by MITx: 7.28.1x Molecular Biology
Looking across evolutionary time and the genomic landscapes of humans and mice, an international group of researchers has found powerful clues to why certain processes and systems in the mouse — such as the immune system, metabolism and stress response — are so different from those in people. Building on years of mouse and gene regulation studies, they have developed a resource that can help scientists better understand how similarities and differences between mice and humans are written in their genomes.
Their findings — reported by the mouse ENCODE Consortium online Nov. 19, 2014 (and in print Nov. 20) in four papers in Nature and in several other publications — examine the genetic and biochemical programs involved in regulating mouse and human genomes. The scientists found that, in general, the systems that are used to control gene activity have many similarities in mice and humans, and have been conserved, or continued, through evolutionary time.
The results may offer insights into gene regulation and other systems important to mammalian biology. They also provide new information to determine when the mouse is an appropriate model to study human biology and disease, and may help to explain some of its limitations.
The latest research results are from the mouse ENCODE project, which is part of the ENCODE, or ENCyclopedia Of DNA Elements, program supported by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. ENCODE is building a comprehensive catalog of functional elements in the human and mouse genomes. Such elements include genes that provide instructions to build proteins, non-protein-coding genes and regulatory elements that control which genes are turned on or off, and when.
“The mouse has long been a mainstay of biological research models,” said NHGRI Director Eric Green, M.D., Ph.D. “These results provide a wealth of information about how the mouse genome works, and a foundation on which scientists can build to further understand both mouse and human biology. The collection of mouse ENCODE data is a tremendously useful resource for the research community.”
“This is the first systematic comparison of the mouse and human at the genomic level,” said Bing Ren, Ph.D., co-senior author on the Consortium’s main Nature study and professor of cellular and molecular medicine at the University of California, San Diego. “We have known that the mouse was mostly a good model for humans. We found that many processes and pathways are conserved from mouse to human. This allows us to study human disease by studying those aspects of mouse biology that reflect human biology.”
In many cases, the investigators found that some DNA sequence differences linked to diseases in humans appeared to have counterparts in the mouse genome. They also showed that certain genes and elements are similar in both species, providing a basis to use the mouse to study relevant human disease. However, they also uncovered many DNA variations and gene expression patterns that are not shared, potentially limiting the mouse’s use as a disease model. Mice and humans share approximately 70 percent of the same protein-coding gene sequences, which is just 1.5 percent of these genomes.
For example, investigators found that for the mouse immune system, metabolic processes and stress response, the activity of some genes varied between mice and humans, which echoes earlier research. The researchers subsequently identified genes and other elements potentially involved in regulating these mouse genes, some of which lacked counterparts in humans. “We look at the mouse genome as a book with certain sections added and certain sections taken out by evolution. That may be a result of mouse and human adaptation to their respective environments,” said Dr. Ren, who is also a member of the Ludwig Institute for Cancer Research, San Diego.
“In general, the gene regulation machinery and networks are conserved in mouse and human, but the details differ quite a bit,” noted co-senior author Michael Snyder, Ph.D., director, Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California. “By understanding the differences, we can understand how and when the mouse model can best be used.”
In the Nature papers, the researchers compared gene transcription, chromatin modification and other processes that control gene activity in a wide range of mouse and human tissues and cell types. Transcription is the process by which a gene’s instructions are read. Chromatin is the protein packaging that helps regulate genome function by controlling access to DNA; changes in this packaging can affect gene regulation.
While both species carry a core group of similar programs to regulate gene activity, the researchers found that differences appeared in specific tissue and cell types.
“We didn’t know before these results came out that there are a large number of genes with expression levels systematically different between mouse and human,” said Ross Hardison, Ph.D., director, Huck Institute for Comparative Genomics and Bioinformatics at Pennsylvania State University, University Park, and a co-senior author on the mainNature study and other publications. “Now we know which genes have expression patterns conserved between mouse and humans. For biological processes using these genes, mouse is an excellent model for aspects of human biology.” Dr. Hardison noted that the opposite is also true: researchers need to take into account systematic differences in gene expression patterns between the species when considering the mouse as a model for humans.
Two companion studies further illustrate differences between mouse and human. Co-senior Nature author John Stamatoyannopoulos, M.D., associate professor of genome sciences and medicine at the University of Washington, Seattle, and his colleagues compared more than 1.3 million genome locations called DNase 1 hypersensitivity sites (which identify regulatory DNA) in 45 mouse cell and tissue types to those in humans. They reported in Science that about 35 percent of these elements were shared by mouse and human and were active in different types of cells. “We looked inside the shared regulatory sequences and found mouse and human genomes to have a common language in regulation, but that there is a tremendous amount of flexibility in evolution. For example, an element active in the mouse liver might be repurposed to be active in the brain in the human,” he said. “Such repurposing represents a tremendously facile switch that nature can use to achieve regulatory control.”
In a study in Proceedings of the National Academy of Sciences, Dr. Snyder and his colleagues compared gene expression in 15 different tissue types in mice and humans. Contrary to previous evidence, they found that some aspects of the gene readouts were more similar between different tissues in the same species than they were between the same tissues in both species.
More than a dozen related studies also appear or will appear in journals such asGenome Research, Genome Biology, Blood, and Nature Communications.
ENCODE data are freely shared with the biomedical community, and the mouse resource has been used by outside researchers in about 50 publications to date.
French post-Impressionist artist Paul Gauguin famously once said, “I shut my eyes in order to see,” meaning he shut out the rest of the world to come up with great ideas.
More than a century later, scientists are able to prove Gauguin was onto something.
This moment occurs when you go from being stuck on a problem to having the ability to reinterpret a “stimulus, situation, or event to produce a nonobvious, nondominant interpretation.”
Through their extensive research, Kounios, a professor of psychology at Drexel University, and Beeman, of Northwestern, found that milliseconds before epiphanies, the activity in the brain’s visual area basically shuts down. That’s the moment right before the solution hits you. Kounios calls this moment a “brain blink,” which is when your brain turns inward just before the “aha!”
A simple example to illustrate this, Kounios tells Fast Company, is when you ask someone a tough question and they look away or down so they can think of the solution. In that moment, their brain is momentarily reducing visual input.
In the lab, Kounios and Beeman, authors of the upcoming book The Eureka Factor, used puzzles and problems to study brain activity. They found that right before the problem is presented, activity in the visual part of an analytical person’s brain would amp up to take in as much information as possible. On the other hand, the visual cortex would shut down for those who don’t solve problems in a methodical way, which allows them to block out the environment, look inward, and “find and retrieve subconscious ideas,” says Kounios.
While more creative people shut down visual information before their “aha!” moment, these people tend to take in more visuals compared to others on a daily basis. Kounios says when these people walk down the street, they tend to study others, take in information, and may seem very scattered about their own agenda. However, the information they take in and synthesis may be a product of unconscious processing for years before ideas emerge. Those who are more analytical are more focused with their attention. When they walk down the street, they are focused on where they’re going and how they’re going to get there. They tend not to stray into different areas of thoughts.
Research on the “aha!” moment began more than a century ago, but it wasn’t until neuroimaging, which shows where cognitive change is happening, and electrophysiological techniques, which shows when cognitive change is happening, were scientists able to see what happens when the brain goes from a state where there’s no idea to a flow of creative insights.
Before brain imaging was readily available, researchers believed that the mental process was a gradual change, says Kounios. Your brain is always working, acquiring information that you can brew or incubate for years, but the change right before all that information pops into awareness isn’t gradual. It’s a burst of activity that can happen at any time and there’s nothing that you can do to force or coax it, he explains.
What you can do is be receptive and expose yourself to a lot of insight triggers. Also, positive moods tend to promote eureka moments. On the contrary, anxiety will promote analytical thoughts.
Lastly, Kounios advises to people who want epiphanies to get more sleep.
“There’s a process of memory consolidation that happens when you sleep,” he says. “These memories are transformed … they bring out hidden details or non-obvious connections between ideas. Getting lots of sleep leads to insights.”
If all else fails, simply follow Gauguin’s process and look inward instead of outward to come up with your next best ideas.
A genetic analysis of 409 pairs of gay brothers, including sets of twins, has provided the strongest evidence yet that gay people are born gay. The study clearly links sexual orientation in men with two regions of the human genome that have been implicated before, one on the X chromosome and one on chromosome 8.
The finding is an important contribution to mounting evidence that being gay is biologically determined rather than a lifestyle choice. In some countries, such as Uganda, being gay is still criminalised, and some religious groups believe that gay people can be “treated” to make them straight.
“It erodes the notion that sexual orientation is a choice,” says study leader Alan Sanders of the NorthShore Research Institute in Evanston, Illinois.
The region on the X chromosome picked out by the study, called Xq28, wasoriginally identified in 1993 by Dean Hamer of the US National Institutes of Health in Bethesda, Maryland, but attempts to validate the finding since have been mixed. The other region picked out is in the twist in the centre of chromosome 8. Known as 8q12, it was first signposted in 2005.
The latest study involves about three times as many people as the previous largest study, which means it is significantly more statistically robust.
Over the past five years, Sanders has collected blood and saliva samples from 409 pairs of gay brothers, including non-identical twins, from 384 families. This compares, for example, with 40 pairs of brothers recruited for Hamer’s study.
The team combed through the samples, looking at the locations of genetic markers called single nucleotide polymorphisms (SNPs) – differences of a single letter in the genetic code – and measuring the extent to which each of the SNPs were shared by the men in the study.
The only trait unequivocally shared by all 818 men was being gay. All other traits, such as hair colour, height and intelligence, varied by different degrees between each brothers in a pair and between all sets of brothers. Therefore, any SNPs consistently found in the same genetic locations across the group would most likely be associated with sexual orientation.
Only five SNPs stood out and of these, the ones most commonly shared were from the Xq28 and 8q12 regions on the X chromosome and chromosome 8 respectively. But this doesn’t mean the study found two “gay genes”. Both regions contain many genes, and the next step will be to home in on which ones might be contributing to sexual orientation.
Sanders says he has already completed the work for that next step: he has compared SNPs in those specific regions in gay and straight men to see if there are obvious differences in the gene variants, and is now preparing the results for publication. “Through this study, we have the potential to narrow down to fewer genes,” says Sanders.
Not just genetic
Whatever the results, Sanders stresses that complex traits such as sexual orientation depend on multiple factors, both environmental and genetic. Even if he has hit on individual genes, they will likely only have at most a small effect on their own, as has also been seen in studies of the genetic basis for intelligence, for example.
Other researchers who have looked at the biological origins of sexual orientation have welcomed the latest findings, saying they help resolve contradictory results from earlier, smaller studies. “The most pleasing aspect is that the confirmation comes from a team that was in the past somewhat sceptical and critical of the earlier findings,” says Andrea Camperio Ciani of the University of Padua in Italy.
“This study knocks another nail into the coffin of the ‘chosen lifestyle’ theory of homosexuality,” says Simon LeVay, the neuroscientist and writer who, in 1991, claimed to have found that a specific brain region, within the hypothalamus, is smaller in gay men. “Yes, we have a choice in life, to be ourselves or to conform to someone else’s idea of normality, but being straight, bisexual or gay, or none of these, is a central part of who we are, thanks in part to the DNA we were born with.”
“Much hard work now lies ahead to identify the specific genes involved and how they work, as well as to find equivalent genes in women,” he adds.
Hamer himself, now a documentary film-maker, is delighted with the result. “Twenty years is a long time to wait for validation, but now it’s clear the original results were right,” he says. “It’s very nice to see it confirmed.”
Noroviruses are best known for the diarrhea and vomiting they produce in people. But a mouse norovirus can do the work of friendly gut bacteria to protect the intestines and boost the immune systems of mice, researchers from New York University School of Medicine report November 19 in Nature. The findings add to other studies suggesting that some of the many viruses infecting people and animals can help, not hurt (SN: 1/11/14, p. 18).
Previous research has shown that in mice raised without any gut microbes, the intestines don’t develop properly and the immune system is frail. A two-week course of antibiotics that kills gut bacteria can also weaken the immune system and lead to thin intestinal lining, the researchers found. Several different strains of norovirus could reverse those problems.
Norovirus also helped fight a disease-causing bacterium called Citrobacter rodentium.
Maybe you have a fitness tracker. Maybe you’ve gotten your genome sequenced before. Probably your medical records are kept in electronic, instead of paper, form. Now some companies are seeking to combine all those things and more into a talking, personalized, health-advice app. Not sure when to give yourself your next insulin shot after having a croissant for breakfast? You can ask the app. How much exercise should someone with your genetic makeup be getting? The app will give you suggestions.
At least, that’s the goal of the app-makers, who include developers from IBM and a startup called Pathway Genomics. If the app, called Pathway Panorama, works as expected, it will be one of the most detailed and personalized health-advice apps we’ve ever heard of. It will bring an unprecedented amount of information to bear on the advice it gives you.
Pathway Genomics can sequence your DNA and provide an analysis as to what what those jumbled letters mean. Meanwhile, IBM’s artificial intelligence engine, Watson, will make it possible for the app to understand what users are asking it. Watson also is able to read and understand information online, so it will be able to do things like “read” published medical literature to help answer users’ questions. After all, that’s how Watson won Jeopardy, when IBM first introduced it.
Pathway expects to have the Panorama app ready by mid-2015, according to a blog post by Pathway chief medical officer Michael Nova. Nova didn’t offer any pricing details, but said that it would entail a “small monthly fee.” The app effort is being funded by IBM, which invested an “undisclosed amount” in Pathway Genomics, Wired reports. The funding is part of IBM’s efforts to sell Watson as a multipurpose engine for apps and software.
When Pathway Panorama comes out, it will be interesting to see just how detailed it is. The job of combining genetic test results and a patient’s history into health advice has traditionally fallen to highly-trained humans, such as doctors and genetic counselors. Even then, it’s a hard job because the science linking genes and health isn’t always easy to interpret. How well can a computer program do that? Even if a program is pretty savvy at that task, how much, legally, can it do?
Around this time last year, the U.S. Food and Drug Administration forced the direct-to-consumer genetics-reading company 23andMe to stop giving out health diagnoses. Pathway Genomics’ tests are still legal because they require a doctor to order them; it’s pretty indisputable that a doctor’s office should have the power to order genetics tests. The upcoming app is a different beast, however. The FDA regulates some health apps—ones it considers as offering diagnoses or treatment advice—but it’s unclear whether Panorama will fall under the FDA’s purview… or what the company may leave out, if it tries to design the app not to require FDA clearance.
Scientists say that they have identified the parts of the brain that are responsible for generating these spooky sensations.
They have also created an experiment that makes some people feel like there is a ghost nearby.
The research is published in the journal Current Biology.
There are many tales of the paranormal, but an often-reported phenomenon is that of the invisible apparition.
Dr Giulio Rognini, from the Swiss Federal Institute of Technology (EPFL), says: “The sensation is very vivid. They feel somebody but they cannot see it. It is always a felt presence.”
He said it was common in those who experience extreme conditions, such as mountaineers and explorers, and people with some neurological conditions, among others.
“What is astonishing is that they frequently report that the movements they are doing or the posture they are assuming at that specific moment is replicated by the presence. So if the patient is sitting, they feel the presence is sitting. If they are standing, the presence is standing, and so on,” he explained.
To investigate, the researchers scanned the brains of 12 people with neurological disorders, who had reported experiencing a ghostly presence.
They found that all of these patients had some kind of damage in the parts of the brain associated with self-awareness, movement and the body’s position in space.
In further tests, the scientists turned to 48 healthy volunteers, who had not previously experienced the paranormal, and devised an experiment to alter the neural signals in these regions of the brain.
They blindfolded the participants, and asked them to manipulate a robot with their hands. As they did this, another robot traced these exact movements on the volunteers’ backs.
When the movements at the front and back of the volunteer’s body took place at exactly the same time, they reported nothing strange.
But when there was a delay between the timing of the movements, one third of the participants reported feeling that there was a ghostly presence in the room, and some reported feeling up to four apparitions were there.
Two of the participants found the sensation so strange, they asked for the experiments to stop.
The researchers say that these strange interactions with the robot are temporarily changing brain function in the regions associated with self-awareness and perception of the body’s position.
The team believes when people sense a ghostly presence, the brain is getting confused: it’s miscalculating the body’s position and identifying it as belonging to someone else.
Dr Rognini said: “Our brain possesses several representations of our body in space.
“Under normal conditions, it is able to assemble a unified self-perception of the self from these representations.
“But when the system malfunctions because of disease – or, in this case, a robot – this can sometimes create a second representation of one’s own body, which is no longer perceived as ‘me’ but as someone else, a ‘presence’.”
The researchers said that their findings could help to better understand neurological conditions such as schizophrenia.
Your starbase is almost complete. All you need is a few more tons of ore. You could take the afternoon to mine it from an asteroid field, but you’ve heard of a Ska’ari who trades ore for cheap. So you message your alliance, use your connections to set up a meeting, and hop in your spacecraft. It’s good to have friends, even if they are virtual.
An online science fiction game may not seem like the ideal place to study human behavior, but physicist Stefan Thurner has shown that the way people act in the virtual world isn’t so different from how they act in the real one. Thurner studies all sorts of complex systems at the Medical University of Vienna, so when one of his doctoral students just happened to create one of the most popular free browser-based games in Europe, Thurner suggested using the game, called Pardus, to study the spontaneous organization of people in a closed society. For almost three-and-a-half years, they monitored the interactions of roughly 7000 active players at one time within the game’s virtual world.
Unlike in real life, Pardus players’ moves are tracked and their interactions are recorded automatically by the game. “We have information about everything,” Thurner says. “We know who is where at what point in time, … who exchanges things or money with whom, who is friends with whom, … who hates someone else, who collaborates with whom in entrepreneurial activities, who is in a criminal gang with whom, etc. Even though the society is artificial, it’s a human society.”
Thurner was especially interested in testing the theory in anthropology that there is a limit to the number of face-to-face relationships a person can maintain at once. “One hundred and fifty is the number of people you can have meaningful relationships with,” at least when you’re talking about real-world interactions, says Robin Dunbar, an anthropologist at the University of Oxford in the United Kingdom who discovered the limit and was not involved in the new work. “This turns out to be correlated with core areas of the brain,” particularly “the frontal lobes and the temporal lobes.” In other words, our brains aren’t large enough or interconnected enough to maintain an infinite number of personal relationships.
Some scientists theorize that the so-called Dunbar’s number could be larger for online relationships, because the time it takes to have a social interaction is reduced when all you have to do is send a quick message, as opposed to meeting up for coffee, a meal, or a full day of activities. Pardus offered an interesting way to study this, Thurner says, because players can form different kinds of relationships with each other. In the game, players choose an official faction to join, which determines which side a player is on. Within these factions, players are able to communicate and create formal groups known as alliances. Players can also declare other players as friends. Thurner and his colleagues then used their data on interpersonal interactions to divide these friendships into two groups: close friends, or players who had declared friendship and communicated through private messaging, and acquaintances, or players who had designated each other as friends but did not message.
Remarkably, though the game sets no constraints on the size of alliances, players organized themselves into social structures that matched those found in the real world. The largest alliance in Pardus was only 136 members, suggesting that the limit of 150 personal connections is an inherent part of our social psychology, Thurner and colleagues report this month in Scientific Reports.
That’s not the only way relationships in Pardus mirrored offline friendships. In real life, we’re more emotionally invested in those we consider our close friends, creating smaller groups of relationships within our 150-person circle that we spend the most time and energy tending. Correspondingly, Pardus players invested more time interacting with friends they messaged, concentrating their social attention on close friends rather than distributing it among a larger web of acquaintances. Thurner suggests that we may characterize people into different groups in order to keep connections straight in our heads, but that “no one knows how this mental map is organized.” In this study, “we may have seen the first insight into how this is managed in humans.”
“This is a good example of a paper that suggests a clear correspondence between how people behave in real life and virtual environments,” says social scientist James Ivory, who studies social and psychological aspects of people online at Virginia Polytechnic Institute and State University in Blacksburg. “People tend to behave like people, whether they’re in a prehistoric world, a business, a knitting group, or a video game. Instead of looking at behavior in video games as alien, what you basically have is a place where you can study people.”
From runners to cyclists to boot-camp fanatics the strategy involves alternating between periods of high-intensity and lower-intensity aerobic training.
And the type of exercise involved? Taking an hourlong walk each day outdoors or on a treadmill.
As part of the study, researchers enrolled about 30 volunteers with Type 2 diabetes who were in their late 50s and early 60s.
The volunteers were divided into groups. One group was instructed to walk three minutes briskly, followed by three minutes at a more restful pace, and repeat that process for an hour.
Another group walked at a continuous pace for the same amount of time.
A third group, a control group, kept up normal routines, which didn’t include daily exercise.
“What we expected to see … was that both exercising groups would have an improvement in their glucose [or blood sugar] control,” says study author Thomas Solomon, an associate professor at the University of Copenhagen who studies how exercise affects glycemic control.
But that’s not what happened.
But the steady-paced walkers saw no improvement at all.
“This was somewhat surprising, considering that they were doing one hour of exercising a day for four months,” says Solomon.
So what explains the benefits of interval walking? It’s not exactly clear, but there’s a leading theory.
“It’s this switch between the intensities that we think is critical here,” says Solomon. “You’re able to work hard, and then rest hard … rather than just walking at a fixed pace.”
And during the high-intensity bursts, your muscles need more fuel in the form of glucose.
“It makes sense that intervals would help people with blood sugar control,” says Dr. Tim Church, a professor of preventive medicine at the Pennington Biomedical Research Center in Baton Rouge, La.
So, when we do things such as short bursts of high-impact aerobic activity, “you’re pulling excess sugar out of the blood, which results in healthier blood sugar levels,” Church says.
This study is small, but the findings match other research on intervals, which find benefits that seem to go beyond better blood sugar.
In a study published in Diabetes Care in 2013, which also compared interval walkers with continuous-paced walkers, Solomon and his colleagues found that the interval walkers lost more weight and lowered their cholesterol levels.
“There are a number of studies that have shown that when you increase the intensity [of aerobic exercise] in the form of doing intervals, there’s additional benefits beyond just the calories burned,” Solomon says.
There are still unanswered questions, he adds, such as can interval walking cut the risk of strokes or other health problems that are associated with diabetes?
“We really need to understand how this has an impact on the long-term health of these patients with diabetes,” Solomon says.