Genetics

Last night I listened squeamishly to my 13-year-old daughter and her friends compete in a (loud!) Fear-Factor-type eating contest in the other room (a sample dish: gummi worms covered in coleslaw – shudder). Fortunately for her (and all of us, really), the old adage “you are what you eat” is a vast oversimplification of nutrition science; many factors actually influence our overall health and body composition.

A similar simplification existed at one time in genetics, when it was believed that the DNA sequence of our genes determined our biological destiny. But over time scientists have learned that many variables affect how, when and even to what degree these genes are expressed, or transformed, into proteins. For instance, I may have the same DNA sequence for gene A as my friend, but I may make more, or fewer, molecules of protein A than she does, and therefore have a significantly different biological outcome. Unfortunately, it’s been difficult to accurately quantify and compare protein levels among individuals and groups.

Now research led by Stanford geneticists Hua Tang, PhD, and Michael Snyder, PhD, published yesterday in Nature (subscription required), has shown that these variations in gene expression levels are inherited over generations. In other words, your levels of expression of individual genes is likely to be similar to that of your parents. What’s more, genes involved in common processes tend to vary in similar ways – indicating a high degree of coordination of expression. As Tang explained in an e-mail to me:

We’ve found that the abundance of many proteins varies considerably among individuals, and we have identified numerous DNA variants that may influence the protein expression of a neighboring gene. We also showed that proteins that co-vary tend to have related biological functions or physical interactions.

The researchers used a sophisticated variation of a technique called quantitative mass spectrometry to determine the relative level of nearly 6,000 proteins in cells from 95 people from around the world. Until recently, most researchers relied on an indirect, and inexact, method that estimated protein levels within a cell based on the prevalence of RNA messages encoding that protein. Co-first author and research associate Sophie Candille, PhD, (who co-authored the research with postdoctoral scholar Linfeng Wu, PhD) explained:

RNA is in fact an intermediary molecule in the expression of the protein-coding genome. Proteins are the end product and active agents of the cell but their quantification has been challenging and therefore has lagged behind that of RNA.

By analyzing which proteins co-vary, the researchers were able to identify new functional groups that hint at previously unknown protein networks and interactions. Postdoctoral scholar and co-first author Linfeng Wu, PhD, concluded:

This research is important because many proteins are involved in the human immune response and diseases such as cancer. Therefore, the DNA variants that influence gene expression at the protein level are likely to be associated with disease phenotypes.

As Wu explained, the researchers are particularly interested in understanding how variation in protein expression levels affects disease risk or physical attributes. In my case, I can’t help wondering whether I have a genetic predisposition to nausea when I hear talk of eating bananas with Baconnaise or Spam with chocolate sauce (gag). But maybe, my reaction isn’t all that unusual?

Previously: Stanford geneticist talks tracking biological data points and personalized medicine

What if it were possible, when faced with a devastating neurological disease like multiple sclerosis, to coax the brain to heal itself? Unfortunately, we’re probably still years away from any kind of quick fix for these conditions (if, in fact, one exists at all). But recent research by Stanford geneticist Anne Brunet, PhD, describes an intriguing way to delay the onset of a multiple-sclerosis-like disease in laboratory mice. The study is published in the most recent issue of Nature Cell Biology.

We’re excited by the potential implications our study has on demyelinating diseases and injuries

Specifically, the researchers created a type of mouse in which they could turn the expression of a protein called SIRT1 on and off in the neural stem cells in the animals’ brains. (They wanted to investigate SIRT1′s involvement in the disease because it appears to be highly expressed in the brains of mice with multiple sclerosis.) They found that animals in which the protein’s expression was blocked developed the characteristic paralysis of the disorder more slowly than their peers with normal levels of SIRT1 expression.

From our article:

Blocking SIRT1 expression appears to work by promoting the development of neural stem cells in the brain into a type of cell called an oligodendrocyte precursor. These cells, in turn, become the mature oligodendrocytes that wrap the long arms of neurons with myelin — a fatty material necessary to facilitate the transmission of the electrical impulses from one nerve cell to another. In humans, most myelination occurs during infancy and adolescence.

Diseases such as multiple sclerosis wreak havoc in the central nervous system by damaging this protective myelin coating and impeding communication between nerve cells.

Brunet, who last year received a Pioneer Award from the National Institutes of Health for her work in studying the inheritance of longevity, worked with Stanford neurologist and noted multiple sclerosis researcher Lawrence Steinman, MD, to conduct the study. She told me:

We are excited by the potential implications our study has on demyelinating diseases and injuries… It’s intriguing because activating SIRT1 is typically considered to be beneficial for metabolism and health, but in this case, inactivating SIRT1 can provide protection against a demyelinating injury.

Previously: NIH awards nine Stanford faculty funding for innovative research, Black hat in Alzheimer’s, white hat in multiple sclerosis? and Amyloid, schmamaloid: Stanford MS expert finds dreaded proteins may not be all bad.

Does it make a difference if a gene – or group of genes – is inherited from your mother or your father?

That’s the question behind the study of genomic imprinting, a phenomenon in which a small percent of genes are thought to be expressed differently depending on which parent they came from. In particular, animal research suggests imprinting may affect aspects of brain development. Researchers wonder if genomic imprinting might explain differences in brain anatomy seen between men and women, such as men’s larger brain volumes.

A new Stanford study, published today in the Journal of Neuroscience, adds to evidence that genomic imprinting is, in fact, happening in humans’ brains. The finding comes from MRI brain scans performed on a group of young girls with Turner syndrome, a chromosomal disorder in which a girl or woman has one missing or malfunctioning X chromosome. Turner syndrome gives an unusual opportunity to study genetic imprinting, because it allows comparisons of individuals who received a single X from Mom to those who got a single X from Dad. (The typical two-X-chromosome female body expresses a mosaic of Mom’s X and Dad’s X, making it impossible to tease apart the effects of the two parents. Males invariably get their single X chromosome from their mothers, so their cells always express the maternal X.)

The Stanford team, led by Allan Reiss, MD, documented several distinctions between the brains of Turner syndrome girls who have only a maternal X, those with only a paternal X, and typical girls with two X chromosomes, such as differences in the thickness and volume of the cortex, and in the surface area of the brain. The work helps clarify murky results from earlier studies of adults with Turner syndrome, the researchers say, because many adult women with Turner syndrome take estrogen supplements, which may have their own effects on brain development. None of the girls in the new study had taken estrogen.

The most tantalizing part of the paper is the scientists’ comment on the implications of their work for our general understanding of genetic imprinting. In part, they say:

By far, the most consistent finding with regard to sex differences in brain anatomy is the larger brain volume found in males compared with females. Although our groups did not differ on most whole-brain measures, our analyses revealed the existence of significant trends on total brain volume, gray matter volume and surface area, where these variables increased linearly from the Xp [paternal X] group being smallest, to the Xm [maternal X] group being largest, with typically developing girls in between. Considering that typically developing males invariably inherit the maternal X chromosome, while typically developing females inherit both and randomly express one of them in each cell, a linear increase in brain volume as seen in the present study is in agreement with what would be expected if imprinted genes located on the X chromosome were involved in brain size determination.

In other words, men may have their mothers to thank for their larger brains.

Karyotype image from a Turner Syndrome patient by S Suttur M, R Mysore S, Krishnamurthy B, B Nallur R – Indian J Hum Genet (2009).

A growing body of scientific evidence shows that mindful-based therapies, such as meditation, can lower psychological stress and boost both mental and physical health. Now findings recently published in PLoS One suggest that such practices may also change gene activity.

In the small study, researchers recruited individuals who had no prior meditation experience and examined participants’ genetic profile prior to their adoption of a basic daily relaxation practice. The 10- to 20-minute routine included reciting words, breathing exercises and attempts to exclude everyday thought. The New Scientist reports:

After eight weeks of performing the technique daily, the volunteers gene profile was analysed again. Clusters of important beneficial genes had become more active and harmful ones less so.

The boosted genes had three main beneficial effects: improving the efficiency of mitochondria, the powerhouse of cells; boosting insulin production, which improves control of blood sugar; and preventing the depletion of telomeres, caps on chromosomes that help to keep DNA stable and so prevent cells wearing out and ageing.

Clusters of genes that became less active were those governed by a master gene called NF-kappaB, which triggers chronic inflammation leading to diseases including high blood pressure, heart disease, inflammatory bowel disease and some cancers.

Even more interesting was that researchers found evidence to suggest that such changes can occur quickly and that regularly meditating can have lasting health effects:

By taking blood immediately after before and after performing the technique on a single day, researchers also showed that the gene changes happened within minutes.

For comparison, the researchers also took samples from 26 volunteers who had practised relaxation techniques for at least three years. They had beneficial gene profiles even before performing their routines in the lab, suggesting that the techniques had resulted in long term changes to their genes.

Previously: How mindfulness-based therapies can improve attention and health, Study offers insights into how yoga eases stress, Stanford scientists examine meditation and compassion in the brain and Study shows meditation may alter areas of the brain associated with psychiatric disorders
Photo by Georgie Sharp

When I recently learned that my cholesterol was a bit high, I was told that a regular exercise routine and a couple of oatmeal breakfasts per week should do the trick to bring the numbers back to a normal range. But for Brenda Gundell, a genetic disease called Familial Hypercholesterolemia, or FH, means that simple lifestyle changes won’t make for a quick fix.

FH affects cholesterol processing from birth, and while the condition is common – affecting more than 600,000 people in the U.S. – it is diagnosed in less than 10 percent of those who have it. Gundell was only 15 when she first heard about FH; her father, just 39 at the time, had such extreme levels of total cholesterol that they led to a fatal heart attack. Fortunately for Gundell, while the disease can be destructive, it is, in fact, treatable. And, with the help of FH specialists at Stanford’s Preventive Cardiology Clinic, Gundell has kept her cholesterol in check for the last 17 years and is looking forward to a long life.

Grundell’s story is detailed in the Stanford Hospital video above.

A million years ago (all the way back in 2006!) I wrote an article for Stanford Medicine magazine about genetic technologies and the eugenics movement in this country during the first part of the 1900s. I still remember it as one of the most fascinating of my articles to research, demanding as it did that I speak with a variety of geneticists and ethicists about the increasing control that humans have over their genetic destiny.

When, last year, I had the privilege of writing about Stanford biophysicist Stephen Quake, PhD, and his work on whole-genome sequencing of fetuses before birth, I couldn’t help but remember that article of yore. What are we getting ourselves into?

Now MIT Technology Review has recognized whole-genome fetal sequencing as one of its “10 Breakthrough Technologies 2013.” Accompanying the designation is an in-depth review of the technology and its implications – which are far more complex than I could have imagined six years ago. The article contains comments from several experts, including Stanford law professor and bioethicist Hank Greely, JD, and Quake:

Quake says proving that a full genome readout is possible was the “logical extension” of the underlying technology. Yet what’s much less clear to Quake and others is whether a universal DNA test will ever become important or routine in medicine, as the more targeted test for Down syndrome has become. “We did it as an academic exercise, just for the hell of it,” he says. “But if you ask me, ‘Are we going to know the genomes of children at birth?’ I’d ask you, ‘Why?’ I get stuck on the why.” Quake says he’s now refining the technology so that it could be used to inexpensively pull out information on just the most medically important genes.

In my opinion, experts are right to consider the impact of this type of technology before it becomes commonplace. The ethical implications of parents learning their child’s genome sequence within a few weeks of conception – and of possibly using that information to make decisions about the pregnancy’s outcome – are substantial. Thankfully, some really smart people have been asking these questions in one form or another for years, even though the answers seem to end up more grey than black and white. From that ancient article I wrote six years ago:

For example, even though sex selection of embryos fertilized in vitro has many people up in arms, there’s no evidence that it’s on track to alter the gender balance in this country: Boys and girls are nearly equally sought after, says [medical geneticist and associate chair of pediatrics Eugene Hoyme, MD]. And although some parents will terminate a pregnancy if the fetus has a genetic or developmental problem that they feel isn’t compatible with a meaningful life, different families draw this line at dramatically different points in the sand. For some, it’s too much to consider having a child with Down syndrome. For others it’s important to sustain life as long as possible regardless of the severity of the condition. Still others might choose to have a child as similar to them as possible, down to sharing disabilities such as deafness.

“Eugenics is here now,” says Stanford bioethicist David Magnus, PhD. “So what? We allow parents to have virtually unlimited control over what school their child attends, what church they go to and how much exercise they get. All of these things have a much bigger impact on a child’s future than the limited genetic choices available to us now. As long as these are safe and effective, why not give parents this option as well?”

Previously: New techniques to diagnose disease in a fetus, Better know a bioengineer: Stephen Quake and Stanford bioethicists discuss pro, cons of biotech patents
Photo by paparutzi

As you likely heard, the Supreme Court heard oral arguments yesterday in a case that’s of interest to many biomedical researchers. That case, widely known as the “gene patenting case,” has a single question presented: “Are human genes patentable?” It may irk some researchers and clinicians that the answer isn’t a straightforward “no.” But the issues are surprisingly complex: How does one define a “gene,” and a “human” vs. a “synthetic” one at that? What about primers, probes, and cDNA? And what does one mean by “patentable”?

First, a brief lay of the legal landscape. Typically, an inventor cannot patent a “product of nature.” But ever since a 1911 appellate decision (.pdf), a natural product can be patented if it’s “isolated and purified” from its surrounding environment. Thus, the chemical compound adrenaline was itself patented because it was isolated and purified from adrenal glands. Shockingly, the Supreme Court has never directly reviewed this isolated and purified doctrine, even after 102 years.

This all raises the question of whether human genes should be allowed to be patented as a matter of policy, if not law.

And so, on this basis, isolated human genes have long been patented. In 1994, researchers at the University of Utah finally located and sequenced (.pdf) the BRCA-1 and BRCA-2 genes, variants of which put women at astonishingly high risk for early onset breast and ovarian cancer. Those researchers obtained patents on both the isolated sequences and cDNA variants of those, and assigned them to Myriad Genetics, a diagnostic testing company.

Arguments at the Supreme Court - and the justices themselves – grappled with the distinctions between isolated genomic DNA and cDNA. Lower court opinions had made a significant case out of the fact that because the covalent bonds of isolated genomic DNA were cleaved from the surrounding chromosome, an isolated gene was, in fact, a new chemical entity. Similarly, several justices suggested that because cDNA was not found in nature, it too, was patentable – even if it was simply the product of reverse transcribing an mRNA sequence. (For a further breakdown on the oral arguments themselves, see Stanford’s Center for Law and the Biosciences’ oral argument recap.)

But it seems that at least five justices – and thus, a majority – believe that patents on isolated DNA are not eligible for patent protection. They don’t seem to buy the argument that simple covalent cleavage renders something a new chemical entity. The Court and lawyers deployed various analogies to make this point: gold from ore, a piece of wood from a tree, a liver from a patient, etc. It seems less clear, however, whether a majority will similarly rule cDNA to be patent ineligible.

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Until recently, scientists studying whole human genomes focused primarily on variations among the four nucleotides, or “letters”, that make up our DNA. Differences in the sequence, or spelling, of these regions are responsible for diversity among individuals and ethnic groups, and the cause of many diseases. But they’re not the only source of human variation. Odd, but not uncommon, blips of missing or added material–called short insertions and deletions, or “indels”– in between stretches of similarity were not regularly cataloged due in part to technological limitations.

A recent study in Genome Research lead by Stanford geneticist Stephen Montgomery, PhD, has now done just that. Montgomery, along with senior author Gerton Lunter, PhD, from the Wellcome Trust Centre for Human Genetics in the United Kingdoms, found that indels may be a major source of human genetic variation.  According to Montgomery:

In this study, we were able to leverage advances in sequencing technology to systematically characterize this abundant but lesser explored class of human genetic variation. Understanding indels will be essential to further more-complete interpretation of individual genomes.  With this rich catalog of indels, we are now able to identify frequently mutated genes and implicate these variants as causal agents that influence gene expression and complex disorders.

Indels have already been implicated in some disorders such as Huntington’s disease, in which repeated expansions of a short, three-nucleotide stretch increase the severity and decrease the age of onset of the disease. The researchers used data from the 1000 Genomes Project to compare the location and prevalence of more than 1.6 million indels in 179 individuals from three populations. Intriguingly, they found that over half of the indels occur in just four percent of the genome–often in regions where the nucleotide sequence encourages the DNA replication machinery to stutter and slip rather than plodding along tamely.

The study highlights an important class of human genetic variation that, until now, has been largely overlooked, and the researchers are eager to learn how indels have affected human evolution and contribute to disease.

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Genetic and genomic testing for medical purposes is becoming increasingly common. But what should a doctor do if a patient undergoing testing for a disease-causing mutation in one gene is discovered to have another, unrelated mutation for a different, unsuspected condition? The American College of Medical Genetics and Genomics today issued recommendations regarding this very situation (called an “incidental finding”). The results may surprise some people.

ScienceInsider summarized the results nicely in a post earlier today:

Fourteen genetics experts, with the backing of the American College of Medical Genetics and Genomics (ACMG), are proposing a radical shift in how and what patients learn about what’s in their DNA. They argue that anyone whose genome is sequenced for any medical reason should automatically learn whether 57 of their genes put them at risk of certain cancers, potentially fatal heart conditions, and other serious health problems. The information would be provided whether [or not] patients want it—and often when they’re seeking care from a doctor for something else entirely—because, the experts say, knowing the makeup of this DNA could save an individual’s life. The recommendations apply to sequencing children’s DNA as well, even if there’s no preventive care available until adulthood.

Stanford genetic counselor Kelly Ormond was a member of the task force that came up with the guidelines. She elaborated the thinking of the group and the reasons behind the changes to me in a recent conversation:

We believe that there are a number of conditions that a patient would wish to know about, including BRCA1, colon cancer risk and others. This information should be given regardless of the age of the patient because it’s useful information. If the patient is a child, it’s possible that steps can be taken to reduce the risk or to incorporate screening to detect the disease as the child matures. There’s another reason, though. If a child has a mutation that clearly confers increased risk, it’s likely that he or she inherited that mutation from the parents. Informing the parents of their child’s mutation may allow them to undergo relevant screening, and hopefully keep them healthier, as well.

The college’s recommendations are just that: recommendations. Doctors can still make their own judgment calls, or even discuss with the patient or parents prior to the test the types of information they’d like to receive (in some cases, this may mean opting for a lab to process the genetic sample that doesn’t divulge any incidental findings). And the “should be informed” list is limited to those mutations that meet two criteria: They must carry a significantly increased risk of disease and there must be something that can be done clinically to mitigate this risk. Diseases (such as Huntington’s or Alzheimer’s disease, for example) for which there is a clear genetic cause, but no treatment or cure, are not included on the list.

Previously: When it comes to your genetic data, 23andMe’s Anne Wojcicki says: Just own it, Film to document Stanford student’s decision to be genetically tested for Huntington’s disease, and How genome testing can help guide preventative medicine

Ever notice how some people tend to age gracefully with a full head of illustrious locks, while others start sporting a receding hairline after their 30th birthdays? While some blame hair loss on stress or lifestyle habits, such as too much smoking or drinking, and others believe certain soaps or shampoos are the culprits, the answer is likely tied to genetics.

As this newly posted AsapScience video explains, the most influential hair loss gene is located on the X chromosome only and, as a result, baldness is partially hereditary and passed through the maternal side. Watch the short clip to learn more about how genes play a key role in hair loss.