The DNA Network

Researchers pinpoint gene mutations responsible for 10 percent of schizophrenia [Think Gene]

Posted: 30 May 2008 08:30 PM CDT

Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations that account for at least 10 percent of the non-familial cases of the disease. Researchers describe specific genetic mutations present in individuals who have schizophrenia, but not present in their biological parents who do not have the disease. These individuals were eight times more likely to have these mutations than unaffected individuals. This new data, reported in the May 30 on-line issue of Nature Genetics, will help researchers account for the persistence of schizophrenia in the population despite low birth rates among people with the disease.

Researchers at Columbia University Medical Center scanned the genome of 1,077 people which included 152 individuals with schizophrenia, 159 individuals without schizophrenia, and both of their biological parents for copy number mutations. They found mutations, either a gain or loss of genes, in 15 individuals diagnosed with schizophrenia that were not present in the chromosomes of either biological unaffected parent. Only two of such mutations were found in those without schizophrenia. Study subjects were from the European-origin Afrikaner population in South Africa, a genetically homogenous population that is ideal for genetic evaluation.

"We now know the cause of around 10 percent of the cases of sporadic schizophrenia," said Maria Karayiorgou, M.D., professor of psychiatry, Columbia University Medical Center, the senior author on the study. "Schizophrenia is not as much of a 'big black box' as it used to be. The identification of these genes lets us know what brain development pathways are involved in disease onset, so that in the future we can look at better ways of treating this devastating disease."

Schizophrenia affects approximately 1 percent of the population worldwide. About 40 percent of the disease is thought to be inherited, with the other 60 percent sporadically showing up in people whose family history does not include the disease.

One of the new or de novo mutations researchers found in more than one affected individual in this study was a deletion of a region of chromosome 22. Dr. Karayiorgou had previously provided evidence that loss of genes in this region, 22q11.2, was responsible for introducing "new" or sporadic cases of schizophrenia in the population. This confirms 22q11.2 as the only known recurrent such mutation linked to schizophrenia.

"We have already demonstrated 22q11.2 to be involved in sporadic schizophrenia and we have made considerable progress in understanding the underlying biological mechanisms," said Dr. Gogos. "Now, we have a new set of mutations that we can investigate. The more information we have about the biological basis for this disease, the more information we can provide to those who suffer from it and their families."

"Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism," explains National Institute of Mental Health Director Thomas R. Insel, M.D. "Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may stem from both hereditary and non-hereditary processes. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders."

Karayiorgou and co-senior author Joseph A. Gogos, M.D., Ph.D., associate professor of physiology and neuroscience at Columbia University Medical Center, agree that the goal is for psychiatrists to be able to inform patients that they have a mutation that is causing their disease and ultimately to be able to tailor treatments to individual patients based on their specific mutation. This tailored treatment is a ways off, according to Dr. Karayiorgou, but she says patients and their families are relieved to know that there is a biological cause of their illness.

The researchers plan to extend their screen for additional de novo mutations by using increased resolution scans to study additional families. They also plan to scrutinize further genes affected by the identified mutations through human genetics and animal model approaches.

Source: Columbia University Medical Center

Strong association of de novo copy number mutations with sporadic schizophrenia. Bin Xu, J Louw Roos, Shawn Levy, E. J. van Rensburg, Joseph A Gogos & Karayiorgou. Nature Genetics. 30 May 2008. doi:10.1038/ng.162

Josh says:

This isn’t the first time gene duplications or nucleotide duplications have been known to cause a disease. I remember a case from one of my classes where there was a disease, and with each generation the onset was earlier and earlier. It basically worked out that the grandmother, mother, and daughter all got the disease at the exact same time. What was occuring was that DNA polymerase would “skip” over a long strand of repeats, making it longer with each cell division.

Anyone going to HBES 2008? [HENRY » genetics]

Posted: 30 May 2008 07:59 PM CDT

The annual Human Behavior and Evolution Society meeting is on next week in Kyoto, Japan. Anyone going? Looks like there’s going to be a lot of interesting primatology talks…

Self-assembled viruses [Think Gene]

Posted: 30 May 2008 06:20 PM CDT

Viruses are true experts at importing genetic material into the cells of an infected organism. This trait is now being exploited for gene therapy, in which genes are brought into the cells of a patient to treat genetic diseases or genetic defects. Korean researchers have now made an artificial virus. As described in the journal Angewandte Chemie, they have been able to use it to transport both genes and drugs into the interior of cancer cells.

Natural viruses are extremely effective at transporting genes into cells for gene therapy; their disadvantage is that they can initiate an immune response or cause cancer. Artificial viruses do not have these side effects, but are not especially effective because their size and shape are very difficult to control—but crucial to their effectiveness. A research team headed by Myongsoo Lee has now developed a new strategy that allows the artificial viruses to maintain a defined form and size.

The researchers started with a ribbonlike protein structure (â-sheet) as their template. The protein ribbons organized themselves into a defined threadlike double layer that sets the shape and size. Coupled to the outside are “protein arms” that bind short RNA helices and embed them. If this RNA is made complementary to a specific gene sequence, it can very specifically block the reading of this gene. Known as small interfering RNAs (siRNA), these sequences represent a promising approach to gene therapy.

Glucose building blocks on the surfaces of the artificial viruses should improve binding of the artificial virus to the glucose transporters on the surfaces of the target cells. These transporters are present in nearly all mammalian cells. Tumor cells have an especially large number of these transporters.

Trials with a line of human cancer cells demonstrated that the artificial viruses very effectively transport an siRNA and block the target gene.

In addition, the researchers were able to attach hydrophobic (water repellent) molecules—for demonstration purposes a dye—to the artificial viruses. The dye was transported into the nuclei of tumor cells. This result is particularly interesting because the nucleus is the target for many important antitumor agents.

Source: Wiley-Blackwell

Yong-beom Lim, Eunji Lee, You-Rim Yoon, Myeong Sup Lee, Myongsoo Lee. Filamentous Artificial Virus from a Self-Assembled Discrete Nanoribbon. Angewandte Chemie International Edition 2008, 47, No. 24, 4525. May 7 2008. doi: 10.1002/anie.200800266

Josh says:

This is a really interesting approach. I wouldn’t go so far as to call it a “virus”, since it doesn’t reproduce within the cell. It’s more like they created a structure that resembles a viral envelope that can bind to cells and deliver its “contents”, which in this case are RNAs designed to be siRNA for a gene of choice.

Genetic Polymorphisms Associated with Methylphenidate [A Forum for Improving Drug Safety]

Posted: 30 May 2008 06:01 PM CDT

COMMENT
Attention Deficit Hyperactivity Disorder is one of the most common psychiatric diagnoses of childhood, and many formulations of methylphenidate (e.g., Metadate CD, Focalin and Focalin XR, Ritalin LA, Concerta) are utilized for its treatment. Clinicians have puzzled why some individuals seem to be usually sensitive to methylphenidate products while others require high dosages. It has long been known that carboxylesterase 1 is the enzyme that metabolizes methylphenidate. However, this study presents evidence that polymorphisms of this gene can lead to unexpectedly high levels of methylphenidate. This finding has particular importance in light of the FDA review of possible cardiovascular adverse effects of psychostimulants. It might be shown in the future that individuals with these genetic alterations may be at risk to develop serious cardiovascular side effects associated with their high blood levels of methylphenidate.

ABSTRACT
Am J Hum Genet. 2008 May 14. Two CES1 Gene Mutations Lead to Dysfunctional Carboxylesterase 1 Activity in Man: Clinical Significance and Molecular Basis. Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, Devane CL, Malcolm R, Johnson JA, Youngblood GL, Sweet DH, Langaee TY, Markowitz JS.

The human carboxylesterase 1 (CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject’s CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260-299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate, p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (V(max)/K(m)) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates.

The World Science Festival [Tomorrow's Table]

Posted: 30 May 2008 05:46 PM CDT

Once in a while I wish Davis, California was a litle closer to New York City. This week is one of those times.

If so, I could attend the World Science Festival . The aim of the festival is to "spark a movement in which science shifts from the cultural outskirts to the cultural center". There you can:

see Alan Alda discuss the treasure trove of letters written by Albert Einstein,

meet Brian Greene, physicist, science writer and co-founder of the festival,

watch high school students interview Nobel Laureate physicist Leon Lederman and ground-breaking robotic engineer Cynthia Breazeal,

hear Science Friday's Ira Flatow in conversation with leading cosmologists Lawrence Krauss, Paul Steinhardt, and Lyman Page, and historian of science,

listen to neurologist and best-selling author Oliver Sacks and NPR's Robert Krulwich illuminate the often surprising relationship between vision and the brain and

hear Nobel Laureate Paul Nurse talk with geneticists Francis Collins and Jim Evans and renowned ethicists about how personal genomics will affect our lives.

To see Brian Greene on the Colbert Report and learn more about the festival see their blog.

Red Flags for Hereditary Cancer [DNA Direct Talk]

Posted: 30 May 2008 04:38 PM CDT

Guest post from Lisa Kessler, DNA Direct’s Senior Genetic Counselor: A recent article in the New York Times about red flags for hereditary cancer went into detail about specific findings in families. About 5-10% of cancers are thought to be strongly hereditary; for people who worry about their genetic risk, and who have a family history [...]

New Genome Browser from DecodeMe [ScienceRoll]

Posted: 30 May 2008 02:09 PM CDT

I’ve already analyzed the genome browser of 23andMe, one of the best known personalized genetic companies. Now here is the new genome browser of DecodeMe, another famous company. You open the browser:

Then you can choose which SNPs you are interested in:

It looks impressive. Give it a try and let me know your feedback.

Table of contents for TED Talks

Previous in series

Fruits, vegetables and teas may protect smokers from lung cancer, UCLA researchers report [Think Gene]

Posted: 30 May 2008 12:43 AM CDT

Tobacco smokers who eat three servings of fruits and vegetables per day and drink green or black tea may be protecting themselves from lung cancer, according to a first-of-its-kind study by UCLA cancer researchers.

UCLA researchers found that smokers who ingested high levels of natural chemicals called flavonoids in their diet had a lower risk of developing lung cancer, an important finding since more than 90 percent of lung cancers are caused by tobacco smoking.

The study was published this month in the journal CANCER.

"What we found was extremely interesting, that several types of flavonoids are associated with a reduced risk of lung cancer among smokers," said Dr. Zuo-Feng Zhang, a researcher at UCLA's Jonsson Cancer Center and a professor of public health and epidemiology. "The findings were especially interesting because tobacco smoking is the major risk factor for lung cancer."

Flavonoids are water-soluble plant pigments that have antioxidant and anti-inflammatory properties, both of which can counteract damage to tissues. For the UCLA study, researchers looked at 558 people with lung cancer and 837 people who did not have lung cancer and analyzed their dietary history.

Researchers found that study participants who ate foods containing certain flavonoids seemed to be protected from developing lung cancer. Zhang said the flavonoids that appeared to be the most protective included catechin, found in strawberries and green and black teas, kaempferol, found in Brussels sprouts and apples, and quercetin, found in beans, onions and apples.

So should smokers run out and stock up on the teas, apples, beans and strawberries? Quitting smoking is the best course of action, Zhang said, but eating more fruits and vegetables and drinking more black and green teas won't hurt.

"Since this study is the first of its type, I would usually be hesitant to make any recommendations to people about their diet," Zhang said. "We really need to have several larger studies with similar results to confirm our finding. However, it's not a bad idea for everyone to eat more fruits and vegetables and drink more tea."

Zhang said flavonoids protect against lung cancer by blocking the formation of blood vessels that tumors develop so they can grow and spread, a process called angiogenesis. They also stop cancer cells from growing, allowing for naturally programmed cell death, or apoptosis, to occur.

The antioxidant properties found in the flavonoids also may work to counteract the DNA damaging effects of tobacco smoking, Zhang said, explaining why they affected the development of lung cancer in smokers but not in non-smokers.

"The naturally occurring chemicals may be working to reduce the damage caused by smoking," Zhang said.

The next step, Zhang said, are laboratory-based studies of flavonoids on cell lines and animal models to determine how they are protecting smokers from developing lung cancer. And in addition to larger studies to confirm these findings, other studies need to be done to see if the protective effects of flavonoids extend to other smoking-related cancers, such as bladder, head and neck and kidney cancers.

Zhang and his team also plan to study which types of fruits and vegetables have the highest levels of the flavonoids found to be helpful in this study and what the optimal number of servings per day might be to provide the greatest protection.

Source: University of California - Los Angeles

Josh says:

I unfortunately can’t find the paper, as there are a lot of journals called “Cancer” and the paper may or may not actually be available yet. This is just yet another study that demonstrates how good for you flavinoids are. I remember another study that said flavinoids cause an immune response, which may be why they’re helpful for preventing disease.

Dehydrated tomatoes show promise for preventing prostate cancer [Think Gene]

Posted: 30 May 2008 12:38 AM CDT

New research suggests that the form of tomato product one eats could be the key to unlocking its prostate cancer-fighting potential, according to a report in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.

"Processing of many edible plants through heating, grinding, mixing or drying dramatically increases their nutrition value, including their cancer prevention potential. It appears that the greatest protective effect from tomatoes comes by rehydrating tomato powder into tomato paste," said Valeri V. Mossine, Ph.D., research assistant professor of biochemistry at the University of Missouri.

The protective effect of tomato products against prostate cancer has been suggested in many studies, but researchers remain uncertain about the exact mechanisms. Mossine and colleagues demonstrated that FruHis, an organic carbohydrate present in dehydrated tomato products, exerts a strong protective effect.

Researchers divided rats into groups of 20 and fed them a control diet or a diet that included tomato paste, tomato powder or tomato paste plus additional FruHis. All animals were then injected with prostate cancer-causing chemicals.

Animals fed the tomato paste plus FruHis diet had the longest survival from cancer at 51 weeks compared with 50 weeks in the tomato powder group, 45 weeks in the tomato paste alone group and 40 weeks in the control group.

On post-mortem exam, prostate tumors were found in 10 percent of the rats that had been given a combination of tomato paste and FruHis, compared with 30 percent of animals in the tomato powder group, 25 percent in the tomato paste alone group and 60 percent in the control group.

Mossine said the protective effect of tomato-based products was restricted to prostate tumors, which is consistent with other research on tomatoes and cancer. Incidence of other tumors was too small to examine.

In vitro, Mossine and colleagues evaluated the anti-cancer properties of FruHis and 14 other D-fructose amino acids and found that FruHis in a concentrated form protected against DNA damage known to lead to prostate cancer. When combined with lycopene, FruHis stopped cancerous cell growth more than 98 percent of the time.

"Before this study, researchers attributed the protective effect of tomatoes to ascorbic acid, carotenoids, or phenolic compounds," Mossine said. "FruHis may represent a novel type of potential dietary antioxidant. Experiments like these suggest that a combination of FruHis and lycopene should be investigated as a potential therapeutic anti-tumor agent, not just a prevention strategy."

Although Mossine cautioned against drawing broad conclusions from this animal study, he said, "the result may introduce an additional intrigue into an ongoing dispute over the beneficial effects of dietary lycopene and tomato products in lowering the risk of prostate cancer. Human trials are certainly warranted."

Source: American Association for Cancer Research

Josh says:

The paper is not currently available. I wonder how long it will take for FruHis to be available as a supplment or added to multivitamins. It certainly should be easy enough to mass produce.

Succinct, Short, and Sweet: Stewart Scherer's guide to the human genome [Discovering Biology in a Digital World]

Posted: 30 May 2008 12:30 AM CDT

I got my copy of "A short guide to the human genome" by Stewart Scherer today from Cold Spring Harbor Laboratory Press (2008, ISBN 978-087969791-4). Usually, I would wait until after I've read a book to write a review, but this book doesn't require that kind of study. As soon I skimmed through it and read some of the questions and answers, I knew this would be the kind of quick reference that I would like to have sitting above my desk.

Read the rest of this post... | Read the comments on this post...

GINA Series: Health Care and Genetic Testing [Page 4] [Think Gene]

Posted: 29 May 2008 11:00 PM CDT

Recently, President Bush signed GINA, the Genetic Information Nondiscrimination Act, into law. GINA makes it illegal for employers or health insurers to discriminate based on genetics. Virtually the entire genetics community has lauds this legislation, yet few have written why its wrong that employers and services review objective facts to make decisions.

“It’s not fair…” but why?

Health Care and Genetic Testing

Modern health care has evolved into more social infrastructure than private living expense, like education.

Could you imagine treating our intellectual health like our physical health? That we only learn to react to emergencies? That people are loathe to reveal a need for learning lest they are ostracized by educators? That higher learning is an elite, private service while most wallow in ignorance and fear?

Yet this is health care is today. People hide from an institution that will take their money, but avoid providing care.

Health insurance is still modeled to pay for individual emergency medical interventions. The old idea is that these interventions are rare, but if needed, are both expensive and vital —too vital to ignore, yet too expensive for any individual to afford.

The new idea is that with genomics, is not just that disease can be prevented, but that humans can be improved. It’s not “just another treatment,” it’s a fundamental shift of what health is.

I think that health insurance companies should know our genomes so that we can best plan for and provide preventive care. Rather than hiding risks, we’ll actively reveal them. Why? For better treatment. To prevent that risk from realization. To prepare for the uncommon yet necessary support one will need to continue to be a functional member of society.

But then, these won’t be insurance providers, but Health Providers.

But when an individual’s health is no longer a private asset, the idea that birth is outside societies jurisdiction must be revised. Already, we demand that life is not endangered irresponsibly . Safety isn’t optional. Ending life is a crime. One is liable for not applying the latest advances in safety and health. We fear ending life, but the chronic geometric consequences of creating it are taboo.

We don’t consider an individual’s intellect to be private. We cooperate to run schools and universities to “preemptive” learn about our world. Why shouldn’t we “preemptive” live in our world, too?

Addenum:

Very few health professionals are getting this yet. One who does is Dr. Steve Murphy of Helix Health. I highly recommend his blog: The Gene Sherpa.” Steve doesn’t necessarily share nor endorse any ideas I’ve written above .

Page: [1] [2] [3] [4]

Hypermethylation of the 5′CpG island of the FHIT gene in clear cell renal carcinomas. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Kvasha S, Gordiyuk V, Kondratov A, Ugryn D, Zgonnyk YM, Rynditch AV, Vozianov AF
Cancer Lett (Jul 2008)

FHIT is a tumour suppressor gene which is frequently inactivated in different types of cancer. Both genetic (mutations, deletions, chromosomal rearrangements) and epigenetic (aberrant methylation of the 5′CpG island) alterations of the FHIT gene have been reported in various malignancies. Yet little is known about the mechanism of FHIT inactivation in clear cell renal carcinomas. Since genetic alterations were not frequently observed in DNA corresponding to the FHIT gene in renal tumours, to elucidate the mechanism of FHIT gene silencing we examined 22 paired samples of clear cell renal carcinoma and non-malignant renal tissue for the methylation of the FHIT 5′CpG island by methylation-specific PCR. Hypermethylation of the FHIT 5′CpG island was detected in 54.5% (12/22) of clear cell renal carcinomas. Bisulfite sequencing of the FHIT 5′CpG island confirmed the results obtained by methylation-specific PCR for selected samples. We showed here that expression of the FHIT gene is inversely correlated with hypermethylation of the FHIT 5′CpG island in the selected samples. Our results suggest that hypermethylation of the FHIT 5′CpG island may be responsible for inactivation of the FHIT gene in clear cell renal carcinomas.

Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H
Cancer (Jun 2008)

Decitabine (5-aza-2′-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at ‘optimal biologic’ doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies. Cancer 2008. (c)2008 American Cancer Society.

Calculating human exposure to endocrine disrupting pesticides via agricultural and non-agricultural exposure routes. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

McKinlay R, Plant JA, Bell JN, Voulvoulis N
Sci Total Environ (Jul 2008)

Endocrine Disrupting Chemicals (EDCs) are of increasing concern because of their potential impacts on the environment, wildlife and human health. Pesticides and some pesticide metabolites are an important group of EDC, and exposure to them is a poorly quantified source of human and environmental exposure to such chemicals generally. Models for estimating human exposure to Endocrine Disrupting (ED) pesticides are an important risk management tool. Probabilistic models are now being used in addition to deterministic ones in all areas of risk assessment. These can provide more realistic exposure estimates, because they are better able to deal with variation and uncertainty more effectively and better inform risk management decisions. Deterministic models are still used and are of great value where exposure data are scarce. Models or groups of models that provide holistic human ED pesticide exposure estimates are required if the risk posed to humans by ED pesticides is to be better assessed. Much more research is needed to quantify different exposure routes such as exposure from agricultural spray drift and the medical use of pesticides to develop such models. Most available probabilistic models of human exposure were developed in the USA and require modification for use elsewhere. In particular, datasets equivalent to those used to create and apply the American models are required. This paper examines the known routes of human pesticide exposure with particular reference to ED pesticides and their quantification as unlike pesticides generally, many ED pesticides are harmful at very low doses, especially if exposure occurs during sensitive stages of development, producing effects that may not manifest for many years or that affect descendants via epigenetic changes. It also summarises available deterministic and probabilistic models commonly used to calculate human exposure. The main requirement if such models are to be used in the UK is more quantitative data on the sources and pathways of human ED pesticide exposure.

Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T, Vonk R, van der Schot AC, Nolen W, Kahn RS, McGuffin P, Murray RM, Craig IW
Am J Med Genet B Neuropsychiatr Genet (Jun 2008)

Monozygotic (MZ) twins may be subject to epigenetic modifications that could result in different patterns of gene expression. Several lines of evidence suggest that epigenetic factors may underlie mental disorders such as bipolar disorder (BD) and schizophrenia (SZ). One important epigenetic modification, of relevance to female MZ twins, is X-chromosome inactivation. Some MZ female twin pairs are discordant for monogenic X linked disorders because of differential X inactivation. We postulated that similar mechanisms may also occur in disorders with more complex inheritance including BD and SZ. Examination of X-chromosome inactivation patterns in DNA samples from blood and/or buccal swabs in a series of 63 female MZ twin pairs concordant or discordant for BD or SZ and healthy MZ controls suggests a potential contribution from X-linked loci to discordance within twin pairs for BD but is inconclusive for SZ. Discordant female bipolar twins showed greater differences in the methylation of the maternal and paternal X alleles than concordant twin pairs and suggest that differential skewing of X-chromosome inactivation may contribute to the discordance observed for bipolar disorder in female MZ twin pairs and the potential involvement of X-linked loci in the disorder.

Heterochromatin tells CENP-A where to go. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Durand-Dubief M, Ekwall K
Bioessays (Jun 2008)

The centromere is the region of the chromosome where the kinetochore forms. Kinetochores are the attachment sites for spindle microtubules that separate duplicated chromosomes in mitosis and meiosis. Kinetochore formation depends on a special chromatin structure containing the histone H3 variant CENP-A. The epigenetic mechanisms that maintain CENP-A chromatin throughout the cell cycle have been studied extensively but little is known about the mechanism that targets CENP-A to naked centromeric DNA templates. In a recent report published in Science, such de novo centromere assembly of CENP-A is shown to be dependent on heterochromatin and the RNA interference pathway.

Exploring the behavior of small eukaryotic gene networks. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Bruggeman FJ, Oancea I, van Driel R
J Theor Biol (Jun 2008)

Analysis of the genome organization of higher eukaryotes indicates that it contains many clusters of functionally related genes. In these clusters, the activity of a single gene is regulated hierarchically at a local gene-level and a global cluster-level. Whether a single gene can be activated by a dedicated transcription factor depends on the epigenetic status of the cluster, i.e. whether it is epigenetically permissive or silenced. The consequence of gene clusters for the functioning of gene networks is largely unexplored. The accumulating biological knowledge about mechanisms for epigenetic regulation, signal transduction, and gene clusters makes such explorations a timely challenge. We explore the steady-state behavior of two gene clusters that mutually inhibit each other. This gives rise to multiple steady states in this simple system of interacting clusters. We illustrate that a gene cluster encoding a module composed of a signal transduction network and a transcription factor can generate versatile temporal dynamics that resembles cellular differentiation. The gene cluster can be epigenetically silenced and activated by a dedicated transcription factor. This module displays transient signal sensitivity, and irreversible decisions (commitment; hysteresis) depending on the identity and temporal sequence of external signals.

Characterization of Dnmt3b:thymine-DNA glycosylase interaction and stimulation of thymine glycosylase-mediated repair by DNA methyltransferase(s) and RNA. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Boland MJ, Christman JK
J Mol Biol (Jun 2008)

Methylation of cytosine residues in CpG dinucleotides plays an important role in epigenetic regulation of gene expression and chromatin structure/stability in higher eukaryotes. DNA methylation patterns are established and maintained at CpG dinucleotides by DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b). In mammals and many other eukaryotes, the CpG dinucleotide is underrepresented in the genome. This loss is postulated to be the result of unrepaired deamination of cytosine and 5-methylcytosine to uracil and thymine, respectively. Two thymine glycosylases are believed to reduce the impact of 5-methylcytosine deamination. G/T mismatch-specific thymine-DNA glycosylase (Tdg) and methyl-CpG binding domain protein 4 can both excise uracil or thymine at U.G and T.G mismatches to initiate base excision repair. Here, we report the characterization of interactions between Dnmt3b and both Tdg and methyl-CpG binding domain protein 4. Our results demonstrate (1) that both Tdg and Dnmt3b are colocalized to heterochromatin and (2) reduction of T.G mismatch repair efficiency upon loss of DNA methyltransferase expression, as well as a requirement for an RNA component for correct T.G mismatch repair.

Epigenetic regulator polycomb group protein complexes control cell fate and cancer. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Kanno R, Janakiraman H, Kanno M
Cancer Sci (Jun 2008)

The chromatin-associated Polycomb group (PcG) proteins were first identified in genetic screens for homeotic transformations in Drosophila melanogaster. Besides body patterning, members of the PcG are now known to regulate epigenetic cellular memory, stem cell self-renewal, and cancer development. Here, we discuss the multifarious functions of the PcG family, isoforms of protein complexes, and its enzymatic activities, for example histone methylation, links to DNA methylation, its phosphorylation status, H2A mono-ubiquitination, SUMOylation, and links to non-coding RNA. We also discuss the function of cytosolic PcG complexes as a regulator of receptor-induced actin polymerization and proliferation in a methylation-dependent manner. We propose that the functional versatility of PcG protein complexes contributed significantly to the complexity of heritable gene repression mechanisms, signal transduction, and cell proliferation in cancer development.

Epigenetic mechanisms regulating fate specification of neural stem cells. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Namihira M, Kohyama J, Abematsu M, Nakashima K
Philos Trans R Soc Lond B Biol Sci (Jun 2008)

Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.

Epigenetic remodeling of the fungal secondary metabolome. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH
Org Biomol Chem (Jun 2008)

Fungi treated with DNA methyltransferase and histone deacetylase inhibitors exhibited natural product profiles with enhanced chemical diversity demonstrating that small-molecule epigenetic modifiers are effective tools for rationally controlling the native expression of fungal biosynthetic pathways and generating new biomolecules.

Stable long-period cycling and complex dynamics in a single-locus fertility model with genomic imprinting. [Epigenetics News]

Posted: 29 May 2008 10:40 PM CDT

Van Cleve J, Feldman MW
J Math Biol (Aug 2008)

Although long-period population size cycles and chaotic fluctuations in abundance are common in ecological models, such dynamics are uncommon in simple population-genetic models where convergence to a fixed equilibrium is most typical. When genotype-frequency cycling does occur, it is most often due to frequency-dependent selection that results from individual or species interactions. In this paper, we demonstrate that fertility selection and genomic imprinting are sufficient to generate a Hopf bifurcation and complex genotype-frequency cycling in a single-locus population-genetic model. Previous studies have shown that on its own, fertility selection can yield stable two-cycles but not long-period cycling characteristic of a Hopf bifurcation. Genomic imprinting, a molecular mechanism by which the expression of an allele depends on the sex of the donating parent, allows fitness matrices to be nonsymmetric, and this additional flexibility is crucial to the complex dynamics we observe in this fertility selection model. Additionally, we find under certain conditions that stable oscillations and a stable equilibrium point can coexist. These dynamics are characteristic of a Chenciner (generalized Hopf) bifurcation. We believe this model to be the simplest population-genetic model with such dynamics.

agribusiness

Friday, May 30, 2008

The DNA Network

The DNA Network

Table of contents for TED Talks

No comments:

Blog Archive

About Me