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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

Addiction, Behavioral Science, Genetics, Research

Alcohol-use disorder can be inherited: But why?

Alcohol-use disorder can be inherited: But why?

man-69287_1280Drop into any support group meeting, and you’ll likely find that many of the addicts there had a parent who was also an addict. It’s estimated that alcoholism (now sometimes called alcohol-use disorder) is 50 percent heritable, although researchers have struggled to identify genes specifically associated with the condition.

The hunt continues for alcohol-use disorder related genes, and a new frontier in the field is the study of the epigenome, a term that refers to inherited changes that affect gene expression, rather than the genes themselves. A new review by a team based at the University of Pittsburgh School of Medicine in the journal Alcohol compiles all that is known about the effects of the epigenome on alcohol inheritance.

“Only recently, with improvements in technology to identify epigenetic modifications in germ cells, has it been possible to identify mechanisms by which paternal ethanol (alcohol) exposure alters offspring behavior,” the researchers wrote.

The basic mechanism is that traits can be passed on through modification of the proteins associated with DNA; these proteins control how genes are expressed. Several studies have examined the role of a father’s alcohol use in the time period surrounding conception, finding their children more likely to suffer from some psychiatric disorders; in research on mice, some effects of paternal alcohol use include low birth weight and decreased grooming. These effects are likely attributed to the alteration of the development of sperm, the researchers write.

Many mysteries remain, leaving plenty of opportunities for additional research. Now, the team is starting to examine how paternal exposure affects offspring’s alcohol consumption.

Previously: Alcoholism: Not just a man’s problem, Could better alcohol screening during doctor visits reduce underage drinking? and Are some teens’ brains pre-wired for drug and alcohol experimentation?
Image by geralt

Big data, Cancer, Genetics, Immunology, Research, Science, Stanford News

Linking cancer gene expression with survival rates, Stanford researchers bring “big data” into the clinic

Linking cancer gene expression with survival rates, Stanford researchers bring "big data" into the clinic

Magic 8 ball“What’s my prognosis?” is a question that’s likely on the mind, and lips, of nearly every person newly diagnosed with any form of cancer. But, with a few exceptions, there’s still not a good way for clinicians to answer. Every tumor is highly individual, and it’s difficult to identify anything more than general trends with regard to the type and stage of the tumor.

Now, hematologist and oncologist Ash Alizadeh, MD, PhD; radiologist Sylvia Plevritis, PhD; postdoctoral scholar Aaron Newman, PhD; and senior research scientist Andrew Gentles, PhD, have created a database that links the gene-expression patterns of individual cancers of 39 types with the survival data of the more than 18,000 patients from whom they were isolated. The researchers hope that the resource, which they’ve termed PRECOG, for “prediction of cancer outcomes from genomic profiles” will provide a better understanding of why some cancer patients do well, and some do poorly. Their research was published today in Nature Medicine.

As I describe in our release:

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. By doing so, it may be possible to learn what has gone wrong in the cancer cells, and give ideas as to how best to block the cells’ destructive growth. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

Instead, the researchers pulled back and sought patterns that might become clear only when many types of cancers, and thousands of patients were lumped together for study:

Gentles and Alizadeh first collected publicly available data on gene expression patterns of many types of cancers. They then painstakingly matched the gene expression profiles with clinical information about the patients, including their age, disease status and how long they survived after diagnosis. Together with Newman, they combined the studies into a final database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” said Alizadeh. “Then we could ask what we could learn more broadly.”

The researchers found that they were able to identify key molecular pathways that could stratify survival across many cancer types:

In particular, [they] found that high expression of a gene called FOXM1, which is involved in cell growth, was associated with a poor prognosis across multiple cancers, while the expression of the KLRB1 gene, which modulates the body’s immune response to cancer, seemed to confer a protective effect.

Alizadeh and Plevritis are both members of the Stanford Cancer Institute.

Previously: What is big data?Identifying relapse in lymphoma patients with circulating tumor DNA,  Smoking gun or hit-and-run? How oncogenes make good cells go bad and Big data = big finds: Clinical trial for deadly lung cancer launched by Stanford study
Photo by CRASH:candy

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