[Centraal] Evolutie in het nieuws

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A research team at the Broad Institute of Harvard and MIT and Beth Israel Deaconess Medical Center has uncovered a vast new class of previously unrecognized mammalian genes that do not encode proteins, but instead function as long RNA molecules.

Their findings, published in the February 1st advance online issue of the journal Nature, demonstrate that this novel class of "large intervening non-coding RNAs" or "lincRNAs" plays critical roles in both health and disease, including cancer, immune signaling and stem cell biology.

Standard "textbook" genes encode RNAs that are translated into proteins, and mammalian genomes harbor about 20,000 such protein-coding genes. Some genes, however, encode functional RNAs that are never translated into proteins. These include a handful of classical examples known for decades and some recently discovered classes of tiny RNAs, such as microRNAs.

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By contrast, the newly discovered lincRNAs are thousands of bases long. Because only about ten examples of functional lincRNAs were known previously, they seemed more like genomic oddities than critical components. The new Nature study shows that there are actually thousands of such genes and that they have been conserved across mammalian evolution.

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To uncover this large collection of new genes, the Broad scientific team looked not at the RNA molecules themselves but at telltale signs in the DNA called chromatin modifications or epigenomic marks. They searched for genomic regions that have the same chromatin patterns as protein-coding genes, but do not encode proteins. By surveying the genomes of four different types of mouse cells (including embryonic stem cells and cells from various tissue types), they found an astounding 1,586 such loci that had not been previously described. The researchers also found that the vast majority of these genomic regions are transcribed into lincRNAs, and that these are conserved across mammals.

"The epigenomic marks revealed where these genes were hiding," said Mitch Guttman, a MIT graduate student working at the Broad Institute. "Analysis of their sequence then revealed that the genes are highly conserved in mammalian genomes, which strongly suggested that these genes play critical biological functions."

By correlating the expression patterns of lincRNAs in various cell types with the expression patterns of known critical protein-coding genes in those same cells, the scientists observed that lincRNAs likely play critical roles in helping to regulate a variety of different cellular processes, including cell proliferation, immune surveillance, maintenance of embryonic stem cell pluripotency, neuronal and muscle development, and gametogenesis. Further experimental evidence from several of the identified lincRNAs verified these observations.

Because of the stringent experimental conditions imposed by the researchers in identifying the 1,600 lincRNAs in the Nature study, it is likely that there are many more lincRNA genes hiding in plain sight in the genome, as well as other RNA-encoding genes that are as important to genome function as their better-recognized protein-coding counterparts.

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Guttman, M. et al. (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature, advance online

There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise5, 6. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified approx1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFkappaB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.

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Rapidly Evolving Gene Contributes To Origin Of Species

ScienceDaily (Feb. 7, 2009) — A gene that helped one species split into two species shows evidence of adapting much faster than other genes in the genome, raising questions about what is driving its rapid evolution.

The paper in the Feb 5 issue of Science shows that the gene has connections to another previously identified "speciation gene." Both genes code for key proteins that control molecular traffic into and out of a cell's nucleus. The researchers believe an arms race of sorts inside the cell drives these genes to evolve rapidly—and as a consequence makes closely related species genetically incompatible with one another.

"When we cross two species of fruit fly, which had split from one another 3 million years ago, some of the hybrid offspring die," says Daven Presgraves, professor of biology at the University of Rochester and Grass Fellow at the Radcliffe Institute for Advanced Study at Harvard University. "This tells us that genes from one species are no longer compatible with genes from the other species. We've now found that a functionally related group of genes is responsible, with different versions of the genes having evolved in the two species. And just as Darwin predicted 150 years ago, they evolved by natural selection."

Presgraves has some ideas why two of the genes in particular, called Nup160 and Nup96, have evolved so quickly: they act as gatekeepers of a cell's nucleus, a favorite target for viruses and even malicious genes within the fly's own genome. Presgraves says that these genes probably experience constant assault and thus must constantly adapt. That these genes also prevent genetic mixing between closely related species is incidental—the origin of new species is just a by-product of evolutionary arms races, he says.

When two populations become separated by a geographic barrier—a mountain range or an ocean—they evolve independently. Presgraves and his graduate student Shanwu Tang studied a fruit fly species from Madagascar that long ago become separated from its sister species in Africa. Separated by an expanse of the Indian Ocean, the two independently evolving species accumulated genetic differences. Tang and Presgraves's unexpected finding, however, was that in both species, the Nup160 and Nup96 genes became so different so quickly that they are no longer compatible.

"When the same genes in two different species evolve quickly, they become so different that they can be incompatible," says Tang. "The genes from one species can't talk to the genes in the other species any more."

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Biologists Find Gene Network That Gave Rise To First Tooth

ScienceDaily (Feb. 10, 2009) — A new paper in PLoS Biology reports that a common gene regulatory circuit controls the development of all dentitions, from the first teeth in the throats of jawless fishes that lived half a billion years ago, to the incisors and molars of modern vertebrates, including you and me.

"It's likely that every tooth made throughout the evolution of vertebrates has used this core set of genes," said Gareth Fraser, postdoctoral fellow at Georgia Tech's School of Biology.

The first vertebrates to have teeth were a group of eel-like jawless fish known as the conodonts that had teeth not in their mouth, but lining the throat. This particular group is long since extinct, but some modern fish retain teeth in the throat (pharynx). Dr. Fraser and colleagues studied tooth formation in a group of fish known for their rapid rate of evolution, the cichlids of Africa's Lake Malawi. The cichlids have teeth both in their oral jaws, like humans, and deep in their throats on a pharyngeal jaw. A co-author of the paper, Darrin Hulsey, first identified a surprising positive correlation between the number of teeth in the oral jaw and in the throat in these fish.

"Originally, I thought there wouldn't be a correlation due to the developmental differences and the evolutionary distinction between the two jaw regions, but it turns out there is," explained Fraser. "So fish that have fewer oral teeth also have fewer pharyngeal teeth. This shows that on some level there's a genetic control that governs the number of teeth in both regions."

The team investigated what this control might be by using a technique localizing gene expression in the cells during tooth development, known as in situ hybridization, and found that a common genetic network governs teeth in the two locations.

"So seemingly, regardless of where you grow a tooth, whether it's in the jaw or the pharynx, you use the same core set of genes to do it," said co-author J. Todd Streelman. "We also think it's probable that this network is not just acting in teeth, but also in other similarly patterned structures like hair and feathers."

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Deducing Diet Of Prehistoric Hominid With Mathematical Models

ScienceDaily (Feb. 11, 2009) — In an unusual intersection of materials science and anthropology, researchers from the National Institute of Standards and Technology (NIST) and The George Washington University (GWU) have applied materials-science-based mathematical models to help shed light on the dietary habits of some of mankind’s prehistoric relatives. Their work forms part of a newly published, multidisciplinary analysis of the early hominid Australopithecus africanus by anthropologists at the State University of New York at Albany and elsewhere.

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A. africanus presented a puzzle. Classical analysis of the skull—large molars and premolars with thick enamel, thick heavy jawbones, strong chewing muscles as evidenced by their anchor points on the bone—pointed to a diet of small, hard seeds. The finite-element analysis threw a spanner in the works. It suggested that A. africanus’s facial and jaw anatomy was optimized to handle stress on the premolars, teeth located farther forward in the mouth and most useful for chewing larger hard objects. But recent studies had shown that the teeth lacked the microscopic wear patterns characteristic of chewing hard objects, a contradiction.

Here, work by NIST researcher Brian Lawn and a group at GWU headed by Peter Lucas came in handy. Driven by an interest in tooth restoration materials, they had been studying teeth using fracture mechanics, a field that considers how materials fail under excessive loads. “Our analytical approach produces equations that predict how each mode of damage will occur under different conditions and this enables us to determine trends for different tooth sizes, different food sizes, different food hardness and so on,” explained Lawn. “What they show is that, under some conditions, teeth will actually fracture before they wear.” This explained the absence of microwear patterns in the teeth, which would normally not be used for chewing small hard seeds. “A lot of people have thought the most important part of the survival of the tooth is wear, but it’s now becoming evident that the fracture properties are also very important because there’s a limit to the force that you can apply. Wear is important, but when you start to bite on harder, larger objects, fracture becomes more important,” Lawn said.

“This is a neat example of how really basic materials science—fracture mechanics—has important implications for biological sciences and anthropology,” Strait observed. In the bigger picture, said Strait, the new understanding about A. africanus’s diet may help to explain its successful adaptation to changing climates. A large hard nut that had to be cracked with the premolars may not have been a preferred meal, but it could be something to fall back on when other foods were scarce.

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Did Burst Of Gene Duplication Set Stage For Human Evolution?

ScienceDaily (Feb. 12, 2009) — Roughly 10 million years ago, a major genetic change occurred in a common ancestor of gorillas, chimpanzees, and humans. Segments of DNA in its genome began to form duplicate copies at a greater rate than in the past, creating an instability that persists in the genome of modern humans and contributes to diseases like autism and schizophrenia. But that gene duplication also may be responsible for a genetic flexibility that has resulted in some uniquely human characteristics.

"Because of the architecture of the human genome, genetic material is constantly being added and deleted in certain regions," says Howard Hughes Medical Institute investigator and University of Washington geneticist Evan Eichler, who led the project that uncovered the new findings. "These are really like volcanoes in the genome, blowing out pieces of DNA."

Eichler and his colleagues focused on the genomes of four different species: macaques, orangutans, chimpanzees, and humans. All are descended from a single ancestral species that lived about 25 million years ago. The line leading to macaques broke off first, so that macaques are the most distantly related to humans in evolutionary terms. Orangutans, chimpanzees, and humans share a common ancestor that lived 12-16 million years ago. Chimps and humans are descended from a common ancestral species that lived about 6 million years ago.

By comparing the DNA sequences of the four species, Eichler and his colleagues identified gene duplications in the lineages leading to these species since they shared a common ancestor. They also were able to estimate when a duplication occurred from the number of species sharing that duplication. For example, a duplication observed in orangutan, chimpanzees, and humans but not in macaques must have occurred sometime after 25 million years ago but before the orangutan lineage branched off.

Eichler's research team found an especially high rate of duplications in the ancestral species leading to chimps and humans, even though other mutational processes, such as changes in single DNA letters, were slowing down during this period. "There's a big burst of activity that happens where genomes are suddenly rearranged and changed," he says. Surprisingly, the rate of duplications slowed down again after the lineages leading to humans and to chimpanzees diverged. "You might like to think that humans are special because we have more duplications than did earlier species," he says, "but that's not the case."

These duplications have created regions of our genomes that are especially prone to large-scale reorganizations. "That architecture predisposes to recurrent deletions and duplications that are associated with autism and schizophrenia and with a whole host of other diseases," says Eichler.

Yet these regions also exhibit signs of being under positive selection, meaning that some of the rearrangements must have conferred advantages on the individuals who inherited them. Eichler thinks that uncharacterized genes or regulatory signals in the duplicated regions must have created some sort of reproductive edge. "I believe that the negative selection of these duplications is being outweighed by the selective advantage of having these newly minted genes, but that's still unproven," he said.

An important task for future studies is to identify the genes in these regions and analyze their functions, according to Eichler. "Geneticists have to figure out the genes in these regions and how variation leads to different aspects of the human condition such as disease. Then, they can pass that information on to neuroscientists and physiologist and biochemists who can work out what these proteins are and what they do," he says. "There is the possibility that these genes might be important for language or for aspects of cognition, though much more work has to be done before we'll be able to say that for sure."

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Survival Of The Weakest? Cyclical Competition Of 3 Species Favors Weakest As Victor

ScienceDaily (Feb. 13, 2009) — The extinction of species is a consequence of their inability to adapt to new environmental conditions, and also of their competition with other species. Besides selection and the appearance of new species, the possibility of adaptation is also one of the driving forces behind evolution. According to the interpretation that has been familiar since Darwin, these processes increase the “fitness” of the species overall, since, of two competing species, only the fittest would survive.

LMU researchers have now simulated the progression of a cyclic competition of three species. It means that each participant is superior to one other species, but will be beaten by a third interaction partner. “In this kind of cyclical concurrence, the weakest species proves the winner almost without exception,” reports Professor Erwin Frey, who headed the study. “The two stronger species, on the other hand, die out, as experiments with bacteria have already shown. Our results are not only a big surprise, they are important to our understanding of evolution of ecosystems and the development of new strategies for the protection of species.”

Ecosystems are composed of a large number of different species, which interact and compete with one another for scarce resources. This competition between species in turn affects the probability with which the individual can reproduce and survive – a matter of life and death, as it were. All of these processes are also largely probabilistic and lead to fluctuations that ultimately lead to the extinction of species. We know that up to 50 species become extinct every day on Earth, which at this high rate can be attributed to the influence of man.

Yet, the phenomenon of extinction of species itself cannot be avoided altogether – and is still only barely understood. Theoretical ecologists and biophysicists are therefore intensively researching conditions and mechanisms that affect the biodiversity of Earth. Cyclic dominance is a particularly interesting constellation of species competing with each other. It means that each participant is superior to one other interaction partner, but will be beaten by a third. In ecosystems, this would be three subpopulations – in the simplified model – which dominate in turn. In fact, communities of subpopulations following such rules have been identified in numerous ecosystems, ranging from coral reef invertebrates to lizards in the inner Coast Range of California.

Such cyclical interaction is also familiarly termed “rock-paper-scissors” interaction. This is where the rock blunts the scissors, which cut the paper, which in turn wraps around the rock. Together, these non-hierarchical relationships form a cyclical motion. “The game can help describe the diversity of species,” explains Frey. “The background is a branch of mathematics called game theory, and in this case evolutionary game theory. It helps analyze systems that involve multiple actors whose interactions are similar to those in parlor games.”

Using game theory, one can also study the collective development of populations. In their study, the scientists working with Frey developed elaborate computer simulations in order to calculate the probabilities with which species in cyclical competition will survive. The games started off with three species coexisting in the systems, and ran until two species became extinct – with the third being the only remaining survivors. “What we saw was that in large populations, the weakest species would – with very high probability – come out as the victor,” says Frey.

This “law of the weakest” even held true when the difference between the competing species was slight. “This result was just as unexpected for us,” reports Frey. “But it shows once more that chance plays a big part in the dynamics of an ecosystem. Incidentally, in experiments that were conducted a couple of years ago on bacterial colonies, in order to study cyclical competition, there was one clear result: The weakest of the three species emerged victorious from the competition.”

The project was supported by the cluster of excellence “Nanoinitiative Munich (NIM)”, of which Professor Erwin Frey is a principal investigator.