Discovery Of Facial Malformation Gene

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ScienceDaily (June 19, 2009) — The first specific genetic mutation which can cause a potentially serious facial disfigurement has been identified by researchers at Oxford University. The finding, published online in the American Journal of Human Genetics, offers the promise of improved genetic counselling for parents at risk.

Formation of the human face is a complex and exquisitely orchestrated developmental process that occurs between four and eight weeks of embryonic development. Disturbance to this development can lead to malformations of the head and face, including abnormal nasal configuration, cleft lip, and widely spaced eyes.
Most cases of disfigurement are caused by damage to the developing embryo early in pregnancy; genetic causes are thought to be responsible for only a minority of cases, and these usually also involve other parts of the body. No mutation of a single gene has previously been identified that leads specifically to facial malformations.
Researchers, led by Professor Andrew Wilkie from the Weatherall Institute for Molecular Medicine at the University of Oxford and Dr Irene Mathijssen from the Erasmus Medical Centre in the Netherlands and funded by the Wellcome Trust, identified individuals from seven families who shared a similar, distinctive facial appearance, including an abnormally large distance between the eyes and a wide, malformed nose. They termed this condition ‘frontorhiny’.
Genetic analysis showed that each of the individuals carried two copies of a mutation in the gene ALX3. Mouse models have previously highlighted the involvement of the equivalent gene in the production of a protein which regulates other genes involved in facial development – in other words, switching them on and off. However, while the absence of the protein produced by this gene does not disrupt facial development in mice, Professor Wilkie and colleagues found that in humans it leads to frontorhiny.
‘Frontorhiny can be a very distressing condition,’ says Professor Wilkie. ‘It causes facial disfigurement and other health problems, such as breathing difficulties and dermoids (benign cysts under the skin). The cosmetic surgery can be very challenging, requiring multiple operations.’
By identifying and naming the condition, the researchers believe that they will be able to diagnose more cases and provide improved genetic counselling. Because this is a recessive genetic disorder, a parent with the condition is very unlikely to have a similarly affected child. However, where unaffected parents have a child with the condition, they have a one in four chance of each future child being affected.
‘This finding is very important from the point of view of genetic counselling and offers hope to those families considered to be at risk,’ explains Professor Wilkie. ‘For example, by correctly diagnosing the condition in an adult, we can reassure them that their children are unlikely be affected.’
Professor Wilkie believes that the research also highlights the power of genetics to identify the origins of genetic disorders.
‘This study illustrates the tremendous power of genetics to identify the origins of rare disorders such as frontorhiny, even when working with very small numbers of individuals. In this research, just three affected individuals helped us to narrow the search for the particular genetic mutation responsible to around one three thousandth of the human genome. The previous mouse genetic work then helped finish the job for us.’
Adapted from materials provided by University of Oxford.

Silver nanoparticles show 'immense potential' in prevention of blood clots

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Silver nanoparticles (shown) could help prevent blood clots. Credit: The American Chemical Society.
Scientists are reporting discovery of a potential new alternative to aspirin, ReoPro, and other anti-platelet agents used widely to prevent blood clots in coronary artery disease, heart attack and stroke. Their study, scheduled for the June 23 issue of ACS Nano, a monthly journal, involves particles of silver -- 1/50,000th the diameter of a human hair -- that are injected into the bloodstream.

Debabrata Dash and colleagues point out that patients urgently need new anti-thrombotic agents because traditionally prescribed medications too-often cause dangerous bleeding. At the same time, aging of the population, sedentary lifestyle and spiraling rates of certain diseases have increased the use of these drugs. Researchers are seeking treatments that more gently orchestrate activity of platelets, disk-shaped particles in the blood that form clots.
The scientists describe development and lab testing of silver nanoparticles that seem to keep platelets in an inactive state. Low levels of the nanosilver, injected into mice, reduced the ability of platelets to clump together by as much as 40 percent with no apparent harmful side effects.
The nanoparticles “hold immense potential to be promoted as an antiplatelet agent,” the researchers note. “Nanosilver appears to possess dual significant properties critically helpful to the health of mankind — antibacterial and antiplatelet — which together can have unique utilities, for example in coronary stents.”
More information: ACS Nano, Journal Article: “Characterization of Antiplatelet Properties of Silver Nanoparticles”
Provided by American Chemical Society (news : web)

Personal Genomes: Mainstream In Five Years, But Who Should Have Access?

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http://www.sciencedaily.com/releases/2007/09/070920145356.htm

Science Daily — Imagine this: you visit your clinician, undergo genetic testing, and then you are handed a miniature hard drive containing your personal genome sequence, which is subsequently uploaded onto publicly accessible databases. This may sound like science fiction, but it is scientific fact, and it is already happening.

In an article published in the upcoming issue of Science, University of Alberta researcher Tim Caulfield and co-authors highlight the need to proceed with caution when it comes to personal genomics projects that represent research milestones but are also fraught with ethical, social and clinical implications. Caulfield, who is the Canada Research Chair in Health Law at the U of A and professor and research director in public health sciences, is recognized as one of the foremost experts in health law research in Canada.
Scientists predict that within five years DNA sequencing technologies will be affordable enough that personal genomics will be integrated into routine clinical care. Companies are responding by offering their services for ancestry tracing, forensics, nutritional advice and reproductive assistance. It won't be long before companies are able to offer Facebook-like social networking services centred around our genomes.
Once we have our personal genomic information, what will we do with it and how might this information be used outside the medical context? How will physicians educate patients about the significance of genetic risk information? Will already-strained health-care systems be able to cope with the inevitable influx of "worried well" patients seeking follow-up investigations for genetic risks that are not clinically meaningful?
Caulfield and his colleagues pose these questions and warn that the routine generation of individual genome sequences will pose challenges to our health-care system.
They argue that only clinically meaningful genomic test results should be integrated into medical decision-making--however, this will require clear standards, multidisciplinary collaboration and careful consideration of the ethical, social and clinical implications.
Note: This story has been adapted from a news release issued by University of Alberta.

Fausto Intilla

www.oloscience.com

Skin As A Living Coloring Book

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http://www.sciencedaily.com/releases/2007/09/070906132823.htm

Science Daily — The pigment melanin, which is responsible for skin and hair color in mammals, is produced in specialized cells called melanocytes and then distributed to other cells. But not every cell in the complex layers of skin becomes pigmented. The question of how melanin is delivered to appropriate locations may have been answered by a study from researchers at the Massachusetts General Hospital (MGH) Cutaneous Biology Research Center (CBRC).

"Pigment recipient cells essentially tell melanocytes where to deposit melanin, and the pattern of those recipients determines pigment patterns," says Janice Brissette, PhD, who led the study. "Recipient cells act like the outlines in a child's coloring book; as recipient cells develop, they form a 'picture' that is initially colorless but is then 'colored in' by the melanocytes."
In humans, melanin is deposited in both the skin and the hair; but in some other mammals such as mice, melanin is primarily deposited in the coat, leaving the skin beneath the coat unpigmented. Melanocytes deposit melanin via cellular extensions called dendrites that reach out to other cells in the epidermis (the outer layer of skin) or the hair follicles. But the mechanism determining whether melanin is delivered to a particular cell has been unknown.
The MGH-CBRC researchers theorized that a mouse gene known as Foxn1 might play a role. Lack of Foxn1 is responsible for so-called 'nude mice,' which have hair that is so brittle it breaks off, resulting in virtually total hairlessness, and other defects of the skin. A similar phenomenon exists in humans with inactivation of the corresponding gene.
When the researchers developed a strain of transgenic mice in which Foxn1 is misexpressed in cells that do not usually contain melanin, they found those normally colorless areas became pigmented. Examining the skin of the transgenic mice revealed that melanocytes were contacting and delivering melanin to the cells in which Foxn1 was abnormally activated. No pigment was observed in the corresponding tissues of normal mice. Examination of human skin samples showed that the human version of Foxn1 was also expressed in cells known to be pigment recipients. Further experiments revealed that Foxn1 signals melanocytes through a protein called Fgf2, levels of which rise as Foxn1 expression increases.
"Foxn1 makes epithelial cells into pigment recipients, which attract melanocytes and stimulate pigment transfer, engineering their own pigmentation," says Brissette, an associate professor of Dermatology at Harvard Medical School. She and her colleagues note that the Foxn1/Fgf2 pathway probably has additional functions in the skin and that it is probably not the only pathway responsible for the targeting of pigment.
"We know that Foxn1 and Fgf2 act in concert with other factors and function within a larger network of genes. Our next step will be to identify other genes that can confer the pigment recipient phenotype or control the targeting of pigment," Brissette adds. Her research may eventually be relevant to disorders such as vitiligo -- in which pigment disappears from patches of skin -- age spots, the greying of hair and even the deadly melanocyte-based skin cancer melanoma.
The report appears in the Sept. 7 issue of Cell.
The co-first authors of the Cell report are Lorin Weiner, PhD, and Rong Han, PhD, both of the MGH-CBRC. Additional co-authors are Jian Li, PhD, Kiyotaka Hasegawa, MS, and David Lee, MGH-CBRC; Bianca Scicchitano, PhD, now at La Sapienza/University of Rome; and Maddalena Grossi, PhD, University of Lausanne, Switzerland. The study was supported by the National Institutes of Health and by the CBRC.
Note: This story has been adapted from a news release issued by Massachusetts General Hospital.

Fausto Intilla

www.oloscience.com

Pivotal Hearing Structure Revealed

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http://www.sciencedaily.com/releases/2007/09/070905133615.htm

Science Daily — Scientists have shed light on how our bodies convert vibrations entering the ear into electrical signals that can be interpreted by the brain. Exactly how the electrical signal is generated has been the subject of ongoing research interest.

When a noise occurs, such as a car honking or a person laughing, sound vibrations entering the ear first bounce against the eardrum, causing it to vibrate. This, in turn, causes three bones in the middle ear to vibrate, amplifying the sound. Vibrations from the middle ear set fluid in the inner ear, or cochlea, into motion and a traveling wave to form along a membrane running down its length.
Sensory cells (called hair cells) sitting atop the membrane "ride the wave" and in doing so, bump up against an overlying membrane. When this happens, bristly structures protruding from their tops (called stereocilia) deflect, or tilt to one side. The tilting of the stereocilia cause pore-sized channels to open up, ions to rush in, and an electrical signal to be generated that travels to the brain, a process called mechanoelectrical transduction.
Most scientists believe that the channel gates are opened and closed by microscopic bridges--called "tip links"--that connect shorter stereocilia to taller ones positioned behind them. If scientists could determine what the tip links are made of, they'd be one step closer to understanding what causes the channel gates to open. This is no easy feat, however, because stereocilia are extremely small, scarce, and difficult to handle. Several proteins had been reported to occur at the tip link in earlier studies, but results have been conflicting to this point.
In a study published in the September 6, 2007, issue of the journal Nature, researchers showed that two key proteins join together at the precise location where energy of motion is turned into electrical impulses. These proteins, cadherin 23 and protocadherin 15, are part of a complex of proteins called "tip links" that are on hair cells in the inner ear. The tip link is believed to have a central function in the conversion of physical cues into electrochemical signals.
"Mutations in [the genes] cadherin 23 and protocadherin 15 can cause deafness as well as Usher syndrome, the leading cause of deaf-blindness in humans," says Professor Ulrich Mueller, of the Scripps Research Department of Cell Biology and Institute for Childhood and Neglected Diseases. "Age-related hearing loss in humans may also be related to problems in the tip links."
"This team has helped solve one of the lingering mysteries of the field," says James F. Battey, Jr., director of the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health (NIH). "The better we understand the pivotal point at which a person is able to discern sound, the closer we are to developing more precise therapies for treating people with hearing loss, a condition that affects roughly 32.5 million people in the United States alone."
Physiology of hearing and deafness
Childhood and age-related hearing impairment is a major issue in our society. According to the NIDCD, one in three people older than 60 and about half of all people over 75 suffer some form of hearing loss. And about four out of every 100,000 babies born in the United States have Usher syndrome, the major cause of deaf-blindness.
Hearing is a classic example of a phenomenon called mechanotransduction, a process that is important not only for hearing, but also for a number of other bodily functions, such as the pereception of touch. It is a complicated process whereby spatial and physical cues are transduced into electrical signals that run along nerve fibers to areas in the brain where they are interpreted.
"Hearing is the least well understood of the senses," notes Mueller.
We do know that sound starts as waves of mechanical vibrations that travel through the air from their source to a person's ear through the compression of air molecules. When these vibrational waves hit a person's outer ear, they go down the ear canal into the middle ear and strike the ear drum. The vibrating ear drum moves a set of delicate bones that communicate the vibrations to a fluid-filled spiral structure in the inner ear known as the cochlea. When sound causes these bones to move, they compress a membrane on one entrance of the cochlea and this causes the fluid inside to move accordingly.
Inside the cochlea are specialized "hair" cells that have symmetric arrays of stereocilia extending out from their surface. The movement of the fluid inside the cochlea causes the stereocilia to move. This physical change creates an electrical change and causes ion channels to open. The opening of these channels is monitored by sensory neurons surrounding the hair cells, and these neurons then communicate the electrical signals to neurons in the auditory association cortex of the brain.
In Usher syndrome and some other "sensory neuronal" diseases that cause deafness, the hair cells in the cochlea are unable to maintain the symmetric arrays of stereocilia.
A few decades ago, a molecular complex called the tip link was discovered in the stereocilia. These tip links connect the tips of stereocilia and are also thought to be important for the transmission of physical force to mechanically gated ion channels. For years, in part because stereocilia are extremely small, scarce, and difficult to handle, the molecules that made up the tip link remained elusive.
But a few years ago, Mueller and his colleagues identified one of the key proteins that formed the tip link-the protein cadherin 23. In their March 26, 2004, Nature article, Mueller and colleagues showed that the protein cadherin 23 was expressed in the right place in the hair cell to be part of the tip link, that it had the correct biochemistry, and that it seemed to be responsible for opening the ion channels. They also showed that cadherin 23 protein formed a complex with another protein called myosin 1c, which helped to close the channel once open.
"The current study provides a higher degree of resolution than the 2004 study, thanks to a collaboration with NIH Researcher Bechara Kachar and Scripps Research Professor Ron Milligan and his advanced imaging facilities," says Mueller. "Now, we put to rest any doubts about the details of our findings."
Three lines of evidence
The current study used three lines of evidence to demonstrate that cadherin 23 and protocadherin 15 unite and adhere to one another to form the tip link.
The researchers first created antibodies that would bind to and label short segments on the cadherin 23 and protocadherin 15 proteins in the inner ears of rats and guinea pigs. Using immuno-fluorescence and electron microscopy studies, they showed that cadherin 23 was located on the side of the taller stereocilium and protocadherin 15 was present on the tip of the shorter one, with their loose ends overlapping in between.
The researchers were able to identify both proteins by removing an obstacle to the antibody-binding process: calcium. Under normal conditions, cadherin 23 and protocadherin 15 are studded with calcium ions, which prevent antibodies from binding to the targeted sites. When calcium was removed through the addition of a chemical known as BAPTA, both labels became visible.
Next, the researchers built a structure resembling a tip link by expressing the cadherin 23 and protocadherin 15 proteins in the laboratory and watching how they interacted. When conditions were right, the two proteins wound themselves tightly together from one end to the other in a configuration that mirrored a naturally occurring tip link. As with normal tip links, the structure thrived in calcium concentrations that paralleled those found in fluid of the inner ear, while a drastic reduction in calcium disrupted the structure.
Lastly, the scientists found that one mutation of protocadherin 15 that causes one form of deafness inhibited the interaction of the two proteins, leading them to conclude that the mutation reduces the adhesive properties of the two proteins and prevents the formation of the tip link. In a second mutation of protocadherin 15, the tip link was not destroyed; the scientists suggested that the deafness is not likely caused by the breakup of the tip link but by interference with its mechanical properties.
Knowing precisely the composition and configuration of the tip link, scientists can now explore how these proteins interact with other components to form the rest of the transduction machinery. In addition, scientists can study how new treatments might be developed to address the breaking up of tip links through environmental factors, such as loud noise.
In addition to Mueller, other authors of the study, "Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells," were: Piotr Kazmierczak, Elizabeth M. Wilson-Kubalek, and Ronald A. Milligan of The Scripps Research Institute, and Hirofumi Sakaguchi,, Joshua Tokita, and Bechara Kachar of the Laboratory of Cellular Biology, National Institute on Deafness and other Communication Disorders, National Institutes of Health.
Funding for the study was principally provided by the NIDCD. Other NIH institutes and centers that contributed funding were the National Institute of General Medical Sciences (NIGMS), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Center for Research Resources (NCRR).
Note: This story has been adapted from a news release issued by Scripps Research Institute.

Fausto Intilla

www.oloscience.com

'Skinny Gene' Exists

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http://www.sciencedaily.com/releases/2007/09/070904122434.htm

Science Daily — Researchers at UT Southwestern Medical Center have found that a single gene might control whether or not individuals tend to pile on fat, a discovery that may point to new ways to fight obesity and diabetes.

"From worms to mammals, this gene controls fat formation," said Dr. Jonathan Graff, associate professor of developmental biology and internal medicine at UT Southwestern and senior author of a study appearing in the Sept. 5 issue of Cell Metabolism. "It could explain why so many people struggle to lose weight and suggests an entirely new direction for developing medical treatments that address the current epidemic of diabetes and obesity.
"People who want to fit in their jeans might someday be able to overcome their genes."
The gene, called adipose, was discovered in fat fruit flies more than 50 years ago by a graduate student at Yale University, but few people knew about it. Its mechanism was unknown, and whether it's important in other genes was a mystery.
In the current study, the UT Southwestern researchers examined how adipose works by analyzing fruit flies, tiny worms called C. elegans, cultured cells, and genetically engineered mice, as well as by exploiting sophisticated molecular techniques. Using several methods, they manipulated adipose in the various animals, turning the gene on and off at different stages in the animals' lives and in various parts of their bodies.
It was discovered that the gene, which is also present in humans, is likely to be a high-level master switch that tells the body whether to accumulate or burn fat.
In the mice, the researchers found that increasing adipose activity improved the animals' health in many ways. Mice with experimentally increased adipose activity ate as much or more than normal mice; however, they were leaner, had diabetes-resistant fat cells, and were better able to control insulin and blood-sugar metabolism.
In contrast, animals with reduced adipose activity were fatter, less healthy and had diabetes.
The researchers' work on flies showed that the gene is "dose-sensitive" -- that is, the various combinations of the gene's variants lead to a range of body types from slim to medium to obese.
"This is good news for potential obesity treatments, because it's like a volume control instead of a light switch; it can be turned up or down, not just on or off," Dr. Graff said. "Eventually, of course, the idea is to develop drugs to target this system, but that's in the years to come."
This genetic mechanism makes survival sense, he said, because if a population has many versions of the gene scattered among many different individuals, at least some will survive in different conditions. For instance, a fat fruit fly may be able to survive famine, but a sleeker model might be better at evading predators.
Dr. Graff said the next step is to understand better the exact mechanisms by which adipose exerts its control.
Although the current study finally identifies the adipose gene's function, the gene was discovered more than 50 years ago when Winifred Doane, now a professor emeritus at Arizona State University, was studying fruit flies and noticed that some contained more fat than others. She linked this trait to a gene she named adipose and hypothesized that this natural variation gave the chubbier flies an evolutionary advantage; they could hoard more fat on the same amount of food as their skinnier counterparts, allowing them to survive times of famine.
But for people in developed countries, this trait has backfired. It's all feast and no famine, so the fat builds and builds.
"Even a pound a year adds up over a lifetime," Dr. Graff said.
Other UT Southwestern researchers involved in the study were Dr. Jae Myoung Suh, postdoctoral researcher in developmental biology; Daniel Zeve, Robert Li and Michael Wang, students in the Medical Scientist Training Program; Dr. Renee McKay, instructor of developmental biology; Dr. Jin Seo, postdoctoral researcher in developmental biology; and Zack Salo, undergraduate at UT Arlington.
The work was supported by the National Institutes of Health.
Note: This story has been adapted from a news release issued by UT Southwestern Medical Center.

Fausto Intilla

www.oloscience.com

Fighting Malaria By Tricking Mosquito's Sense Of Smell

Source:

http://www.sciencedaily.com/releases/2007/08/070830122259.htm

Science Daily — By mapping a specialized sensory organ that the malaria mosquito uses to zero in on its human prey, an international team of researchers has taken an important step toward developing new and improved repellents and attractants that can be used to reduce the threat of malaria, generally considered the most prevalent life-threatening disease in the world.

The sensory organ is the maxillary palp. It is one of three structures extending from the mosquito's head that together provide it with its sense of smell and taste. The other two are the feathery antennae that serve as general-purpose olfactory organs and respond to a wide range of different chemicals and the proboscis that contains sensors designed for close-in odor and taste detection.
The detailed map of the maxillary palp, which was published online in the journal Current Biology on Aug. 30, has determined that it contains a unique array of highly specialized receptor cells that detect carbon dioxide and octenol, key chemical signals that the insects use to find human prey.
"These receptors are highly sensitive, which suggests that the maxillary palps may serve as the malaria mosquito's long-range detection system," says Tan Lu, a graduate student at Vanderbilt who is the paper's first author.
"We haven't proven it yet, but the implication is that if you took away the maxillary palp the mosquito would not do nearly as well at finding human prey," adds Laurence J. Zwiebel, professor of biological sciences at Vanderbilt, who headed the study.
The research was performed by collaborators from Vanderbilt, Yale and Wageningen University in the Netherlands. They are part of a team that also includes researchers from the Ifakara Health Research and Development Centre in Tanzania and the Medical Research Council Laboratories in the Gambia that is funded by a grant from the Foundation for the National Institutes of Health through the Grand Challenges to Global Health Initiative in 2005 to develop a chemical strategy to combat the spread of malaria by the Anopheles mosquito.
"This paper marks a threshold in our grand challenge project because it provides a biological context and then strips it down to a few molecular targets that we are using to develop chemical modifiers that should have direct impacts on the mosquito's behavior," says Zwiebel.
The study fills a major gap in the scientific understanding of the malaria mosquito's olfactory system. Although considerable research has been done on the physiology and molecular biology of Anopheles gambiae's antennae and proboscis, there have been few studies of its maxillary palps. Most of the previous work that had been done on this "accessory olfactory appendage" was performed in another species of mosquito, Aedes aeqypti, the carrier of dengue and yellow fever.
Previous work found that the maxillary palps of the A. aeqypti were sensitive to carbon dioxide and octenol. So the discovery that this was also the case in An. gambiae did not come as a big surprise. However, the researchers found that the malaria mosquito uses different sets of receptors for this purpose which help explain why it appears to rely less on carbon dioxide and more on human-specific chemical compounds in seeking out hosts than does A. aegypti.
The mosquito's elaborate "nose" consists of hundreds of hollow hair-like structures called sensilla attached to its antennae, maxillary palps and proboscis. The tips of these structures are perforated with thousands of tiny holes that let aromatic compounds penetrate to their interior, where they encounter thread-like extensions from neurons which are tuned to detect specific molecules.
Compared to the mosquito's antennae, which are designed to detect hundreds of different compounds, the study found that the maxillary palps are highly specialized. "The amazing thing that we found was that all the sensory hairs that line the bottom of the maxillary palps are identical," says Zwiebel. They are all attached to three neurons: one which is tuned to detect carbon dioxide; one which is tuned to detect octenol; and one which serves to enhance general olfactory reception.
In addition to Zwiebel and Lu, the Vanderbilt researchers who contributed to the study are Quirong Wang, Michael Rutzler, Hyung-Wook Kwon and R. Jason Pitts. The Wageningen team consists of Yu Tong Qiu, Joop J.A. van Loon and Willem Takken. The Yale contributors are Jae Young Kwon and John R. Carlson. The research was funded by a Gates Foundation Grand Challenges in Global Health Initiative grant and by grants from the National Institutes of Health. Note: This story has been adapted from a news release issued by Vanderbilt University.

Fausto Intilla

www.oloscience.com

Genome Study Shines Light On Genetic Link To Height

Source:

http://www.sciencedaily.com/releases/2007/09/070902193734.htm

Science Daily — It became clear nearly a century ago that many genes likely influence how tall a person grows, though little progress, if any, has followed in defining the myriad genes. Now an international research team brings light to this age-old question by pinpointing a genetic variant associated with human height -- the first consistent genetic link to be reported.

The findings, published in Nature Genetics, stem from a large-scale effort led by scientists at the Broad Institute of Harvard and MIT, Children's Hospital Boston, the University of Oxford and Peninsula Medical School, Exeter.
Using a new "genome-wide association" method, the research team searched the human genome for single letter differences in the genetic code that appear more often in tall individuals compared to shorter individuals. By analyzing DNA from nearly 35,000 people, the researchers zeroed in on a difference in the HMGA2 gene -- a 'C' written in the DNA code instead of a 'T'. Inheriting the 'C'-containing copy of the gene often makes people taller: one copy can add about a half centimeter in height while two copies can add almost a full centimeter.
"This is the first convincing result that explains how DNA can affect normal variation in human height," said co-senior author Joel Hirschhorn, an associate member of the Broad Institute, a pediatric endocrinologist at Children's Hospital Boston, and an associate professor of genetics at Harvard Medical School. "Because height is a complex trait, involving a variety of genetic and non-genetic factors, it can teach us valuable lessons about the genetic framework of other complex traits -- such as diabetes, cancer and other common human diseases."
In addition to being a textbook example of a complex trait, height is a common reason children are referred to medical specialists. Although short stature by itself typically does not signal cause for concern, delayed growth can sometimes reflect a serious underlying health condition. "By defining the genes that normally affect stature, we might someday be able to better reassure parents that their child's height is within the range predicted by DNA, rather than a consequence of disease," said Hirschhorn.
Nearly 90% of the variation in height among most human populations can be attributed to DNA. The remainder is due to environmental and lifestyle factors, such as nutrition. Although a few genes have been uncovered through studies of rare, single-gene stature disorders, most do not seem to be associated with height in the general population. Recent advances, including the completion of the HapMap project and the availability of large-scale research tools, enabled the scientists to take a systematic approach to understand how common genetic differences can impact a person's height.
The results of the research team, which also includes co-senior authors Timothy Frayling of the Peninsula Medical School, Exeter and Mark McCarthy of the University of Oxford, spring from data made available in two recent genome-wide association studies of type 2 diabetes. The studies, one led by the Diabetes Genetics Initiative and the other by the Wellcome Trust Case Control Consortium, involved nearly 5,000 patients who generously volunteered DNA samples as well as pertinent clinical information, such as height and weight.
After scrutinizing the initial data, the scientists identified a single letter change -- known as a single nucleotide polymorphism or SNP -- in the HMGA2 gene as the most promising result. They collaborated with additional researchers to study this SNP through a second phase of analysis that encompassed nearly 30,000 individuals: adults and children from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Exeter Family Study of Childhood Health (EFSOCH),
European adults taking part in a study of type 2 diabetes risk (UKT2D GCC), Finnish individuals participating in the FINRISK1997 health survey, and a set of tall and short European American and Polish adults assembled for studies of height. This two-pronged approach enabled co-first author Guillaume Lettre, a researcher at the Broad Institute and Children's Hospital Boston, and his colleagues to convincingly prove that the DNA variation in HMGA2 influences height.
The genomic find, though, is not the only indication that HMGA2 affects height. Previous studies in mice and humans revealed that a handful of rare stature disorders result from severe mutations in the gene. Taken together, the findings provide strong evidence for a role for HMGA2 in height. However, the identified SNP accounts for just 0.3% of the normal variability in human stature, which means there are probably many others yet to be found. To do this, researchers will need to study even larger groups of individuals.
"Unlike most other complex traits, height is something that can be easily defined and measured in very large numbers of people," said Hirschhorn. "Soon the scientific community will have access to many more large-scale genomic data sets, making it feasible to identify additional genes involved in height."
While surprisingly little is known about how genes hardwire humans for growth, some initial clues have already surfaced as a result of the HMGA2 discovery. The gene is active in the first months of fetal growth and shuts off shortly before birth, suggesting it orchestrates growth-related events early in human development. Moreover, it appears to influence the overall longitudinal growth of the skeleton, as scientists found that the T-to-C change in the gene's DNA sequence correlates with an increased length of both the limbs and spine in young children. HMGA2 has also been implicated in certain forms of cancer. Thus, further studies may help dissect the relationship between normal growth and the deranged growth central to cancer.
Citation: Weedon MN et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genetics; DOI:10.1038/ng2121
Note: This story has been adapted from a news release issued by Broad Institute of MIT and Harvard.

Fausto Intilla

www.oloscience.com