Posted: 03 Dec 2008 07:45 PM CST
I usually don't comment on this type of study, but this time the hype is just too much for me: New Scientist describes the study as "a milestone in the quest to understand" the placebo effect; an article in ScienceNow quotes a psychiatrist saying that "the findings could have major implications for research design". The article itself certainly doesn't talk down its results, with the first sentence of the discussion stating:
The present study demonstrates that the magnitude of the placebo response [...] is tied to attenuated amygdala excitability, which in turn is linked to serotonergic genetic variation.
The problem? The study examined just 25 subjects, and if there's one clear lesson from the history of candidate gene asociation studies it's that such tiny studies are essentially worthless: systematic reviews of the field (e.g. here, here and here) have consistently found that the majority of such associations are never replicated, suggesting that positive results in small studies are substantially more likely to arise through a combination of chance, error and publication bias than through a genuine causal link.
It's only relatively recently that genetic association studies have come of age, with the advent of agnostic genome-wide association studies, massive sample sizes, rigorous statistical frameworks and the use of independent replication cohorts. Unfortunately, it appears that such novelties haven't yet permeated Uppsala University's Department of Psychology - but that hasn't stopped their study from generating media attention, in publications that should really have known better.
So don't believe the hype: as a good rule of thumb, if a genetic association study contains fewer than 100 subjects, it's not a "milestone" with "major implications" - in fact, you might as well simply pretend it doesn't exist at all. (Many studies with more than 100 subjects are also crap, but at least there's a chance they're capturing a genuine causal variant.) I'm deadly serious about this. The field is so littered with the stinking carcasses of unreplicated candidate gene associations that it's a reasonable default to simply assume that any small, unreplicated study is false.
Now, if only there was a way to get some science journalists to internalise that little rule of thumb...Read the comments on this post...
Posted: 03 Dec 2008 06:38 PM CST
I don't quite fully get this, but the point of the method that they propose is to look at paralogous genes to more efficiently pinpoint the actual causal variants from among the many "hits" that pop up in GWASs.
Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins
Mark Yandell, Barry Moore, Fidel Salas, Chris Mungall, Andrew MacBride, Charles White, Martin G. Reese
PLoS Comput Biol 4(11): e1000218
Abstract: The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes.
Posted: 03 Dec 2008 06:04 PM CST
Posted: 03 Dec 2008 05:47 PM CST
First up read yesterday's entry on Genomic Organization.
Now that you've done that, let's talk about a paper that appeared in Nature about a month ago. The article is entitled:
Stepwise chromatin remodelling by a cascade of transcription initiation of non-coding RNAs (link)
Superficially you would look at this title and exclaim Wow another function for non-coding RNAs! Well not exactly. It would seem that everyone is going ga-ga over these non-coding RNAs, but if you dig deeper, something else is going on. Note that I'm not saying that the paper is crap, in fact the results are VERY interesting, but you have to keep in mind that this paper is describing is how the act of transcribing non-coding RNA affects genomic organization.
But before we begin, let's dust off our lexicon. Here are some definitions that I did not bring up yesterday. Chromatin can be thought of as the configuration of DNA with its associated proteins, mainly nucleosomes. Chromatin remodelling refers to alterations in the packaging of this DNA so that the tightness and location of nucleosomes have been altered. As I described yesterday, these changes will affect how DNA binding proteins associate with the genome, which in turn modifies what regions are transcribed into RNA.You'll also remember that the theme of that post was that RNA Polymerase II (aka Pol II) and nucleosomes have a strange relationship. In fact Pol II can directly alter the modifications found on histones and can also influence how DNA is bound to its nucleosomes. So there is a constant conversation between chromatin structure and Pol II.
The Nature paper illustrates this principle nicely. It demonstrates how one gene, fbp1, is activated in response to glucose deprivation. Strangely, Pol II plays a big part in initiating gene activation by allowing the chromatin to be remodelled.
You see it would seem that when the gene is "inactive", Pol II transcribes very long RNAs that start well before the fbp1 gene. These "pioneer" transcripts cover a whole section just before and then continue past the gene and end at the normal termination site. These long mRNAs are even polyadenylated at their end. But they are weird. These RNAs are neither spliced nor translated into protein. The transcripts are found at a very low level and seem to be unstable (I'm inferring that the transcripts have a short half-life from some of their gels, but unfortunately the authors don't measure this parameter). When glucose levels are lowered, the long transcripts disappear and instead new shorter RNAs are made by Pol II molecules. These shorter RNAs begin at points closer to the gene's start site but again end at the gene's termination site. The short guys are however much more numerous as compared to the initial pioneer transcripts. Eventually very short transcripts are made. These transcripts start at the "consensus start site" of the fbp1 gene and are not only properly spliced but are translated into protein.
Now here is the cool part, if you genetically modify the yeast genome so that a transcriptional terminator is introduced in front of the fbp1 gene, you not only prematurely truncate these long pioneer transcripts but you prevent the production of all the shorter transcripts. Yes you prevent the stepwise activation of the gene.
So what is happening?Read the rest of this post... | Read the comments on this post...
Posted: 03 Dec 2008 04:02 PM CST
I have found that many Catholics are confused about genetic testing and the ethical issues that surround it. So I have decided to write a two part series on the ethics of genetic testing.
Part 1: Genetic testing is not all bad.
A colleague's battle with cancer is a good example of the use of genetic testing to prevent disease. We now know that mutations in the BCRA1 or BCRA2 gene put a woman at high risk of developing breast or ovarian cancer. My colleague's mother, aunts, and cousin had breast or ovarian cancer. She, herself, was an ovarian cancer survivor. When the test for mutations in the BCRA1 gene became available, she found that she did have the mutation. Her sister was also tested, had the mutation, but had yet to develop cancer. Knowing she was at high risk, the sister underwent preventive surgery and now regularly gets screened for tumors. Hopefully, she will never develop cancer, but, if she does, it will be caught early, increasing her chances for survival.Doctors often use genetic testing to help treat their patients. A good example is the test for a mutation in the Factor V Leiden gene. Factor V Leiden is the most common hereditary blood coagulation disorder in the United States. Patients with a mutation in this gene are at greater risk of developing potentially deadly blood clots. If a doctor knows that a patient has an increased risk of developing a clot, they can prescribe medication or monitor the patient closely after surgery.
Genetic testing also provides information on Hereditary Hemochromatosis (HHC), the most common form of iron overload disease. HHC is an inherited disorder that causes the body to absorb and store too much iron. If the disease is not detected early and treated, iron will accumulate in body tissues and may eventually lead to serious problems. Mutations in the HFE gene are the thought to be the cause of HHC. A genetic test can identify patients who are at risk for developing HHC before they begin to have symptoms. In fact, there are countless such conditions and diseases, linked to genetic factors, that will be positively impacted by genetic testing, including diabetes and Alzheimer's disease.Genetic testing has also created an exciting new field called pharmacogenetics. Pharmacogenetics is the study of how
people's genetic make-up affects their response to medicines. Because each person metabolizes drugs differently, it can take a lot of trial and error before a doctor will find the right drug or combination of drugs and dosage(s) for a particular patient. Scientists continue to find genes that regulate the metabolism of drugs. Discovering the genetic profile of how a patient may react to a class of drugs will facilitate the doctor's decision on which drug and what dosage is appropriate for that patient. Recently, a sales representative showed me a microarray DNA chip that tests the genes responsible for the metabolism of psychiatric drugs. This test will provide psychiatrists with valuable information, so they can better prescribe medications, increasing effectiveness and reducing side effects.
Prenatal diagnosis of the unborn, using genetic testing, is always an ethically sticky subject. There are several immoral uses of prenatal genetic testing that I address in Unethical Uses of Genetic Testing, but, as Catholics, we cannot automatically assume that prenatal genetic testing is immoral. An obstetrician opposed to abortion once told me that, in his observation, genetic testing has often prevented a couple from aborting their child. He said that not knowing is often more scary than knowing, and couples may be more likely to abort if they do not have all of the information available. In the future, with the perfection of surgery on the unborn in the womb, prenatal genetic testing may actually save unborn lives. The Vatican Congregation of the Doctrine of the Faith has made a statement on prenatal diagnosis:
"Is prenatal diagnosis morally licit? If prenatal diagnosis respects the life and the integrity of the embryo and the human fetus and is directed toward safeguarding or healing as an individual, then the answer is affirmative."All of the benefits of genetic testing are too numerous to list here. The Catholic Church welcomes genetic testing when its function is to improve sound medical practice. The possibilities of genetic testing prompted John Paul II to make the following statement:
Indeed, the biomedical sciences are currently experiencing a period of rapid and marvelous growth, especially with regard to new discoveries in the areas of genetics . But if scientific research is to be directed toward respect for personal dignity and support of human life, its scientific validity according to the rules of each discipline is not enough. It must also qualify positively from the ethical point of view, and this presupposes that from the outset it endeavors to promote the true good of human beings as individuals and as a community. This happens when efforts are made to eliminate the causes of disease by putting real prevention into practice, or whenever more effective therapies are sought for the treatment of serious illnesses.
Posted: 03 Dec 2008 03:57 PM CST
Check this out...
Hawking plans long commute to Canada
Posted: 03 Dec 2008 01:50 PM CST
JoVE is the Journal of Visualized Experiments, a journal of videos indexed by Pubmed as well. Now, they expanded their video-based model of scientific publishing to include medicine and psychology protocols. We had to wait for this improvement, but now it happened.
The first two videos:
Posted: 03 Dec 2008 09:52 AM CST
College tuition has increased 439% since 1984, and the net yearly cost of college at a 4-year public university is 76% of the median family income, according to a story in today's NY Times. Even community colleges don't end up being a much better deal. It's a scandal. We're pricing most people out of college at a time when middle-class income is stagnating and education is more critical than ever for career success.
Posted: 03 Dec 2008 09:25 AM CST
Posted: 03 Dec 2008 07:00 AM CST
As regular readers know, I like to keep a fairly close eye on what Sciencebase visitors are searching for so that I can put together new posts that provide answers to the questions readers want answering. Recently, there has been a spate of search queries related to neon signs. Perhaps not the most exciting of subjects, but there is some nice chemistry to be learned from all the different colours available, so I thought I’d shed some light on the subject of noble gas illumination.
Incidentally, for those unaware of the history of noble gases, they were at one time known as inert gases because chemists though their full outer shell of electrons made them unreactive. As more and more reactions for these so-called inert gases were discovered, it became necessary to give them another label, hence noble.
A neon light is not really much more than a fluorescent tube (actually, it’s less as it needs no phosphor coating on the inside), but instead of containing mercury vapour to give a bright “white” light, neon tubes contain the noble gas neon, surprise, surprise. Pass an electric discharge through a tube containing low pressure neon and it will glow with that familiar orange-red glow, so evocative of late-night bars and sleazy movies.
A neon light uses a very high voltage to propel an electric current through a low-density gas of neon atoms held in a glass tube. Charges from the electrode at each end of the tube fly through the gas colliding frequently with neon atoms and transferring some of their energy to the neon atoms. This kicks the neon atoms into a higher energy, excited state, with an electron in a higher orbital than normal. This excited state does not last and as the electron loses energy the atom drops back to a lower energy state and releases a photon of light. The energy of this photon is equivalent to the energy fall and for neon atoms that coincides with an energy that produces a reddish glow.
Many people, unfamiliar with the noble gas group of the periodic table - the p-block, assume that all coloured fluorescent tubes used in signage are neon signs. However, there are two ways to produce other colours - paint a standard mercury tube with the colour you want or far more effectively use a different noble gas in the tube instead of neon, perhaps together with mercury vapour to give a stronger glow. Here’s a break down of the discharge colours for each noble gas.
Helium (He) - Orangey white, usually
Of course, it is not only the noble gases and mercury vapour that can be added to lighting tubes. Nitrogen produces a slightly pinker glow than argon, oxygen glows violet-lavender but dimly. Hydrogen glows lavender at low currents, but pinkish magenta above 10 milliAmps, while carbon dioxide produces a slight bluish-white. Mercury can be made to glow in the ultraviolet, and is used in so-called black lights. Sodium vapour at low pressure glows the bright yellow of street lighting, particularly in England. And, even water vapour produces a glow similar to hydrogen, only dimmer .
Posted: 03 Dec 2008 06:57 AM CST
I just read a paper that features fellow science blogger Chris Patil as an author (although he would be the first to state that he was second on the author's list). The manuscript, which appeared in yesterday's edition of PLoS Biology, describes senescence-associated secretory phenotype (aka SASP), a phenomenon that is associated with cancer cells treated with chemotherapeutic reagents that cause DNA-damage and with cells undergoing senescence. From the paper:
Despite support for the idea that senescence is a beneficial anticancer mechanism, indirect evidence suggests that senescent cells can also be deleterious and might contribute to age-related pathologies [10,23-25]. The apparent paradox of contributing to both tumor suppression and aging is consistent with an evolutionary theory of aging, termed antagonistic pleiotropy . Organisms generally evolve in environments that are replete with extrinsic hazards, and so old individuals tend to be rare in natural populations. Therefore, there is little selective pressure for tumor suppressor mechanisms to be effective well into old age; rather, these mechanisms need to be sufficiently effective only to ensure successful reproduction. Further, tumor suppressor mechanisms could in principle even be deleterious at advanced ages, as predicted by evolutionary antagonistic pleiotropy. Consistent with this view, senescent cells increase with age in mammalian tissues , and have been found at sites of age-related pathologies such as osteoarthritis and atherosclerosis [28-30]. Moreover, in mice, chronically active p53 both promotes cellular senescence and accelerates aging phenotypes [31,32].
It turns out that SASP is responsive to oncogenic forms of RAS and loss of p53, two of the most important genetic contributors to cancer.
It will be interesting to tease out whether SASP is solely due to an increase in transcription of a select group of secreted proteins or whether some other aspect of mRNA metabolism is altered (such as a decrease in mRNA turnover). After all, there seems to be a tight connection between stress and mRNA metabolism (see this post). Also it is likely that the secretory potential of the endoplasmic reticulum has to be upregulated and this clearly requires certain branches of the UPR gene regulatory program (unfolded protein response - again another stress response pathway - see this post) to be activated.
Abel Pharmboy has a great post on the article, that I strongly encourage you to go over and check it out.
Posted: 03 Dec 2008 05:30 AM CST
The Scientist magazine has published a list of the top 10 innovations in life science in 2008, as judged by their panel of expert judges.
Among the chosen highlights are:
A Fucci (Fluorescent ubiquitination-based cell cycle indicator)-based system that allows real-time, in vivo imaging of the cell cycle.
A service that allows end users to order customised zinc finger proteins to snip genomic DNA at the precise location they desire for knocking-out, or in, genes.
And a low-cost DNA sequencing system that can sequence the entire human genome for just $60K… and they aim to reduce the cost to $10K by the end of 2008.
Check out the whole list at The Scientist Magazine.
Posted: 03 Dec 2008 01:14 AM CST
As I've previously mentioned, twin studies allow an estimation of the heritability of a trait by comparing the degree of concordance in a given phenotype between MZ (identical) twins and DZ (fraternal) twins.
I recently came across a fascinating study looking at the heritability of intraocular pressure - that is -the pressure on the inside of the eyeball that ophthalmologists and optometrists measure when screening for glaucoma. Carbonaro and colleagues, from the Twin Research and Genetic Epidemiology Unit at King's College London School of Medicine, performed a classical twin study to estimate intraocular pressure (IOP) heritability1. Although there was some modest variability in the heritability estimates depending on which of 3 instruments was utilized to measure IOP, the results suggested that genetic factors explain about 62 percent of the variation in IOP, with individual environmental factors and/or stochastic factors accounting for the remainder.
62 percent is impressively high, but of course does not tell us anything about the genetic architecture of the trait. Although some progress has been made in understanding the genetics of congenital glaucoma, we have much further to go with adult glaucoma/IOP elevation. Despite the existence of a few clues2-4, much work remains to be done.
Posted: 02 Dec 2008 11:03 PM CST
It's hard to believe that it's been a full month since the historic election. Well, depends on how you count a month, but today is the first Tuesday after the first Monday in December.
I was more of a political junkie in my youth, but I haven't sworn off the habit. Only in the last few days was I attempting to handicap the electoral college. TNG was a huge Obama fan, asking every adult in sight whether they would be voting for him. On the flip side, the other ticket had Miss Amanda quite charged up -- the idea of a Canino-American being one heartbeat from the presidency was too much to resist (though she has declared she will nip any groomer who attempts to apply lipstick to her!). Her disappointment that night was quickly salved by Obama's first major policy declaration in his celebratory speech. Alas, her closest kin have not been mentioned as in the running for the White House staff position.
Speaking of Governor Palin, it seems she will not be fading from the limelight. No, indeed it looks like her personal Iditarod will be going for the nomination in 2012. Alaska's chief executive made a number of comments during the campaign which induced consternation in the scientific community. Granted, the fruit fly remark was specifically about research on a totally different bug than Drosophila in a completely agriculturally-targeted setting, but it didn't endear her to the fans of Morgan & Bridges. Given she has four years to prepare, it wouldn't hurt to start now. And, in the spirit of reuse, should she not run it would seem the majority of these queries would apply to the majority of other Republicans who went for the high office this year.
1) You have publically taken stands that some views held by a minority (or less) of the scientific community should be accepted and used as the basis for policy decisions (e.g. the existance and/or cause of global warming trends) and/or taught in public schools as viable alternatives to the majority view (e.g. creationism). How do you choose which 'maverick' scientific theories have merit and which do not?
2) Which of the following maverick theories, relevant to major issues in this country today, should be taught in public schools or used to guide policy:
2.1) Healthcare (research priorities, Medicare/Medicaid reimbursement policy)
2.1.1) Childhood vaccines cause autism
2.1.2) AIDS can be treated more effectively with vitamin combinations than antiretrovirals
2.1.3) AIDS is caused by lifestyle factors and not the virus HIV
2.1.4) High cholesterol levels do not cause heart disease; cholesterol lowering using drugs risks cancer & depression
2.2) Physical sciences
2.2.1) Petroleum is not a limited supply of fossil remains of ancient lifeforms but rather is constantly created by processes deep in the earth (clearly an area where Ms. Palin has declared as in her sphere of expertise)
2.2.2) Manned space travel through the van Allen belts is guaranteed to be lethal; funding an attempt to land on the moon should be cancelled.
2.2.3) Einstein's Theory of Relativity is clearly wrong, as the concept of time dilation is so opposed to normal experience as to be laughable.
3) Should the U.S. government ever fund research outside its borders? Under what conditions should such operations be funded, if ever?
4) To what degree should non-expert politicians alter the research funding priorities set by experts in the field?
5) What, if any, useful science has come from studying fruit flies? Should the U.S. fund any further research? What other organisms do you also feel are not worth researching?
This is just a draft; readers are invited to submit further questions via the comments
Posted: 02 Dec 2008 10:28 PM CST
I’m quite pleased to host this month’s Mendel’s Garden - a blog carnival featuring the best genetics writing on the internets for the last month. Since it’s my party, I’ve picked out a few of my favorite topics to feature. But in the way of introduction for the neophytes in the crowd, let’s define our terms. The first question I ask my students on their first exam is “What is a gene and how is it regulated?”. I’m looking for them to talk about Mendel’s description of units of inheritance and the modern DNA based definition. Well, RPM of Evolgen thinks that it’s time to expand our definition or throw the word out entirely. He makes a solid argument, based on the fact that a lot of things that are transcribed in the genome wouldn’t be considered ‘genes’ by most of us. But if we trash the word, what would geneticists call themselves?
For a perfect example of the beautiful complexity of genetics illustrated, check out this father-son photo from Not Afraid To Use It. About says it all. Without further ado, a few of my favorite things genetical:
I found a couple of great posts about the genetics of autism. Now, to clarify, I’m not a big fan of autism per se, but I got embroiled (in a minor way) in the controversy with this post on the autism-MMR vaccine sham. Since then, I’ve followed the new research on autism with some interest. A post over at Highlight Health describes two genome-wide genetic analyses that identified five genetic loci that contribute to autism susceptibility, lending more support to the argument that autism is largely a heritable disorder. Kristina Chew, of AutismVox, thinks that geneticists sometimes go a bit far, however. Her response to a “sweeping” new theory that an evolutionary tug-of-war between parental genetic contributions is astutely skeptical. And of course, As is the case with any genetic disorder, there is an environmental component to consider. Reviewing an odd study out of Cornell, the Great Beyond details an assertion that autism rates are higher in rainy parts of the world. Take of it what you will, folks.
I’ve become increasingly fascinated with human evolution and in the genomic era research into our roots is just burgeoning. This month, Daniel McArthur at Genetic Future writes about one of the new tools available to evolutionary geneticists and gives an example of its use to look at positive selection at certain human genetic loci. One of the more interesting stories from this field is of the pair of skeletons found in a mass grave in Germany locked in an intimate embrace. The Great Beyond describes the DNA analysis that revealed that the 4600 year old remains were of a parent and child and appear, with fractured skulls and an arrowhead in the spine, to have been unfortunate victims of humanity’s penchant for genocide. Of course, none of this may matter according to UCL’s Steve Jones (as reported on Dick Dawkins dot net) who says that human evolution is done due to a dearth of older fathers. Jones argues that genetic variation comes, in part, from mutations that men accumulateas they get older. Don’t worry, Steve, I think there are plenty of toxins about to keep us mutating.
Speaking of junk science, there was some new junk on junk DNA released as a press release from the Genome Institute of Singapore. As Bayblab points out, this is a new and disturbing way of publishing your results - skip all the hassle of peer review and editing and just throw it out there to the mainstream press. Shame really, because this is my third topic of choice - epigenetics. Yann Klimentidis, on his blog, recounts some recent research looking at epigenetic changes in utero brought on by environmental stress. Zamp Bionews has more about epigenetic control of offspring fertility, which in this case is regulated by small RNAs apparently passed on maternally. Alex at The Daily Transcript has RNA, if not epigenetic, regulation in his post describing how each RNA binding protein in yeast tends to associate with mRNAs of a particular type. He hypothesizes that the expression of entire classes of genes may be subject to coordinated regulation at the level of mRNA metabolism.
And finally this month, a technical brief for those of you doing the hard work of science rather than just writing about it. Sandra, who blogs at Discovering Biology in a Digital World, tells us about a new BLAST feature that allows users to create a custom database. Sandra goes through a step-by-step tut and generates a viral phylogeny. For those Ph.D. students out there in the “Nothing Works Doldrums”, Nick at Bite Size Bio has some reassuring words for you - sometimes things just don’t work. That’s biology.
This posting includes an audio/video/photo media file: Download Now
Posted: 02 Dec 2008 06:15 PM CST
Recently there has been a flood of press about epigenetics and non-coding RNA. What is lacking from these articles is a description of how DNA is packaged and what DNA elements such as promoters and enhancers do. Today I would like to touch upon all of these subjects with a post on how DNA is organized and how this affects the turning on or off of genes.
OK here we go ...
One of the biggest findings over the past couple of years is how the act of transcription feeds back onto the organization of DNA.
What do I mean by that?Read the rest of this post... | Read the comments on this post...
Posted: 01 Dec 2008 06:34 PM CST
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