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Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Genetics, In the News, NIH, Science, Technology

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

5232013153_7808b471a2_zIf you’ve ever tried folding a map, packing an overnight bag or coiling a string of holiday lights, you know that the way you arrange an object affects how much space it takes up and how easy it is to use in the future. This same principle is true of DNA.

As a recent article in Science News explains, the way a DNA double helix is folded, packed and coiled is known to have a big effect on how much space it requires and how easy it is to access the information stored within. But, until recently, researchers lacked the technology to fully explore these four-dimensional DNA structures.

Now, new technology and last year’s launch of the National Institutes of Health‘s five-year, $120 million, 4D Nucleome project is helping researchers reveal the complex architecture of DNA. William Greenleaf, PhD, assistant professor of genetics at Stanford, discusses the significance of a genome‘s arrangement in the Science News article:

Like the genetic text within it, the genome’s shape holds specific instructions. “The way it’s compacted forms this sort of physical memory of what the cell should be doing,” Greenleaf says.

Loops of DNA that aren’t needed by a particular cell are tucked away from the biological machinery that reads genetic blueprints, leaving only relevant genes accessible to produce proteins. Studies have shown that sections of the genome that are shoved toward the edges of a nucleus are often read less than centrally located DNA. Such specialized arrangements allow cells as diverse as brain cells, skin cells and immune cells to perform different jobs, even though each contains the same genome. “In different cell types, there are very large changes to the regions that are being used,” Greenleaf says.

Much more remains to be understood about how a genome’s shape directs its activity. Future maps might zero in on functionally interesting regions of the genome, Greenleaf says. But he cautions there is also a benefit to unbiased, general exploration. Focusing on one location in the nucleome might lead researchers to miss important structural information elsewhere, he says.

Previously: DNA origami: How our genomes foldPacked and ready to go: The link between DNA folding and disease and DNA architecture fascinates Stanford researcher – and dictates biological outcomes
Photo by: Kate Ter Haar

Genetics, Pediatrics, Transplants, Women's Health

Rare African genes might reduce risks to pregnant women and their infants

Rare African genes might reduce risks to pregnant women and their infants

Khoe-SanWhen Hugo Hilton began working at Stanford as a young researcher several years ago, his supervisor set him to work on a minor problem so he could practice some standard lab techniques. His results, however, were anything but standard. His supervisor — senior research scientist Paul Norman — told him to do the work over, convinced the new guy had made a mistake. But Hilton, got the same result the second time, so Norman made him do it over again. And then again.

“This was Hugo’s first PCR reaction in our lab and I gave him the DNA,” recalled Norman, “and the very first one he did, he pulled out this mutation. I was convinced that he’d made a mistake.” Norman even quietly redid the work himself. But the gene variant was real.

Norman and colleagues had been studying the same group of immune genes for decades and he knew them like the back of his hand. Yet he was astonished by what Hilton had stumbled on — a mutation that switched a molecular receptor from one protein target to another. It would be as if you bent your house key ever so slightly and discovered it now opened the door to your neighbor’s apartment — but not yours.

And the mutation, far from causing some illness, might contribute to healthier mothers and babies. Parallel research at another institution suggests the odd gene most likely changes the placenta during early pregnancy, leading to better-nourished babies and a reduced risk of pre-eclampsia, a major cause of maternal death.

The surprising finding grew out of a long-term effort to understand how immune system genes make us reject organ transplants. A big part of that puzzle is understanding how much immune genes can vary. On the surfaces of ordinary cells are proteins called HLAs. Combinations of these proteins mark cells in a way that makes each person’s cells so nearly unique that the immune system can recognize cells as either self or not self. When a surgeon transplants a kidney, the recipient’s immune system can tell that the kidney is someone else’s — just from its cell surface HLA proteins. The patient’s immune system then signals its natural killer cells to attack the transplanted kidney. The key to all that specificity is the huge variation in the genes for the HLA proteins.

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Cardiovascular Medicine, Genetics, Research, Stanford News

A cheaper, faster way to find genetic defects in heart patients

A cheaper, faster way to find genetic defects in heart patients

15907993264_87339bc83f_zIn most people, heart disease develops through a lifetime of cigarettes, trans fats or high glycemic foods. For only a minority of patients does the cause lie in their genes. But when such atypical patients show up for treatment, figuring out why their hearts aren’t working has been a huge challenge for their doctors. The process of deciding if a heart patient’s problem is genetic and, if so, which gene defects might be causing the problem can take weeks or months, cost a thousand dollars or more, and, at the end, leave physicians still scratching their heads over a mountain of uncertain data.

A new genetic test being developed by pathologist Kitchener Wilson, MD, PhD and cardiology and radiology professor Joseph Wu, MD, PhD, may be able to accurately pinpoint the likely genetic causes of a heart patient’s elusive condition in just a couple of days.

Wilson and Wu say that for a patient with a heart condition that’s difficult to diagnose, it makes no sense to sequence the entire 22,000-gene human genome. Such whole-genome sequencing is costly, time consuming, and produces data marred by small but important errors.

So, taking a more focused approach, Wilson and Wu’s team designed a streamlined assay, or test, that looks at just the 88 genes known to carry mutations that cause heart problems. Materials for the new assay cost about $100, and results are back within three days.

Their approach — surveying a small subgroup of relevant genes instead of the whole genome — is already used to look for other genetic diseases, such as cystic fibrosis. But cystic fibrosis results from mutations in a single gene. “The heart diseases are more challenging just because there are so many genes to sequence,” says Wilson.

Wilson and Wu’s assay is a variation on “complementary long padlock probes,” or cLPPs, a class of genetic probes developed at the Stanford Genome Technology Center. These simple probes accurately target specific parts of the genome and are easily customized to target genes of interest. Wilson and Wu spearheaded the effort to put cLPPs to work on genes connected with heart problems and reported their work in the journal Circulation Research, with Wu as senior author and Wilson as first author.

If further tests validate the assay, it could shorten the time it takes to diagnose difficult or unusual heart disease cases—like that of basketball player Hank Gathers above — hastening appropriate treatment for atypical cardiac patients.

Previously: At Stanford Cardiovascular Institute’s annual retreat, a glimpse into the future of cardiovascular medicine and Coming soon: A genome test that costs less than a new pair of shoes
Photo by: Liviu Ghemaru

Cardiovascular Medicine, Evolution, Genetics, Research, Science

Ethiopian gene offers potential help for hypoxia

Ethiopian gene offers potential help for hypoxia

8494671414_5bc71743c8_zGene therapies have been developed for color blindness, Parkinson’s, SCID, and muscular dystrophy, among others. Now there soon could be another to add to the list: hypoxia, or oxygen deprivation.

In a study published in PNAS, researchers investigated how mice with lower levels of the endothelin receptor type B (EDNRB) gene – a gene that is present among Ethiopians, who evolved to live at high elevations where oxygen levels are low – fare in hypoxic conditions. It found that even with five percent oxygen, lower than you’d find atop Mount Everest, the mice with the gene alteration survived. They managed to get oxygen to their vital organs with the help of several “downstream” genes that are regulated by EDNRB.

According to a press release, these three heart-specific genes “help heart cells perform crucial functions such as transport calcium and contract. The finding provides a direct molecular link between EDNRB levels and cardiovascular performance.”

The implications of this work are described in the release by senior author Gabriel Haddad, MD, professor and chair of pediatrics at UC San Diego School of Medicine: “In addition to improving the health of the more than 140 million people living above 8,000 feet, information on how Ethiopians have adapted to high altitude life might help us develop new and better therapies for low oxygen-related diseases at sea level — heart attack and stroke, for example.” Haddad and his team are now testing therapeutic drugs that inhibit ENDRB.

Previously: Near approval: A stem cell gene therapy developed by Stanford researcher, Using genetics to answer fundamental questions in biology, medicine, and anthropology and “It’s not just science fiction anymore”: ChildX researchers talk stem cell and gene therapy
Photo by mariusz klozniak

Behavioral Science, Genetics, Neuroscience

Wishing for a genetic zodiac sign: How much can genes really tell us about personality?

Wishing for a genetic zodiac sign: How much can genes really tell us about personality?

Brain MRIGiven all the recent news on how gene expression influences our brain, from Alzheimer’s to addiction and even our personalities, readers might come away thinking that we’re close to breaking the code and using genetics to understand why we behave the way we do. But, things aren’t that simple.

In a post on the science blog Last Word on Nothing, Eric Vance explores what getting your personal genetic sequence means for your personality – something he calls, tongue-in-cheek, “a genetic tarot card.”

Vance delves into an explanation of one specific mutation in the COMT gene. The gene creates an enzyme that neutralizes dopamine, a neurotransmitter. The gene comes in two forms, and the difference in these two forms is just one base-pair, the individual links in our DNA code. One version of the resulting enzyme is efficient at clearing away extra dopamine. But if the gene codes for the other version, “then the enzyme becomes a wastrel… Work piles up and the brain accumulates a bunch of extra dopamine.”

Because dopamine is such a powerful regulator of mood, and by extension personality, Vance then describes, in surprising detail, personality types he expects people with either version of the gene to have. But genetic information like this is meant to be used at the population, not personal, level. In fact, none of the people in his circle of friends who have had their genome sequenced turns out to be who he expects them to be (which begs the question, how many people does he know who’ve had their DNA sequenced?). Disappointed, he laments:

But that’s not how I want it work. While I don’t like the idea of boiling human emotions down to a couple squishy turning gears, I do like how tidy it is. I want to be able to look up my genome and make broad generalizations about myself. I want to have a genetic tarot card that I can inspect and say “ohhh, that’s why I always forget people’s names” or “that’s why I got in that fight in the third grade.”

Vance concludes, “But that’s not what nature gave us. Nature has given us messy, confusing and vastly complicated brains.” We are more, it turns out, than the sum of our base pairs.

Previously: New research sheds light on connection between dopamine and depression symptoms

Photo by deradrian

Autoimmune Disease, Genetics, Immunology, Science, Stanford News, Technology

Women and men’s immune system genes operate differently, Stanford study shows

Women and men's immune system genes operate differently, Stanford study shows

A new technology for studying the human body’s vast system for toggling genes on and off reveals that genes connected with the immune system switch on and off more frequently than other genes, and those same genes operate differently in women and men. What’s more, the differences in gene activity are mostly not genetic.

A couple of years ago, geneticists Howard Chang, MD, PhD; Will Greenleaf, PhD, and others at Stanford invented a way to map the epigenome – essentially the real time on/off status of each of the 22,000 genes in our cells, along with the switches that control whether each gene is on or off.

Imagine a fancy office vending machine that can dispense 22,000 different drinks and other food items. Some selections are forever pumping out product; other choices are semi permanently unavailable. Still others dispense espresso, a double espresso or hot tea depending on which buttons you push. The activity of the 22,000 genes that make up our genomes are regulated in much the same way.

That’s a lot to keep track of. But Chang and Greenleaf’s technology, called ATAC-seq, makes it almost easy to map all that gene activity in living people as they go about their lives. Their latest study, published in Cell Systems, showed that the genes that switch on and off differently from person to person are more likely to be associated with autoimmune diseases, and also that men and women use different switches for many immune system genes. That sex-based difference in activity might explain the much higher incidence of autoimmune diseases in women — diseases like multiple sclerosis, lupus and rheumatoid arthritis.

The team took ordinary blood samples from 12 healthy volunteers and extracted immune cells called T cells. T cells are easy to isolate from a standard blood test and an important component of the immune system. With T cells in hand, the team looked at how certain genes are switched on and off, and how that pattern varied from individual to individual. Chang’s team also looked at how much change occurred from one blood draw to the next in each volunteer.

Chang told me, “We were interested in exploring the landscape of gene regulation directly from live people and look at differences. We asked, ‘How different or similar are people?’ This is different from asking if they have the same genes.”

Even in identical twins, he said, one twin could have an autoimmune disease and the other could be perfectly well. And, indeed, the team reported that over a third of the variation in gene activity was not connected to a genetic difference, suggesting a strong role for the environment. “I would say the majority of the difference is likely from a nongenetic source,” he said.

Previously: Caught in the act! Fast, cheap, high-resolution, easy way to tell which genes a cell is using
Photo by Baraka Office Support Services

Ask Stanford Med, Cancer, Genetics, Women's Health

Genetic testing and its role in women’s health and cancer screening

Genetic testing and its role in women's health and cancer screening

14342954637_3f8c3fde77_zYears ago, when I first learned that genetic testing could help screen for some cancers, such as breast, ovarian and bone, it seemed like a no-brainer to get this testing done. Now I know better; genetic testing is a helpful tool that can help you assess your risk for certain kinds of cancer, but it’s not recommended for everyone. Senior genetic counselor Kerry Kingham, a clinical assistant professor affiliated with the Cancer Genetics Clinic at Stanford, explains why this is the case in a recent Q&A with BeWell@Stanford.

Cancer can be “hereditary” or “sporadic” in nature, Kingham says. Hereditary cancers, such as the forms of breast cancer related to a mutation in the BRCA1 or BRCA2 genes, are associated with an inherited genetic mutation. In contrast, sporadic cancers arise independent of family history or other risk factors. Since genetics testing detects gene mutations, it can only be used to help screen for the mutations that may lead to forms of hereditary cancer.

Kingham elaborates on this point, when it makes sense to get genetic testing, and what the results may mean in the Q&A:

Twelve percent of women in the U.S. develop breast cancer; it is a common disease. Yet, only five to ten percent of these women will develop breast cancer because of a hereditary gene mutation.

The best step to take prior to deciding whether or not to proceed with genetic testing is to meet with a genetic counselor. Your doctor can provide a referral. The genetic counselor will take a three generation family history, discuss the testing that might be indicated for you or a family member, and explain the risks and benefits of the testing. They also discuss the potential outcomes of the testing: whether a mutation is found, a mutation is not found, or there are uncertain results. Even when a genetic test is negative, this may not mean that the individual or their family is not at risk for cancer.

At this point you may be wondering: Why bother with genetic testing if it’s only useful for hereditary cancers and a negative test result is no guarantee you’re risk-free? Kingham’s closing comment addresses this question nicely: “I would say that your genes don’t change – they are what they are, and knowing what is in our genes can often help us learn how to take better care of our health.”

Previously: Stanford researchers suss out cancer mutations in genome’s dark spotsAngelina Jolie Pitt’s New York Times essay praised by Stanford cancer expertNIH Director highlights Stanford research on breast cancer surgery choices and Researchers take a step towards understanding the genetics behind breast cancer
Photo by Paolo

Cancer, Genetics, Research, Science, Stanford News

Using CRISPR to investigate pancreatic cancer

Using CRISPR to investigate pancreatic cancer

dna-154743_1280Writing about pancreatic cancer always gives me a pang. My grandmother died from the disease over 30 years ago, but I still remember the anguish of her diagnosis and the years of chemotherapy and surgery she endured before her death. This disease is much more personal to me than many I cover.

Unfortunately, survival rates haven’t really budged since I was in high school, in part because the disease is often not diagnosed until it’s well established. As geneticist  Monte Winslow, PhD, described to me in an email:

Pancreatic cancer is very common and almost uniformly fatal. Human pancreatic cancers usually have many mutations in many different genes but we know very little about how most of them drive pancreatic cancer initiation, development, and progression. Recreating these cancer-causing mutations in cells of the mouse pancreas can generate tumors that look and behave very similarly to human pancreas cancer.

Unfortunately, traditional methods used to generate mouse models of human cancer are very time-consuming and costly.

Winslow, along with postdoctoral scholar Shin-Heng Chiou, PhD, and graduate student Ian Winters, turned to the latest darling of the biochemistry world — the gene-editing system known as CRISPR — to devise a way to quickly and efficiently turn off genes implicated in the development of pancreatic cancer in laboratory mice. Their work will be featured on the cover of Genes and Development on Monday. As Winslow described:

Our goal was use CRISPR/Cas9 genome editing to make altering a gene of interest in pancreas cancer simple and fast. Shin-Heng and Ian worked together to develop novel tools and bring them together to generate this new system that we hope will dramatically accelerate our understanding of pancreas cancer. The increased basic understanding of how this cancer works may ultimately lead to better therapies for patients.

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Genetics, Research, Stanford News

Genetic study supports single migratory origin for aboriginal Americans

Genetic study supports single migratory origin for aboriginal Americans

In a long list of hypotheses going back decades, researchers have tried to explain the peopling of North and South America as a series of separate waves of immigration by ancient people from Siberia. For decades, in fact, researchers have been arguing about how many distinct peoples walked over the massive, 600,000-square-mile land bridge that once connected Siberia and Alaska and, also, how many thousands of years ago each of those migrations occurred.

In the last few years, some researchers have begun to suspect that a single group of Siberians may have walked onto that land bridge and became marooned there for several thousand years before traveling the rest of the way into the Americas. But others have been holding out for a two-wave hypothesis, with a first wave of Asians from as far away as India and a later wave of people from farther north.

Today, in Science, an international team of geneticists, evolutionary biologists, and statisticians concluded that all Native Americans descended from a single immigration event out of Siberia. The team looked at the DNA from 110 modern Native Americans and 23 who died 200 to 6,000 years ago and compared their genomes to those of more than 3,000 individuals from around the world.

One of the lead authors is María Ávila-Arcos, PhD, a postdoctoral researcher in the lab of Stanford professor of genetics Carlos Bustamante, PhD. Ávila-Arcos led many of the statistical analyses for the paper, including comparison of whole human genomes from diverse Native American populations—both modern and ancient. Bustamante is also a co-author, along with Stanford professor of structural biology and of microbiology and immunology, Peter Parham, PhD, five other Stanford researchers, and dozens of researchers from around the world.

“For a long time,” Bustamante told me, “we’ve sought to understand the genetic history of the first people to populate the Americas and how they relate to modern day populations. This project brought together a large interdisciplinary team and amassed the largest data set to date on this problem. We found strong evidence for a single major wave and subsequent divergence of the founding population.”

The new genetic analysis suggests that the first immigrants to America left Siberia no more than 23,000 years ago, and then lived in isolation on the grassy plains of the Beringia land bridge for no more than 8,000 years. Those plains disappeared beneath rising seas 10,000 years ago.

Once in the Americas, ancient Native Americans split into two major lineages about 13,000 years ago. One lineage populated both North and South America and one stayed in North America.

Previously: Kennewick Man’s origins revealed by genetic studyUsing genetics to answer fundamental questions in biology, medicine and anthropology and Melting pot or mosaic? International collaboration studies genomic diversity in Mexico
Video by National Climatic Data Center/NOAA via DarthMaximolonus

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