Faces reflect disorders
The general public easily recognises the faces of people with Down’s syndrome, but there are over 700 genetic conditions where there are characteristic facial features: the eyes may be set further apart than usual, the nose shorter and the ears set lower down on the head along with many other possible permutations. Clinical geneticists use these face shape differences as important clues in the early stages of diagnosis prior to detailed clinical examination and genetic testing. These facial differences are often hard to detect, especially for less experienced doctors, but now non-invasive 3D photography and novel analysis techniques are set to make the facial recognition easier.
Professor Peter Hammond from the University College London (UCL) Institute of Child Health has developed new computer software that compares the faces of undiagnosed children with those with a diagnosed condition that also affects the development of their face, with a 90% success rate.
“Faces develop under the influence of many genes and in close synchronisation with the development of the skull and brain. Many genetic conditions or syndromes involve characteristic facial features that are the first clue to a diagnosis and the initiation of diagnostic molecular testing (where it exists). Affected children may have eyes set further apart, ears set lower on the head, a shorter nose, fuller lips, a larger tongue or a mouth narrower than in children of typical development,” says Prof Hammond.
“If a clinician is having difficulty with a particular child's diagnosis, specially written computer software can compare the child's face to groups of individuals with known conditions and select which syndromes look most similar. The clinician can then initiate appropriate molecular testing if it is available for the selected syndromes.”
The technique is an important addition to the diagnostic toolbag as some conditions are so rare that a clinician might only see a handful of cases over a career and so may not recognise the characteristic facial features, especially if the child being examined is much younger than previous cases or from a different ethnic background.
The specially written software is based on dense surface modelling techniques developed at UCL and compares the child’s face to groups of individuals with known conditions and selects which syndromes look most similar. In order to do this, extensive collections of 3D face images of children and adults with the same genetic condition had to be gathered, as well as controls or individuals with no known genetic condition. Each image contains 25,000 or so points on a face surface capturing even the most subtle contours in 3D. The images are then converted to a compact form that requires only a 100 or so numeric values to represent each face in the subsequent analysis.
Once the software has narrowed down conditions with similar facial features, molecular testing can then be used to confirm the diagnosis. Testing for fewer conditions will save money, time and reduce the amount of stress the child and the parents are put under.
“The technique is currently being applied to over 30 conditions with an underlying genetic abnormality. The discriminatory capability of the approach has proven highly accurate in identifying the characteristic facial features of a variety of genetic conditions, including Cornelia de Lange, Fragile X, Noonan, Smith-Magenis and Velocardiofacial syndromes. It has identified unusual facial asymmetry in children with autism spectrum disorder reflecting known brain asymmetry and has helped to identify genes affecting facial development in Williams syndrome,” Prof Hammond says.
How we come to express the genes of one parent over the other is now better understood through studying the platypus and marsupial wallaby – and it doesn’t seem to have originated in association with sex chromosomes. New research published in the online open access journal, BMC Evolutionary Biology, has shed light on the evolution of genomic imprinting, in which specific genes on chromosomes that have been inherited from one parent are expressed in an organism, while the same genes on the chromosome inherited from the other parent are repressed.
Imprinting arises from some kind of ‘epigenetic memory’ – modifications to the DNA from one parent, such as the way the chromosomal material is packaged, that do not allow particular genes to be expressed. The reasons why imprinting evolved are not understood. It is known, however, that different patterns of imprinting occur in different classes of mammals, with some classes of mammals exhibiting the phenomenon and others not. Because the evolutionary relationship between mammals is well documented, patterns of imprinting in the different genomes can provide important clues about the evolution of imprinting.
One theory is that imprinted genes arose from sex chromosomes, which can be epigenetically ‘shut down’ to control the dosage of genes. Another idea is that imprinting arose from an ancestral chromosome that was itself imprinted.
A group led by father and daughter, Malcolm and Anne Ferguson-Smith, of the University of Cambridge tested these ideas by mapping known sequences of imprinted genes in two mammals, the monotreme platypus and the marsupial wallaby, which occupy distinct positions in mammalian evolution.
The results of the distribution studies suggest that imprinted genes were not located on an ancestrally imprinted chromosome, nor were they associated with sex chromosomes. Rather it appears that imprinting evolved in a stepwise, adaptive way, with each gene or cluster becoming imprinted as the need arose.
The study is also important because despite its evolutionary importance, the platypus remains cytogenetically under-characterised. By linking specific sequences to particular chromosomes, the researchers have pinpointed important markers on the platypus genome.
Article: The evolution of imprinting: chromosomal mapping of orthologues of mammalian imprinted domains in monotreme and marsupial mammals
Carol A Edwards, Willem Rens, Oliver Clark, Andrew J Mungall, Timothy Hore, Jennifer A Marshall-Graves, Ian Dunham, Anne C Ferguson-Smith and Malcolm A Ferguson-Smith. BMC Evolutionary Biology
Lung tumour treatment
A new study led by researchers from the Duke University Comprehensive Cancer Center and the Duke Institute for Genome Sciences & Policy (IGSP) in the United States found distinct differences in the way different tumours respond to widely used chemotherapy drugs.
“We were able to predict which tumours would be most likely to respond to standard first-line therapy and which would respond better to what has traditionally been a second-line therapy, based on gene expression profiling,” said David Hsu, MD, PhD an oncologist at Duke and lead author on the publication.
“This represents a big step in the move toward individualised medicine. This could also make a huge difference in the treatment of patients with late-stage lung cancer, as most of these patients gain the most benefit from their initial treatment strategy.”
The researchers published their findings in the October 1, 2007 issue of the Journal of Clinical Oncology. Researchers looked at the sensitivity of multiple cancerous cell lines to cisplatin, the most commonly used agent in the treatment of lung cancer. After determining which cell lines were responsive to cisplatin they looked at the RNA of these tumours and generated a genomic signature – a pattern of gene expression particular to each individual sample.
They were able to draw conclusions about which genes were turned on and which were turned off in these samples, and subsequently created a genomic map for cisplatin sensitivity. The genomic map was then applied to 91 nonsmall cell lung cancer (NSCLC) tumour samples to determine which tumours were most likely to be responsive to cisplatin, Hsu said.
“We found that tumours known to be sensitive to cisplatin expressed certain genes that were not expressed in tumours that were resistant to cisplatin,” said senior author Anil Potti, MD, an oncologist at Duke and a researcher in the IGSP.
“The reverse was true, as well; genes that were not expressed in tumours resistant to cisplatin seemed to be turned on in tumours that were sensitive to it.”
The important second part of this project was to come up with a therapy option for the tumours that weren’t sensitive, Potti said.
“It's one thing for a doctor to tell a patient that he won't respond to cisplatin,” he said, “but we have to know what to do when he asks 'what do you have for me?’ ”
The researchers then examined several common second-line therapies, such as a drug called pemetrexed which uses a different mechanism of action to attack NSCLC tumours.
“We found the strongest inverse correlation between tumours that were sensitive to cisplatin and those that were sensitive to pemetrexed,” Potti said. “This suggests that some patients who are not likely to respond to cisplatin should perhaps be treated with pemetrexed first.”
A clinical trial – the first of its kind in lung cancer – based on the findings of these genomics studies is currently underway at Duke. “These are not experimental drugs, we know they work,” Potti said. “It’s just a matter of giving each patient the right one on the first try.”
Lung disease risk
Diagnosing a risk of fatal lung disorders may be possible by analysing the umbilical cords of premature babies, according to research published in the online open access journal Genome Biology. Until now, paediatricians have not been able to predict the development of bronchopulmonary dysplasia (BPD) because of the difficulties with obtaining lung samples.
Isaac Kohane and his team at the Children's Hospital, Boston, US, collected umbilical cord tissue samples from 54 premature infants born at less than 28 weeks of gestation, including 20 samples from infants who later developed BPD. When DNA expression profiles were compared, the researchers found that infants who subsequently developed BPD had distinct gene expression signatures that differed from the ones who did not develop the disease, although the maternal characteristics (for example, the cause of delivery, race, or inflammation of the uterus) were similar. The genes that differed between the two groups involved chromatin remodelling and histone acetylation pathways.
“This has provided a rare opportunity to examine the influence of foetal physiology on postnatal health and development using the multiple tissues in umbilical cords as a proxy for a wide variety of tissues in the maternal-foetal unit,” says Kohane.
BPD occurs in 20-40% of infants born below 1,000 grammes and before 28 weeks of gestation, and means babies still need supplemental oxygen at 36 weeks postmenstrual age. It is the second leading cause of death among infants born within this gestational age and is characterised by inflammation and scarring in the lungs.
The study by Kohane and colleagues will contribute towards generating prognostic markers for disease from umbilical cord profiles.
Article: Perturbation of gene expression of the chromatin remodeling pathway in premature newborns at risk for bronchopulmonary dysplasia. Jennifer Cohen, Linda J Van Marter, Yao Sun, Elizabeth Allred, Alan Leviton and Isaac Kohane. Genome Biology.
The ‘skinny’ gene
Researchers at University of Texas 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 5 September 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 analysing 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 diabetesresistant 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.
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