From gene to function: Genome wide study into new gene functions in the formation of platelets

ScienceDaily (Nov. 30, 2011) — In a study into the genetics of blood cell formation, researchers have identified 68 regions of the genome that affect the size and number of platelets. Platelets are small cells that circulate in the blood and are key to the processes of blood clotting and wound healing.

In this genome-wide study, the team used a multidisciplinary approach to successfully identify new genetic variants involved in the formation of platelets and more importantly, defined the function of genes near these variants using a series of biological analyses.

Abnormally high or low platelet counts can lead to disease. An increase in the number of platelets, or an increase in their size can lead to an increased risk for thrombotic events, like heart attacks and strokes. A very low number of platelets or platelets that do not function well, increases the risk of bleeding.

"This is a detective story starting with the initial genetic discovery and allowing us to identify new genes that could contribute to platelet associated diseases," says Professor Willem H Ouwehand, senior co-author at the University of Cambridge and NHS Blood and Transplant. "Our aim of this genome-wide meta-analysis study was to discover which genes control the size and number of platelets, to understand how these genes instruct blood stem cells to orchestrate every day the formation of billions of platelets and finally to investigate whether genes associated with heart attacks and strokes overlap with the genes that affect platelet formation."

In this collaborative study, the team first developed a prioritisation strategy that allowed them to identify and pinpoint the genes underlying the formation of platelets through biological annotations of these genes. This effort laid the foundation for the construction of a protein-protein interaction network that shows how the different genetic players interact. Finally, they analysed the role of the genes in model organisms and found their function to be conserved in evolution.

The researchers found the newly identified genes associated with platelet characteristics overlap with other genes implicated in inherited bleeding disorders. This genetic overlap suggests that this study may help discover new genes implicated in severe forms of bleeding disorders, providing evidence that the new findings will be significant in clinical research for improvements in the care of patients.

This study involved about 68,000 individuals from different ancestries (European, South & East Asian) making it the largest genome-wide meta-analysis study to be conducted globally on platelet number and volume.

"This is the largest dataset of this type ever produced, and yields a wealth of new exciting biological discoveries and insights into the genetic control of blood cell formation," says Dr Nicole Soranzo,senior co-author from the Wellcome Trust Sanger Institute. "Our findings will be relevant not only to better understand the mechanisms leading to the formation of blood cells, but also to pinpoint new genes involved in diseases with altered blood clotting."

The team examined the role of the genes they identified in the fruit fly and zebrafish. They found that reducing the activity of one of these genes, ARHGEF3, in fish abrogates not only the production of platelets but also of red blood cells because the blood forming cells cannot capture iron. The study has shown that the human equivalent, ARHGEF3 gene is an important new regulator of the uptake of iron from the diet.

Tropomyosin 1 is a member of a family of genes already known to be involved in the regulation of muscle contraction and plays a role in heart disease. This study found a novel role for this well-known protein in platelet formation.

"This study provides a paradigm for how to successfully translate genome-wide association studies into function" says Dr Christian Gieger, senior co-author from the Institute of Genetic Epidemiology at the Helmholtz Center Munich."We have shown that biologic and functional annotation can greatly enhance our ability to interpret genetic data."

"These genes could be used in the future as new targets to develop better and safer platelet inhibitors for treatments of patients with heart attacks or strokes."

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The above story is reprinted from materials provided by Wellcome Trust Sanger Institute.

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Journal Reference:

Christian Gieger et al. New gene functions in megakaryopoiesis and platelet formation. Nature, 2011; DOI: 10.1038/nature10659

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Astronomers look to neighboring galaxy for star formation insight

ScienceDaily (Nov. 30, 2011) — An international team of astronomers has mapped in detail the star-birthing regions of the nearest star-forming galaxy to our own, a step toward understanding the conditions surrounding star creation.

Led by University of Illinois astronomy professor Tony Wong, the researchers published their findings in the December issue of the Astrophysical Journal Supplement Series.

The Large Magellanic Cloud (LMC) is a popular galaxy among astronomers both for its nearness to our Milky Way and for the spectacular view it provides, a big-picture vista impossible to capture of our own galaxy.

"If you imagine a galaxy being a disc, the LMC is tilted almost face-on so we can look down on it, which gives us a very clear view of what's going on inside," Wong said.

Although astronomers have a working theory of how individual stars form, they know very little about what triggers the process or the environmental conditions that are optimal for star birth. Wong's team focused on areas called molecular clouds, which are dense patches of gas -- primarily molecular hydrogen -- where stars are born. By studying these molecular clouds and their relationship to new stars in the galaxy, the team hopes to learn more about the metamorphosis of gas clouds into stars.

"When we study star formation, an important question is, what is the environment doing? How does the location of star formation reflect the conditions of that environment? There's no better place to study the wider environment than the LMC."

Using a 22-meter-diameter radio telescope in Australia, the astronomers mapped more than 100 molecular clouds in the LMC and estimated their sizes and masses, identifying regions with ample material for making stars. This seemingly simple task engendered a surprising find.

Conventional wisdom states that most of the molecular gas mass in a galaxy is apportioned to a few large clouds. However, Wong's team found many more low-mass clouds than they expected -- so many, in fact, that a majority of the dense gas may be sprinkled across the galaxy in these small molecular clouds, rather than clumped together in a few large blobs.

"We thought that the big clouds hog most of the mass," Wong said, "but we found that in this galaxy, it appears that the playing field is more level. The low-mass clouds are quite numerous and they actually contribute a significant amount of the mass. This provides the first evidence that the common wisdom about molecular clouds may not apply here."

The large numbers of these relatively low-mass clouds means that star-forming conditions in the LMC may be relatively widespread and easy to achieve. The findings raise some interesting questions about why some galaxies stopped their star formation while others have continued it.

To better understand the connection between molecular clouds and star formation, the team compared their molecular cloud maps to maps of infrared radiation, which reveal where young stars are heating cosmic dust.

For the comparison, they exploited a carefully selected sample of newborn heavy stars compiled by U. of I. astronomy professor You-Hua Chu and resident scientist Robert Gruendl, who also were co-authors of the paper. These stars are so young that they are still deeply embedded in cocoons of gas and dust.

"It turns out that there's actually very nice correspondence between these young massive stars and molecular clouds," Wong said. "That's not entirely surprising, but it's reassuring. We assume that these stars have to form in molecular clouds, and it tells us that the molecular clouds do hang around long enough for us to see them associated with these massive young stars."

Wong hopes to continue to study the relationship between molecular clouds and star formation in greater detail. If researchers can determine the relative ages of young stars, they can correlate these against molecular clouds to figure out which clouds have star formation, how long the clouds live and what eventually leads to their destruction. They also plan to use a newly constructed array of telescopes in Chile to see the cloud environment in higher resolution, pinpointing exactly where inside the molecular cloud star formation will occur.

"This study provides us with our most detailed view of an entire population of clouds in another galaxy," Wong said. "We can say with great confidence that these clouds are where the stars form, but we are still trying to figure out why they have the properties they do."

The National Science Foundation and NASA supported this work.

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The above story is reprinted from materials provided by University of Illinois at Urbana-Champaign.

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Journal Reference:

Tony Wong, Annie Hughes, Jürgen Ott, Erik Muller, Jorge L. Pineda, Jean-Philippe Bernard, You-Hua Chu, Yasuo Fukui, Robert A. Gruendl, Christian Henkel, Akiko Kawamura, Ulrich Klein, Leslie W. Looney, Sarah Maddison, Yoji Mizuno, Deborah Paradis, Jonathan Seale. The Magellanic Mopra Assessment (MAGMA). I. The Molecular Cloud Population of the Large Magellanic Cloud. The Astrophysical Journal Supplement Series, 2011; 197 (2): 16 DOI: 10.1088/0067-0049/197/2/16

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