middle-age), a propensity to develop Alzheimer's Disease. Ninety-five percent of Down's cases result from nondisjunction of chromosome 21. Occasional cases result from a translocationin the chromosomes of one parent. Remember that a translocation occurs when one chromosome (or a fragment) is transferred to a non-homologous chromosome. The incidence of Down's Syndrome increases with age of the mother, although 25% of the cases result from an extra chromosome from the father. Click hereto view a drawing (from Bioweb) of a karyotype of Down's syndrome.

Sex-chromosome abnormalities may also be caused by nondisjunction of one or more sex chromosomes. Any combination (up to XXXXY) produces maleness. Males with more than one X are usually underdeveloped and sterile. XXX and XO women are known, although in most cases they are sterile. What meiotic difficulties might a person with Down's syndrome or extra sex-chromosomes face?

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M.J. Farabee: Human Genetics - Estrella Mountain Community ...

The study, published in The American Journal of Human Genetics, detected and identified a new disease gene (ERCC6L2). In its normal form, the gene plays a key role in protecting DNA from damaging agents, but when the gene is mutated the cell is not able to protect itself in the normal way.

The research findings suggest that the gene defect and the subsequent DNA damage was the underlying cause of bone marrow failure among the study participants.

Bone marrow failure is a term used for a group of life threatening disorders associated with an inability of the bone marrow to make an adequate number of mature blood cells.

Patients were recruited from all over the world to join an international bone marrow failure registry and researchers used new DNA sequencing technologies to study cases of bone marrow failure with similar clinical features. These included bone marrow failure associated with neurological abnormalities (learning defects and developmental delay), and patients whose parents were first cousins.

The findings mean it is now possible to carry out a reliable genetic test (including antenatal testing) in these families and get an accurate diagnosis. In the long term, with further research, the findings could lead to the development of new treatment for this specific gene defect.

Professor Inderjeet Dokal, Chair of Paediatrics and Child Health at Queen Mary University of London, comments:

"New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure. This is a promising finding which we hope one day could lead to finding an effective treatment for this type of gene defect. Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.

"Now we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure."

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The above story is based on materials provided by Queen Mary, University of London. Note: Materials may be edited for content and length.

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New disease gene discovery sheds light on cause of bone marrow failure

Researchers from the University of Washington and the HudsonAlpha Institute for Biotechnology have developed a new method for organizing and prioritizing genetic data. The Combined Annotation-Dependent Depletion, or CADD, method will assist scientists in their search for disease-causing mutation events in human genomes.

The new method is the subject of a paper titled "A general framework for estimating the relative pathogenicity of human genetic variants," published in Nature Genetics.

Current methods of organizing human genetic variation look at just one or a few factors and use only a small subset of the information available. For example, the Encyclopedia Of DNA Elements, or ENCODE, catalogs various types of functional elements in human genomes, while sequence conservation looks for similar or identical sequences that have survived across different species through hundreds of millions of years of evolution. CADD brings all of these data together, and more, into one score in order to provide a ranking that helps researchers discern which variants may be linked to disease and which ones may not.

"CADD will substantially improve our ability to identify disease-causal mutations, will continue to get better as genomic databases grow, and is an important analytical advance needed to better exploit the information content of whole-genome sequences in both clinical and research settings," said Gregory M. Cooper, Ph.D., faculty investigator at HudsonAlpha and one of the collaborators on CADD.

The goal in developing the new approach was to take the overwhelming amount of data available and distill it down into a single score that can be more easily evaluated by a researcher or clinician. To accomplish that, CADD compares and contrasts the properties of 15 million genetic variants separating humans from chimpanzees with 15 million simulated variants. Variants observed in humans have survived natural selection, which tends to remove harmful, disease-causing variants, while simulated variants are not exposed to selection. Thus, by comparing observed to simulated variants, CADD is able to identify those properties that make a variant harmful or disease-causing. C scores have been pre-computed for all 8.6 billion possible single nucleotide variants and are freely available for researchers.

"We didn't know what to expect," Cooper said, "but we were pleasantly surprised that CADD was able not only to be applicable to mutations everywhere in the genome but in fact do a substantially better job in nearly every test that we performed than other metrics."

The CADD method is unique from other algorithms in that it assigns scores to mutations anywhere in human genomes, not just the less-than two percent that encode proteins (the "exome"). This unique attribute will be crucial as whole-genome sequencing becomes routine in both clinical and research settings.

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The above story is based on materials provided by HudsonAlpha Institute for Biotechnology. Note: Materials may be edited for content and length.

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Ranking disease-causal mutations within whole genome sequences