Can a Brain Scan Tell You What Drugs to Take and Choices to Make?

The hunt for personality genes could lead to a screening test that reveals what treatments will work best for each individual's psychological makeup.

Carl Zimmer

Ahmad Hariri stands in a dim room at the Duke University Medical Center, watching his experiment unfold. There are five computer monitors spread out before him. On one screen, a giant eye jerks its gaze from one corner to another. On a second, three female faces project terror, only to vanish as three more female faces, this time devoid of emotion, pop up instead. A giant window above the monitors looks into a darkened room illuminated only by the curve of light from the interior of a powerful functional magnetic resonance imaging (fMRI) scanner. A Duke undergraduate—we’ll call him Ross—is lying in the tube of the scanner. He’s looking into his own monitor, where he can observe pictures as the apparatus tracks his eye movements and the blood oxygen levels in his brain.

Ross has just come to the end of an hour-long brain scanning session. One of Hariri’s graduate students, Yuliya Nikolova, speaks into a microphone. “Okay, we’re done,” she says. Ross emerges from the machine, pulls his sweater over his head, and signs off on his paperwork.

As he’s about to leave, he notices the image on the far-left computer screen: It looks like someone has sliced his head open and imprinted a grid of green lines on his brain. The researchers will follow those lines to figure out which parts of Ross’s brain became most active as he looked at the intense pictures of the women. He looks at the brain image, then looks at Hariri with a smile. “So, am I sane?”

Hariri laughs noncommitally. “Well, that I can’t tell you.”

True enough: On its own, Ross’s brain can’t tell Hariri much. But a thousand brains? That’s another matter. Hariri is in the midst of assembling a large cohort of Duke undergraduates and gathering key information—brain scans, psychological tests, and genetic markers—for the Duke Neurogenetics Study. From this mountain of data, Hariri believes he’ll be able to learn a lot about Ross, about himself, about all of us. As a result, someday he may be able to read your DNA and determine your innate level of anxiety, your propensity for drinking, and a range of other psychological traits.

It was just a decade ago that Hariri and colleagues at the National Institutes of Health published what is widely considered the first study linking a particular gene to how our brains work. His subject at the time, the serotonin transporter gene, encodes a protein that helps move the regulatory chemical serotonin into neurons. People carry either short versions of the gene, long versions, or one of each. During the 1990s scientists found that having at least one short version of the serotonin transporter gene increased the odds of suffering from extreme anxiety. The results were intriguing, but other studies failed to confirm a connection.

Hariri and his lab director, Daniel Weinberger, wondered if they could get more concrete answers by comparing people’s genes not just to their behavior or a subjective psychological state, but to brain activity measured by a scan. So they embarked on a study of 28 people, half of whom had one or two short copies of the serotonin transporter gene, and half of whom had two long copies.

The subjects entered the fMRI scanner, where they were shown three faces at a time and asked to indicate which two faces matched. That was a ruse: Hariri wasn’t interested in how well they matched faces. Instead, he wanted to measure how the emotional expressions on the faces triggered changes in each subject’s brain.

In line with prior research, the NIH team had found that fearful or angry faces triggered a strong response from the amygdala, a region of the brain that helps us recognize threats. Now the group found a new nuance. People with a short copy of the gene had a stronger response in the target region of the brain than those with two long copies. Hariri’s success inspired other scientists to look for that connection in other people. All told, almost 30 studies have confirmed the finding and linked short serotonin transporter genes to depression and anxiety-related disorders, marking one of the most replicated associations in psychiatric genetics to date.

To Hariri, it makes sense that it is easier to connect our genes with brain activity than with emotional experiences. The way we feel at any given moment is the result of a staggeringly complex combination of factors. The amygdala interacts with many other parts of the brain, and experiences shape the responses of each of those regions. Genes may influence our emotions, but only by tweaking the way our neurons function. “I’m saying, let’s move closer to what genes actually do,” Hariri says.

Hariri is quick to point out that the serotonin transporter gene is only one small part of the story of our emotions. He estimates that it may account for at best 10 percent of the variation in how people’s amygdalas respond to scared or angry faces. Other genes may also shape how we respond, and our unique personal histories may play a role as well. When it comes to genes and personality, “we’re at the earliest stages of understanding,” he admits.

Over the past decade Hariri has looked for evidence of how other genes affect other aspects of our minds, including self-control and memory. The job hasn’t been easy. One of his challenges has been deciding which genes to investigate.

A traditional way to target a candidate gene is to identify a molecule or process important to, say, emotion, and then go back and find the genes that control it. Serotonin is already known to be involved in emotion—antidepressant drugs like Prozac bind to serotonin transporters—so it makes sense to look to the serotonin transporter gene to help explain variations in people’s emotions. Scientists can also find clues by studying severe genetic disorders. Certain mutations might cause severe retardation, for instance, pointing to specific places to look for a link between genes and intelligence.

But this kind of search is very slow and of limited scope. In 2009 Hariri found a way to accelerate his search. He realized that the new commercial genetic testing labs springing up had the technology he needed to find many more behavior-related genes. For a fee, the California company 23andMe can examine a million different sites in a customer’s genome. Variations at those sites have been linked to diseases such as diabetes and Alzheimer’s. Hariri recognized that he could redirect 23andMe’s test results to his own ends, trawling the data for gene variants linked to the brain activity he recorded in his scans. The more people Hariri studied, the more confidence he could have that these links were authentic. His hope is that a thousand subjects might be a large enough sample to detect even genes that have only a weak effect on the brain.

In January 2010, the Duke Neurogenetics Study was launched. The volunteers, a group that took no psychiatric medicine, underwent a battery of cognitive tests and a psychological interview, in which a researcher asked about their personal history, including drug and alcohol use and the stressful experiences of their lives. Then each subject spent an hour in an fMRI scanner while Hariri ran tests. In one, subjects were shown the terrified or angry faces. In another, they were shown the back of a playing card and asked to guess whether the number on the other side was high or low. Correct guesses could win up to $10. Previous studies have shown that even a simple game like this can activate the brain’s reward-processing regions, for which Hariri wants to find the genetic controls. After the scans, volunteers donated saliva samples for genetic testing at 23andMe.

Each time Hariri and his collaborators added another 200 volunteers to their database, they updated their findings to see if any patterns had emerged. Already they have found some promising results in a gene that codes for a brain enzyme called FAAH. Variations on the FAAH gene can alter how people perceive threats and rewards. Hariri has found that students with a high reward response report drinking more than other students when they experience stress—but only if they also had a lower-than-average threat response. “That’s the double whammy,” he says. But the results are preliminary. It is possible that by the time Hariri gets all 1,000 subjects into his database, that particular link will have vanished. “We have our fingers crossed it will still be there,” he says.

Hariri’s long-term goal is to create a comprehensive genetic test for the mind. “It’s a dream of mine,” he says. Such a test might show how well Prozac or some other psychiatric drug would work on one particular person’s depression. It might also tell people how vulnerable they are to anxiety in the aftermath of a traumatic event.

Knowing their vulnerabilities might allow people to protect themselves in advance. In previous studies, Hariri found that a certain amygdala response makes subjects more prone to anxiety, but only if they lack a strong social support network. If researchers could identify and screen for the responsible genes, such people would know that solitude could leave them vulnerable. “It’s not like we have to spend a decade in a lab to develop a drug,” Hariri says. “Friends and family might work.”

Carl Zimmer is an award-winning biology writer and author of The Tangled Bank: An
Introduction to Evolution. His blog, The Loom, runs on DISCOVER at blogs.discovermagazine.com/loom

http://discovermagazine.com/2012/may/04-the-brain-can-tell-you-what-drugs-take-choices

From the May 2012 issue; published online April 18, 2012

How humans got big brains, barbless penises

Julie Steenhuysen

CHICAGO (Reuters) – Missing chunks of DNA responsible for turning genes on and off help explain some key differences between chimpanzees and humans -- including why humans have big brains and why the human penis is not covered with prickly spines, U.S. researchers said on Wednesday.

The study, published in the journal Nature, reinforces the notion that genes that control the activity of other genes play a big role in what makes humans so different from other mammals.

To study this, David Kingsley of the Howard Hughes Medical Institute and Stanford University School of Medicine in California and colleagues compared the genetic code of humans to chimpanzees -- man's closest relative -- and other mammals.

They found 510 gene segments that are present in chimps and other mammals, but are missing in humans.

Nearly all of these were regulatory genes -- genetic switches that turn up or down the volume of nearby genes.

Then the team did a computer analysis to identify deleted DNA segments that were clustered around particular genes.

"We saw more changes than you would expect near genes involved in steroid hormone signaling," Kingsley said in a statement.

A number of deletions also appeared near genes involved in brain development.

The team kept narrowing the pool until they found a few dozen genes that they thought were involved in the evolution of particular human traits.

They found one of sections of DNA deleted in the human genome was responsible for producing sensory whiskers, such as those in mice, and prickly spines, like those found on the penises of many mammals.

"People are always surprised to hear that the penis of many organisms are covered with these spines," Kingsley said in a telephone interview.

He said penile spines, or barbs, are typically present in species that mate quickly, such as male chimpanzees who must compete to fertilize one or two receptive females.

These spines -- made from keratin, the protein found in fingernails -- often lie over sensory receptors, and some experiments suggest removing them makes copulation last longer.

For humans, losing these penile spines might have prolonged intercourse and helped make monogamous relationships a more attractive option, the team said.

Even more interesting to Kingsley, however, is that another of the DNA deletions was located near a gene that kept brain cell growth in check. The deletion of this DNA may have contributed to the development of larger brains in humans, he said.

Both of these traits may be related to meeting the reproductive needs of humans, which give birth to babies with large brains, requiring parents to mate in pairs -- at least long enough to care for their big-headed offspring.

"Pair bonding is good if you are trying to raise relatively helpless infants," Kingsley said.

More than just explaining physical differences in human evolution, however, the team hopes eventually to discover important physiological differences, including why humans are susceptible to diseases such as arthritis, cancer, malaria, HIV, Alzheimer's and Parkinson's.

(Editing by Philip Barbara)

http://news.yahoo.com/s/nm/20110309/hl_nm/us_humans_dna

本文於 修改第 1 次

Chromosomes Follow Tricky Path to Make Effective Sperm

LiveScience.com

They say opposites attract, and somehow even the wildly different X and Y chromosomes are able to pair up during sperm formation. New research shows how complex that process is, and it pinpoints a step in the process that can go awry, leading to sex-chromosome diseases or infertility.

The research team, which conducted its study on mice, thinks the results also would apply to humans and eventually could result in a new infertility treatment.

Lead researcher Liisa Kauppi, of the Memorial Sloan-Kettering Cancer Center, discovered that the X and Y chromosomes have multiple mechanisms to make sure this unlikely pair are able to combine and effectively separate into individual and viable sperm.

"This is really the Achilles’ heel, the most difficult region of the genome to pair, so that's why these mechanisms have evolved," co-author Maria Jasin, also of Sloan-Kettering Cancer Center, told LiveScience.

Kauppi noted, "the X and Y chromosomes really behave quite differently than the rest of the chromosomes."

Crossed chromosomes

The miracle of conception is not actually a miracle; the bodies of all mammals go through a special type of cell division to make sperm and egg cells. Each cell carries two sets of genes (sequences of DNA), which are twisted into thread-like chromosomes, except for egg and sperm cells, which have only one set.

During fertilization, the half of mom's chromosome set (in the egg) gets paired with the half of dad's set contained in the sperm.  The two sets are very similar, but contain certain differences, so they are called "sister chromosomes." This new set of chromosomes grows into a full-sized human, which then makes it's own sperm or eggs. When the cell gets ready to divide to make sperm, the two sets of chromosomes copy themselves and line up with their sisters in pairs.

To ensure high genetic diversity when the chromosomes pair, they play a game of switcharoo and swap some of their genetic information. They do this by cutting both sister chromosomes in the same place, called a "double-strand break," and then stitching the swapped portion into place, called a "crossover," or recombination.  

"We understand a great deal about the actual mechanism of recombination,” said Scott Hawley, of Stowers Institute for Medical Research in Kansas City, Mo., who wasn't involved in the research. However, “one of the areas that still remains pretty opaque is how cells control where recombination occurs."

Recombination happens pretty easily in most chromosomes, which are very similar to each other and don't need too much help to pair up anywhere along their length. The confusion comes with the male's sex chromosomes – the X and Y (females have two X's which can crossover like any other pair). These two chromosomes are vastly different in size, shape and the sequence of their nucleotides (the chemicals that make up the DNA ladder molecule) yet they are required to pair up and cross over like any other chromosome pair. 

Sexy swapping

The X and Y chromosomes have a tiny region, covering less than 1 percent of their length, where they can match up and perform this strand-swapping. The cells have to make sure to cross over the DNA in this tiny matching area to make viable sperm. If they can't, the X and Y chromosomes won't divide and the sperm cell will die, or genetic diseases such as Klinefelter's (where the child ends up with two Xs and one Y) or Turner's (a single X) could occur.

Kauppi studied sperm formation in normal mice and noticed that the sex chromosome crossover happens after the rest of the chromosomes are paired. The reason simply could be that they take longer to make the double-strand breaks.

But then the team tested mice with different forms of the protein that controls this crossover process, called SPO11beta or SPO11alpha. For the male mice that expressed only SPO11beta, they were infertile about 70 percent of the time; that wasn't the case for males with the alpha form of the protein, which is important for viable sperm formation, Kauppi said.

It is likely that this sex chromosome crossover happens the same way in humans, which is what Kauppi is studying next. Based on rates of X-Y pairing-related diseases, co-author Scott Keeney, also of Sloan-Kettering, noted "there are some individuals who are more prone to having the X and Y misbehave."

"There are many patients who show up in clinics where the actual cause of infertility isn't known," Keeney told LiveScience.

Diagnostic tests could be created to determine if male infertility is a result of these processes, and possible treatment options could be developed. Tests also could help diagnose the likelihood of a sex chromosome anomaly, like Klinefelter's or Turner's syndrome.  

"This opens up the field in a really exciting way," Hawley told LiveScience. "I really thought this was a terrific paper."

You can follow LiveScience staff writer Jennifer Welsh on Twitter @The History and Future of Birth Control

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http://news.yahoo.com/s/livescience/20110224/sc_livescience/chromosomesfollowtrickypathtomakeeffectivesperm

Tiny water flea has more genes than you

WASHINGTON (AFP) – A tiny, translucent water flea that can reproduce without sex and lives in ponds and lakes has more genes than any other creature, said scientists who have sequenced the crustacean's genome.

Daphnia pulex, named after the nymph in Greek mythology who transforms into a tree in order to escape the lovestruck Apollo, has 31,000 genes compared to humans who have about 23,000, said the research in the journal Science.

Often studied by scientists who want to learn about the effects of pollution and environmental changes on water creatures, the almost-microscopic freshwater Daphnia is the first crustacean to have its genome sequenced.

But just because this creature -- viewed as the canary in the gold mine of the world's waters -- has more genes doesn't necessarily mean they are all unique, explained project leader John Colbourne.

"Daphnia's high gene number is largely because its genes are multiplying, by creating copies at a higher rate than other species," said Colbourne, genomics director at the Center for Genomics and Bioinformatics.

Daphnia has a large number of never-before seen genes, as well as a big chunk of the same genes found in humans, the most of any insects or crustacean so far known to scientists.

"More than one-third of Daphnia's genes are undocumented in any other organism -- in other words, they are completely new to science," said Don Gilbert, coauthor and Department of Biology scientist at IU Bloomington.

These unique and previously unknown genes are "involved in response to the environment," the study said.

James Klaunig, professor of environmental health at Indiana University Bloomington, said the genome will help scientists study the effect of environmental pollutants on humans.

"Genome research on the responses of animals to stress has important implications for assessing environmental risks to humans," Klaunig said.

"The Daphnia system is an exquisite aquatic sensor, a potential high-tech and modern version of the mineshaft canary," he said.

"With knowledge of its genome... the possible effects of environmental agents on cellular and molecular processes can be resolved and linked to similar processes in humans."

The water flea can be found throughout North America, Europe and Australia.

The Daphnia Genomics Consortium, led by the Center for Genomics and Bioinformatics at IU Bloomington and the US Department of Energy's Joint Genome Institute, included more than 450 investigators around the globe.

http://news.yahoo.com/s/afp/20110203/sc_afp/scienceusenvironmentgenome