Leonard Zon and colleagues describe how stem cells induce remodeling of the perivascular niche.
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.”