The nationwide experiment will initially include around 100,000 volunteers.
Comparing gene transcripts from different species reveals surprising splicing diversity.
December 20, 2012|
WIKIMEDIA, CORENTIN LE REUNThe majority of mammalian protein-coding genes have a number of possible transcripts, generated by the variable inclusion of exons. It was thought that these so-called alternative splicing events might be conserved between species, but two studies published today (December 20) in Science reveal that most are not. The researchers even propose that the high degree of alternative splicing variability may be a driving force of species divergence .
“It was somewhat generally assumed that splicing differences that you see between brain and muscle in the mouse would be similar between brain and muscle in the human,” said Donny Licatalosi, professor of RNA molecular biology at Case Western Reserve University in Cleveland, Ohio, who did not participate in the studies, “but what both of these studies are showing is that is not the case. There is a large amount of species-specific alternative splicing.”
A major question in vertebrate evolutionary biology is “how do physical and behavioral differences arise if we have a very similar set of genes to that of the mouse, chicken, or frog?” said Ben Blencowe, a cell and molecular biology professor at the University of Toronto, who led one of the studies. A commonly discussed mechanism was variable levels of gene expression, but both Blencowe and Chris Burge, biology and biological engineering professor at Massachusetts Institute of Technology and lead author of the second paper, found that gene expression is relatively conserved among species.
On the other hand, the papers show that most alternative splicing events differ widely between even closely related species. “The alternative splicing patterns are very different even between humans and chimpanzees,” said Blencowe. “Alternative splicing is evolving faster than gene expression,” concluded Tom Cooper, professor of pathology at Baylor College of Medicine in Houston, Texas, who was not involved in the work.
To assess alternative splicing patterns as well as transcription levels, both groups performed high-throughput sequencing of messenger RNA. They extracted RNA from a large array of organs of different vertebrate species, including frogs, chickens, primates, and humans. “It’s a massive amount of data,” said Cooper.
Blencowe’s team showed that the species-specific alternative splicing changes tended to be driven by differences in the transcripts themselves, which carry a splicing code that guides the splicing machinery—rather than differences in the splicing machinery. For example, human transcripts expressed in mouse cells exhibited human, not mouse, splicing patterns, despite being spliced by mouse machinery.
“These are very important papers that provide for the first time a large-scale view of the evolution of alternative splicing in vertebrates,” said Brent Graveley, professor of genetics and developmental biology at the University of Connecticut, who was not involved in the research. “They demonstrate how dramatically rapidly alternative splicing evolves, and suggest that it might play a role in speciation.”
The incredible capacity for alternative splicing could enable cells to try-out new versions of proteins without risking the complete loss of the originals, said Burge. Of course, if a new version then offers an advantage, the associated sequence changes to the splicing code will be selected for. “It is certainly an attractive model, and we think it is what’s going on,” said Burge.
His team found evidence that one way in which alternatively spliced exons could alter protein function was through removal or insertion of phosphorylation sites. Gene database searches revealed “alternative exons that are tissue-specific have a significantly higher density of predicted and validated phosphorylation sites,” Burge said. Phosphorylation states of proteins can influence their interactions, their activity, their subcellular localization, he explained, and alternative splicing could offer “a toggle switch” for controlling protein functions in cells. “That’s pretty new. . . . There hasn’t been an appreciation that splicing could be used in that way,” he said.
Of course phosphorylation is not the only way proteins are regulated, said Cooper. “My guess is there’s going to be a number of functional domains and regions that are going to be altered by splicing.”
N. L. Barbosa-Morais et al., “The Evolutionary Landscape of alternative splicing in vertebrate species,” Science, 388, 1587-93, 2012.
J. Merkin et al., “Evolutionary dynamics of gene and isoform regulation in mammalian tissues,” Science, 388, 1593-99, 2012.
December 23, 2012
Sex differences due to alternative splicings (and species divergence)
"Yet another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes. Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans. That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes."
Instead of simply offering more evolutionary theory, we detailed the link from the sensory environment to sexual orientation (e.g., the epigenetic effects of pheromones on the gonadotropin releasing hormone neuronal system). There are many more details in our 1996 Hormones and Behavior review article, and most have been ignored to favor theories about adaptively evolved behavior that have never "fit" what is known about systems biology (back then, or now). This new focus on alternative splicings may encourage others to take a closer look at what's driving species divergence at the molecular level, but divergence at any level will need to be linked to its obvious origin in nutrient chemical-dependent pheromone-controlled reproduction.