Genetics

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.

Sparks flew at a symposium hosted by the Stanford Center for Health Research on Women & Sex Differences in Medicine, which I attended yesterday. One invited speaker -Louann Brizendine, MD, of the University of California at San Francisco - is the author of a couple of books titled The Male Brain and The Female Brain. Another invited speaker - neuroscientist Daphna Joel, PhD, who’d flown in from the University of Tel Aviv, in Israel - emphatically maintained that there is no such thing as a “male” brain or a “female” brain. “What we know,” she said bluntly, “is that males have brains and females have brains.”

Whatever the semantics of that debate, two things are pretty clear any way you slice it. First, male and female brains are mostly alike. Second, there are measurable and meaningful differences in what goes on inside male versus female brains. As another neuroscientist, UCLA’s Art Arnold, PhD, put it: “Every cell in a female’s brain expresses a set of genes that the cells in a male’s brain express at much lower levels, if at all.”

Adding heft to Arnold’s comment was a presentation by Nirao Shah, MD, PhD, of UCSF. The neuroanatomist showcased research in his lab that had pinpointed specific genes whose activity levels differed significantly in the brains of male and female mice. Many of these genes, he noted, have human analogs that have been implicated in alcoholism, autism, breast and prostate cancers, and more. By conducting rigorous experiments with mice in which one or another of such genes had been put out of commission, Shah and his colleagues were able to tease out the behavioral consequences of specific genes’ inactivation. For example, knocking out a particular gene in female mouse moms results in a massive dimunition in their willingness to defend their nests from intruders - a maternal mandate that normal female mice observe rigorously - yet has no other observable effect on their maternal or sexual behavior. Torpedoing a different gene radically reduces Minnie Mouse’s mating mood; but the Mickeys in which this gene has been trashed “are completely normal, as far as we can tell,” Shah said.

The upshot: Yes, there are significant differences in behavior (and therefore in brain action) and in gene activity in the brain cells of males and females. Those of male and female mice, that is. What about humans’?

Well, nobody was talking about knocking any genes out of people to see if the men indulge in fewer barroom brawls and the women start laughing off their babies’ cries of distress. But there are certainly some strong hints of medically significant differences: The ratio of men to women with autism run somewhere in the neighborhood of 8:1 or even 16:1. Depression is twice as common among women as among men - but only between menarche and menopause. Alzheimer’s disease abounds more in women, even after taking into consideration women’s greater longevity (itself a medically important difference), as does autoimmunity. On the other hand, Parkinson’s and schizophrenia preferentially affect men. There seems to be more at work here than the simple “absorption of gender stereotypes,” and it’s good to see hardcore biologists attacking the problem with all the scientific rigor at their disposal.

Let’s not call the whole thing off.

Previously: A call to advance research on women’s health issues
Photo by namuit

Research recently published in PLOS ONE suggests that genetics may be a primary factor in shaping individuals’ financial decisions. In the paper, Brian Knutson, PhD, associate professor of psychology at Stanford, and colleagues examined how a serotonin gene, known as 5-HTTLPR, influenced participants’ willingness to take risks when investing their money.

As explained in a Stanford Report article published today, we all have two copies, known as alleles, of the 5-HTTLPR gene. Individual combinations can include two short, two long or one short and one long allele. Researchers found that those with two short alleles displayed more neurotic traits and were more risk adverse. Paul Gabrielsen writes:

The researchers asked 60 volunteers from the Bay Area to divvy up $10,000 among three investment options: stocks, bonds or cash. On average, study participants with two short 5-HTTLPR alleles kept 24 percent more of that money in cash than did the two-long-allele carriers, who put more money in stocks.

Knutson and his colleagues had previously measured participants’ financial literacy, cognition and income level, but those factors didn’t explain the variation in investment strategy. Could the gene explain the variation?

“We found that it did,” Knutson said.

Given neurotic participants’ propensity to avoid risk, [Kellogg School of Management professor Camelia Kuhnen, PhD,] hypothesized that they would react just as strongly to a negative outcome. In unpublished research, Kuhnen watched how participants’ brains reacted during a game in which they learned, by trial-and-error, which of two options carried greater financial risk. Short-allele carriers displayed heightened anxiety before making a decision, but reacted no differently than long-allele carriers when they saw a negative outcome.

“The difference between these people is not about how they react to outcomes,” Kuhnen said. “It’s about how, before the choice, they think about the decision.”

The findings, says Knutson, can help in understanding how emotions affect decision making. “You’re not a slave to your genotype,” he notes in the story “If you understand how it’s influencing your behavior, then you have a shot at changing that behavior.”

Photo by Alan Cleaver