Posts tagged genomics
Articles and news from the latest research reports.
The adult human circulatory system contains between 20 and 30 trillion red blood cells (RBCs), the precise size and number of which can vary from person to person. Some people may have fewer, but larger RBCs, while others may have a larger number of smaller RBCs. Although these differences in size and number may seem inconsequential, they raise an important question: Just what controls these characteristics of RBCs?
By analyzing the results of genome-wide association studies (GWAS) in conjunction with experiments on mouse and human red blood cells, researchers in the lab of Whitehead Institute Founding Member Harvey Lodish have identified the protein cyclin D3 as regulating the number of cell divisions RBC progenitors undergo, which ultimately affects the resulting size and quantity of RBCs. Their findings are reported in the September 14 issue of Genes and Development.
People who carry a “G” instead of an “A” at a specific spot in their genetic code have roughly a six-fold higher risk of developing certain types of brain tumors, a Mayo Clinic and University of California, San Francisco study has found. The findings, published online in the journal Nature Genetics, could help researchers identify people at risk of developing certain subtypes of gliomas which account for about 20 percent of new brain cancers diagnosed annually in the U.S. and may lead to better surveillance, diagnosis and treatment.
Researchers still have to confirm whether the spot is the source of tumors, but if it’s not, “it is pretty close,” says senior author Robert Jenkins, M.D., Ph.D., a pathologist at the Mayo Clinic Cancer Center. “Based on our findings, we are already starting to think about clinical tests that can tell patients with abnormal brain scans what kind of tumor they have, just by testing their blood.”
Most experimental cancer drugs never make it to market because they don’t help enough people in early clinical trials. But even in “failed” drug trials, researchers may find that a few patients see their tumors shrink dramatically. Since it’s not clear why some respond but most don’t, researchers typically shake their heads and move on. But researchers today report that by sequencing the entire genome of one outlier patient’s tumor, they learned why her cancer disappeared when she took an experimental drug that didn’t help others. That drug now has a new lease on life for this cancer, and such testing may help revive other cancer drugs that showed promise in lab studies but initially failed in clinical testing.
Early fruits of the collaboration between the Genome 10K project and Beijing Genomics Institute (BGI) to sequence 100 vertebrate species have resulted in the sequencing and release of the genome of one of naturalist Charles Darwin’s Galápagos finches, the medium ground finch Geospiza fortis.
This finch genome, the first of the BGI-Genome 10K collaboration to be made available through the UCSC Genome Browser, represents both a scientific and a symbolic advancement, according to Erich Jarvis, Duke University associate professor who studies the neurobiology of vocal learning in songbirds.
Endemic to the subtropical or tropical dry forests and shrublands of the Galápagos Islands this species evolves rapidly in response to environmental changes. ”These finches are of great historical significance, but when Darwin first studied these birds, he was unlikely to have envisioned how this species would become a perfect model to study evolution in action,” said Goujie Zhang, BGI’s associate director of research. “Having the reference genome of this species has opened the door for carrying out studies that can look at real-time evolutionary changes on a genomic level of all of these enigmatic species.”
(Image by: Petr Baum)
Fathers bequeath more mutations as they age
22 August 2012 by Ewen Callaway
Genome study may explain links between paternal age and conditions such as autism.
Older fathers’ sperm have more mutations — as do their children.
V. Peñafiel/Flickr/GETTY
In the 1930s, the pioneering geneticist J. B. S. Haldane noticed a peculiar inheritance pattern in families with long histories of haemophilia. The faulty mutation responsible for the blood-clotting disorder tended to arise on the X chromosomes that fathers passed to their daughters, rather than on those that mothers passed down. Haldane subsequently proposed that children inherit more mutations from their fathers than their mothers, although he acknowledged that “it is difficult to see how this could be proved or disproved for many years to come”.
(Source: nature.com)
'Genomic CSI' Helps Contain a Killer
22 August 2012
In June of last year, a 43-year old woman was admitted to the Clinical Center of the National Institutes of Health in Bethesda, Maryland, for a lung disease. Doctors knew she was carrying a highly resistant form of a deadly bacterium known as Klebsiella pneumoniae—although it didn’t make her sick—and they placed her in isolation. When the woman was discharged, no one else appeared to have become infected. A few weeks later, however, another patient was found to be carrying the bacterium, and over the next 3 months, 12 more intensive care patients contracted it. Six died as a direct result of the infection.
Doctors could not make sense of the outbreak with the usual methods: A survey of bed locations showed that the first patient had had no direct contact with any of the others and, in theory, Klebsiella might have been introduced into the hospital multiple times. So physicians turned to the bacterium’s genome for answers. The approach, known as genomic epidemiology, helped them track the path of the microbe, contain the disease, and save lives, according to a new study.
Tracking a killer. Full-genome sequencing revealed the movements of Klebsiella (shown) within one hospital. Credit: Image courtesy of Adrian Zelazny
Genomic epidemiology makes use of the fact that when bacteria divide, they accumulate mutations. As a result, the bacterial genome differs slightly—often by just one or two letters of genetic code, or base pairs—from one patient to the next. By fully sequencing the genomes of patients’ bacteria and finding these minute differences, researchers can track microbial movements with unprecedented precision. The technique has already been used to reconstruct the spread of methicillin-resistant Staphylococcus aureus (MRSA) around the world and to pinpoint the origin of a cholera outbreak in Haiti.
It also helped the doctors at the hospital in Bethesda. Comparing the genomes from all patients showed that the female patient admitted in June had indeed initiated the outbreak; the researchers showed that the bacteria had been transmitted from her to other patients three times independently. Apparently, transmission occurred in ways the researchers didn’t understand, says Tara Palmore, an infectious disease physician at the hospital. “When we realized there was more than met the eye, we started testing everyone in the hospital,” she says. That helped identify four more infected patients outside the intensive care unit, the scientists report online today in Science Translational Medicine. They were quickly isolated, which Palmore believes prevented further spread.
Just how the microbes were transmitted is still unclear. Palmore assumes that the bacteria mainly traveled on the hands of doctors. But the clinic had stationed a person outside the isolation rooms to make sure everyone who entered followed a hygiene regimen 24/7. That suggests that bacteria might have established colonies on surfaces or medical equipment and spread that way as well. “The conventional wisdom is that Klebsiellas do not really survive in the environment, but we found them in six sink drains and a ventilator,” Palmore says.
"This small study demonstrates the potential power of whole genome sequencing for outbreak investigation and surveillance," says Sharon Peacock, a microbiologist at the University of Cambridge in the United Kingdom who was not involved in the work. And infectious disease specialist Dag Harmsen of the University Clinic of Münster in Germany says it is "further proof that the time is ripe for using genomic sequencing of pathogens in a hospital setting." The paper also highlights the dangers of resistant Gram-negative bacteria like Klebsiella p., he adds. In many patients, the bacteria were not susceptible to any available antibiotic; not even to colistin, an old compound used only when all else fails. “This is even more dramatic than MRSA, because you have nothing left to treat the patients with,” Harmsen says. Since the outbreak, every patient at the hospital is checked for such dangerous pathogens; one more resistant Klebsiella case—although a different strain—has been found so far.
Genomic epidemiology could make it easier for hospitals to deal with similar outbreaks, Palmore says. “A lot of academic centers have the ability to do this now,” she says. The cost is becoming less of an issue; during last year’s outbreak, scientists still paid about $2000 per genome sequenced; now that would be closer to $500. But Peacock cautions that it still takes bioinformatics specialists several weeks to interpret the data. “This technology will not be applicable to routine clinical practice until automated interpretation tools become available.”
(Source: news.sciencemag.org)
Most babies born in developed countries share a common painful experience — a heel prick that is done soon after birth. Blood from this is deposited onto a slip of paper, called a Guthrie card, which doctors use to screen for devastating and sometimes fatal diseases. A study published today in Genome Research suggests that these cards, which are sometimes stored for decades, could provide an early snapshot of an individual’s epigenome, the chemical changes that influence gene expression and are likely to have a role in heart disease, diabetes, cancer and other diseases.
Making Sense out of the Biological Matrix of Bipolar Disorder
ScienceDaily (Aug. 20, 2012) — The more that we understand the brain, the more complex it becomes. The same can be said about the genetics and neurobiology of psychiatric disorders. For “Mendelian” disorders, like Huntington disease, mutation of a single gene predictably produces a single clinical disorder, following relatively simple genetic principals. Compared to Mendelian disorders, understanding bipolar disorder has been extremely challenging. Its biology is not well understood and its genetics are complex.
In a new paper, Dr. Inti Pedroso and colleagues utilize an integrative approach to probe the biology of bipolar disorder. They combined the results of three genome-wide association studies, which examined the association of common gene variants with bipolar disorder throughout the genome, and a study of gene expression patterns in post-mortem brain tissue from people who had been diagnosed with bipolar disorder. The findings were analyzed within the context of how brain proteins relate to each other based on the Human Protein Reference Database protein-protein interaction network.
"None of our research approaches provides us with sufficient information, by itself, to understand the neurobiology of psychiatric disorders. This innovative paper wrestles with this challenge in a creative way that helps us to move forward in thinking about the neurobiology of bipolar disorder," commented Dr. John Krystal, Editor of Biological Psychiatry.
Dr. Pedroso explained, “We combined information about genetic variation from thousands of cases and controls with brain gene expression data and information from protein databases to identify networks of genes and proteins in the brain that are key in the development of bipolar disorder.”
The analysis resulted in the ability to define risk gene variants that were deemed functional, by virtue of the association with changes in gene expression levels, and to group these functional gene variants in biologically meaningful pathways.
The results implicated genes involved in several neural signaling pathways, including the Notch and Wnt signaling pathways. These pathways are key processes in neurotransmission and brain development and these findings indicate they are also likely to be involved in causing this severe disorder. The authors noted that three features stand out among these genes: i) they localized to the human postsynaptic density, which is crucial for neuronal function; ii) their mouse knockouts present altered behavioral phenotypes; and iii) some are known targets of the pharmacological treatments for bipolar disorder.
Dr. Gerome Breen, senior author on the study and Senior Lecturer at King’s College London Institute of Psychiatry, said, “Our study provides some of the first evidence to show the biochemical and developmental processes involved in causing risk for developing this life-long and costly illness. We have highlighted potential new avenues for new drug treatments and intervention.”
Source: Science Daily
What Is the Human Genome?
The human genome that researchers sequenced at the turn of the century doesn’t really exist as we know it.
The Human Genome project sequenced “the human genome” and is widely credited with setting in motion the most exciting era of fundamental new scientific discovery since Galileo. That’s remarkable, because in important ways “the human genome” that we have labeled as such doesn’t actually exist.
cosmin4000, istockphoto
Plato essentially asserted that things like chairs and dogs, which we observe in this physical world, and even concepts like virtues, are but imperfect representations or instances of some ideal that exists, but not in the material world. Such a Platonic ideal is “the human genome,” a sequence of about 3 billion nucleotides arrayed across a linear scale of position from the start of chromosome 1 to the end of the sex chromosomes. Whether it was obtained from one person or several has so far been shrouded in secrecy for bioethical reasons, but it makes no real difference. What we call the human genome sequence is really just a reference: it cannot account for all the variability that exists in the species, just like no single dog on earth, real or imagined, can fully incorporate all the variability in the characteristics of dogs.
Nor is the human genome we have a “’normal” genome. What would it mean to be “normal” for the nucleotide at position 1,234,547 on chromosome 11? All we know is that the donor(s) had no identified disease when bled for the cause, but sooner or later some disease will arise. Essentially all available whole genome sequences show potentially disease-producing variants, even including nonfunctional genes, in donors who were unaffected at the time.
