November 2, 2007 by dendrite
Image via Wikipedia A look at almost any gene expression pattern in the brain will most certainly confuse you. This is in contrast to functional imaging studies that often show that the brain is organized into neat, aesthetically pleasing functional circuits. Why don’t genes show similar neat expression patterns that reflect a common functional organization ? Some clues to this can be found in the recent paper, “A survey of genetic human cortical gene expression” by Myers and company (DOI). Their joint analysis of individual variation at the level of genome sequence (Affy 500K array) and mRNA-expression (Illumina Refseq-8 Expression BeadChip) shows that most of the correlations between gene sequence and gene expression are between genetic variants that are far away from the genes whose expression they are correlated with (so-called, trans, effects). The team found 433 SNP-transcript pairs (99 transcripts) that showed a significant specific empirical cis association and 16,701 SNP-transcript pairs (2,876 transcripts) that showed a significant trans association. This result is similar to a previous study using mice DOI that found that the expression of the mouse strain-specific genes was driven mainly by cis-acting regulatory elements, whereas the brain region-specific genes were mainly regulated by trans-acting regulators. Thus, it seems that a given non-coding snp variant may be more likely to influence expression outside its local (50kb) neighborhood than close by. The authors generously provide access to this important data for folks who would like to query candidate snps. Manga !
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Posted in Uncategorized | Tagged Gene expression | Leave a Comment »
October 29, 2007 by dendrite
“Love is the answer, but while you’re waiting for the answer, sex raises some pretty interesting questions” so says Woody Allen. Indeed, whether you’re in love or lust, the tiny neuropeptide arginine vasopressin (AVP) is your pal. Recently, Thompson et al., found that AVP increases the perception of friendliness in females exposed to unfamiliar faces (‘tend and befriend’ a stranger), while lowering the perception of friendliness in males (the more typical aggressive response to a stranger). The fascinating modulatory effects of AVP on social affiliation are now better understood in light of the work of Allaman-Exertier and colleagues who explored the relationship between the AVPR1A receptors and the neural circuitry that underlie complex behaviors and feelings of amour. The paper is focused on the lateral septal area which is rich in vasopressinergic axons and contains high amounts of AVPR1A receptors. Mice that lack a particular type of vasopressin receptor, AVPR1A, for example, are impaired in the recall and recognition of social encounters – but, replacing the receptor just in the lateral septum, is enough to restore social recognition. The AVPR1A receptors mediate both excitatory and inhibitory post-synaptic effects within the septal area and thus can modulate activity in downstream centers such as the hypothalamus.
Note: this tid bit of knowledge will not assist in the fulfillment of romantic endeavors !
Posted in AVPR1a, Hypothalamus, Lateral septum | Tagged autism, Emotion | Leave a Comment »
October 25, 2007 by dendrite
$390 for a few restriction digests and gel pic. Impoverished grad students slaving over benches everywhere – I feel your pain.
Posted in Uncategorized | Tagged Art | Leave a Comment »
October 21, 2007 by dendrite
Image by Getty Images via Daylife Psychiatrists and families that cope with mental illness have long been aware of far reaching familial risk. Although the new genomics greatly accelerates the identification of specific risk alleles; the direct functional and mechanistic connections between these tiny bits of nucleic acid and large-scale changes in neural activity and behavior is more often a matter of hand waving than hard science. Monory et al., in their article, “Genetic Dissection of Behavioural and Autonomic Effects of d9-Tetrahydrocannabinol in Mice” (doi:10.1371/journal.pbio.0050269) provide an excellent example of how to relate the effects of a given gene (the CB1 receptor) to changes in behavior (getting stoned, to put it blunt-ly) by first beginning to determine what CB1 expressing cell-types are necessary. For example, ever-mellow GABA-ergic neurons are not involved in mediating the effects of cannabinoids whilst excitatory glutamatergic neurons mediate hypolocomotor effects. Similar analyses of specific (gene x circuit) interactions will build important bridges between genetics and psychiatry. Why do the mice get to have all the fun ?
Posted in CB1 receptor, GABA, Glutamate | Tagged medication, Mental disorder, Pharmacology | Leave a Comment »
October 14, 2007 by dendrite
“Hey, you with the smelly armpits, how about a date ?”
Ahhh, if only this were true ! Sadly, not. However, it would appear that females eschewing us slovenly males may doth protest too much. Recall the popular science lab where females rank their preference to the smell of sweaty t-shirts of unshowered male classmates. Typically, this lab involves the genotyping of a number of Major Histocompatibility (MHC) gene polymorphisms and comparisons that show females prefer the odor of dissimilar MHC genotype. There are, however, well known clusters of odorant receptor genes within the MHC gene super-clusters and these may provide a more direct link from odor to preference. Liza Gross describes related findings in her article, “A Genetic Basis for Hypersensitivity to “Sweaty” Odors in Humans,” where the dosage of an olfactory receptor gene OR11H7P correlated with sensitivity to the odorant isovaleric acid. Although OR11H7P is not located within the commonly assayed MHC super-cluster on human 6p, it is a sweet-smelling step toward understanding mechanisms of female choice.
Posted in MHC loci | Tagged Emotion, Monogamy, Olfaction, placebo | Leave a Comment »
October 7, 2007 by dendrite
Image via Wikipedia Without a doubt, one of the low points of any marriage comes when you have to select a new paint colors. To avoid unnecessary strain, I usually just go along to get along, but Mother Nature allows no easy escape from this inevitable moment in our life cycle. After a third trip to the paint store, I found myself literally, up the wall, painting another test patch in a dark upper corner. Whilst brushing away, I was reminded of a lecture by V. S. Ramachandran who happened upon a colorblind subject who reported subtle differences in the colors of certain digits. In their article, “We also observed one case in which we believe cross activation enables a colorblind synesthete to see numbers tinged with hues he otherwise cannot perceive; charmingly, he refers to these as “Martian colors.” Although his retinal color receptors cannot process certain wavelengths, we suggest that his brain color area is working just fine and being cross-activated when he sees numbers.“Jay Gingrich and colleagues report (DOI) that the serotonin 2A receptors mediate the “synesthesia-like” effects of psychoactive hallucinogens such as LSD specifically via pertussis toxin-sensitive heterotrimeric G(i/o) proteins and src. Now, I’m a fan of genetic conflict hypotheses of all sorts, and perfectly willing to acknowledge that Mother Nature has stacked the deck against my Y-chromosome in many ways, but as my wife complained, yet again, that the new color was not, “the color in her head”, I began to wonder about natural mechanisms of synesthesia and the natural history of HTR2A and Mother Nature’s often dark sense of humor.
Posted in 5HTT, HTR2A, Visual cortex | Tagged Pharmacology, Synesthesia | Leave a Comment »
October 2, 2007 by dendrite
Image by wallyg via Flickr Can you say this 5 times quickly, “secreted sushi containing SRPX2 as a source of sylvian seizures seems like a spandrel” ? Well, if you can, you might say thanks to your FOXP2 gene (much ado recently), but of course its important to say thanks to so many other co-evolutionary substitutions. A recent article by Royer et al. (doi:10.1186/1471-2156-8-72) examines the recent evolution of the SRPX2 gene and found an R75K change that marks a human-primate split and also occurs in an important functional loop of the first sushi domain of SRPX2 (one that carries a mutation that is responsible for sylvian seizures involving oral and speech dyspraxia). Although they did not find evidence for positive selection, its easy to suspect that Lysine-75 plays an important supporting role in our tongue-twisting skills.
Posted in FOXP2, SRPX2, Sylvian fissure | Tagged evolution, language, Neanderthal | Leave a Comment »
September 28, 2007 by dendrite
Image via Wikipedia To go out tonight or stay home? Hillary or Barack? Curly fries or onion rings? How do I make these important choices and why will others decide differently? Although there are many reasons for not stressing-out and over-thinking one’s decisions (except for really important choices like curly fry vs. onion ring), it turns out that variation in your genome, in particular, 3 dopaminergic genes (DARPP-32, DRD2 and COMT: rs907094, rs1800496, rs4680) are influencing your tendency to ‘go for it’ or not to go for it. Frank and colleagues, in their paper, “Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning“, give an in-depth treatment of the neurobiology underlying decision making and reinforcement learning. After carefully reviewing the basic biology of dopaminergic synapses and selecting 3 candidate genetic variants, they find that each is associated with an independent aspect of decision making in a learning paradigm. The paper is an excellent example of how genetic variation can be linked to specific neural processes. Now bring on the curly fries – no wait – the onion rings.
Posted in COMT, DARPP32, Dopamine, DRD2 | Tagged Addiction, Dopamine, Frontal lobe | Leave a Comment »
September 23, 2007 by dendrite
There is no doubt that -omics and digital-bio is improving healthcare, IF, you’re NOT one of the 50 million uninsured human beings in America who lack health insurance. As a fan of all things free-and-open, bioinformatic and health2.0, I was glad to read Timothy Stoltzfus Jost ‘s new book, Health Care at Risk: A Critique of the Consumer-Driven Movement. A review of the historical and economic foundations of the so-called ‘consumer-driven healthcare’ movement which is well underway (supported by leading candidates from both parties), Jost unpacks inefficiencies inherent to both private insurance systems (adverse selection – ‘sick people need NOT apply’) and to public systems (moral hazard and demand inducement – ‘hey dude, pass the twinkies and cigarettes, – no worries, I’ll just rely on my free healthcare’). The main arguments, from Jost, that stuck with me, are that the consumer-directed system, as it stands today, is one that is skewed to address the moral hazard conundrum, and this is not likely to resolve much of the current economic crisis since healthcare spending is distributed very asymmetrically (a tiny fraction of very sick people account for most of spending). Indeed, Jost suggests the current consumer-directed healthcare movement (pass off the first $5,000 spending to the consumer) is likely to make matters worse before they get better. While sobering, the book may prompt a redoubling of the focus of the many free-and-open bioinformatic and health2.0 efforts working to enhance care and access for all.
Posted in Uncategorized | Tagged economics, Health insurance | Leave a Comment »
September 21, 2007 by dendrite
For geezers who may recall the 1994 furor over The Bell Curve, research on genetics and intelligence has a Paris-Lindsay-&-Britney-esque way of drawing media attention. Thankfully, serious research on neurobiological correlates of intelligence does not. A recent paper from a highly regarded research team from UCLA adds more to the complex mystery of intelligence. From their paper, Luders and company found that “positive associations between intelligence and posterior callosal thickness may reflect a more efficient inter-hemispheric information transfer, positively affecting information processing and integration, and thus intellectual performance”. For geneticists and media hounds as well, I’d recommend to study this paper and others in this field very carefully as there are many neuroanatomical and physiological correlates. The genetics may similarly be a thicket of developmental pathways, not to mention a good night’s sleep, an apple a day, and parents who help you with your homework.
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Posted in Corpus callosum, White matter | Tagged Development, Intelligence | Leave a Comment »
September 14, 2007 by dendrite
Image via Wikipedia Skimming the abstracts in BMC, I was surprised to find that a fruit fly logs a slothful 8-14 hours of sleep per day! Douglas and colleagues in their paper, “Sleep in Kcna2 knockout mice” show that the mouse ortholog of the Drosophila mutation, Shaker (an alpha subunit of a voltage activated potassium channel) that disrupts normal fly sleep, also keeps mice awake at night.
Posted in KCNA2 | Tagged Mouse, Sleep | Leave a Comment »
September 7, 2007 by dendrite
Behavioral geneticists are fond of noting that more than half of the risk for mental illness is heritable, and, fonder of the number of specific risk factors that have been identified. What is much less well known however is how these heritable factors interact with the environment to potentiate risk. Psychiatrists, on the other hand, rightly point out that children and adults who experience traumatic and social stress are also at greater risk for psychiatric illness. Indeed, brain imaging has shown a number of anatomical regions where activity declines in subjects and patients alike who experience trauma or other difficult experience. In their recent paper, “Stress-induced changes in primate prefrontal profiles of gene expression,” Karssen and colleagues take a major step towards bridging the gene-by-experience puzzle and examine how gene expression changes in response to socially stressful experience. Using a squirrel monkey model, an experimental group of males was subjected to intermittent social separation and also exposure to new roommates – conditions known to elevate cortisol levels. Using a (note the caveat here) human microarray platform and several signal analysis protocols, the investigators present several hundred genes differentially (interestingly mostly down-regulated) expressed in the frontal cortex. So – the question begs – were any of the genes identified in the Karssen study the same, or in the same pathways, as known genetic risk factors ? Yes – well sort of. The authors present several genes, including a few involved in GABA signaling, that had previously been linked via gene expression studies to mood disorders in humans. Certainly, these are attractive candidates for family- and population-based association studies.
Posted in Frontal cortex, GABA | Tagged Frontal lobe, Gene expression, Mental disorder, Stress | Leave a Comment »
September 1, 2007 by dendrite
Image via Wikipedia The recent paper, “Genetic Markers of Suicidal Ideation Emerging During Citalopram Treatment of Major Depression” finds that among 68 candidate genes, markers for 2 AMPA-type glutamate receptors (rs4825476, rs2518224: GRIA3 and GRIK2) show significant association in 120 individuals who experienced suicidal ideation in a large medication trial for major depressive disorder. Many families with loved ones suffering from depression remain wary and confused about a possible causal relationship between selective serotonin reuptake inhibitor (SSRI) antidepressants and suicide. A current FDA-mandated black box warning advises youths on the potential risks. This recent genetic study seems to provide a meaningful step forward in better understanding the mechanism of shifts in mood and cognition that occur in some individuals. But like many brain research studies though, shining a tiny ray of light on a puzzle suddenly illuminates massive complexities, previously unseen. A great deal of research shows that SSRI exposure leads to long lasting changes in AMPA receptor expression, localization and function, – but it’s unclear where a specific link between this and changes in mood and cognition will be drawn.
Posted in 5HTT, AMPA receptor, Glutamate, GRIA3, GRIK2 | Tagged Antidepressant, Depression, Major depressive disorder, SSRI, Suicide | Leave a Comment »
August 28, 2007 by dendrite
I much enjoyed the June 15th podcast “Blame it on my genes” hosted at the New York Academy of Sciences. Here, Professor Paul Appelbaum lays out a biological framework for behavioral genetics wherein genes influence an individual’s sensitivity to experience in ways that predispose or insulate them from illness. As the basic science begins to map specific (gene x environment) examples, how, then, might this knowledge play out in the justice system where it could be used in “determinations of culpability?” Indeed, as covered by Professor Appelbaum, our justice system allows individuals to be excused from culpability when they are incapacitated (insanity defense) or via automatism (a sleepwalker commits a crime but is not consciously aware of it). Can, or should, genetic background be used in this way (a genetic determinism defense)? Professor Appelbaum reviews a key Supreme Court ruling from “Robinson v. California” citing the opinions of Justice Hugo Black that recognize that just because someone is influenced by causal factors, does not mean that that person cannot choose rationally. This opinion is based on the principle of compatibilism (free will and determinism are compatible) which apparently is rooted in an ancient school of Greek philosophers. Nevertheless, there is a lot of action in the lower courts where genetic evidence is being proffered to mitigate or lessen culpability – interesting times ahead. Perhaps the judiciary is already subscribed to “The DNA Network!”
Posted in Uncategorized | Tagged Depression, law, medication, Mental health, Supreme Court | Leave a Comment »
August 21, 2007 by dendrite
New York Times reporter Andrew Pollack covers recent evolutions in the DNA synthesis business in his September 12 article, “How Do You Like Your Genes? Biofabs Take Orders.” Apparently, the traditional high-school-science-lab-methods for cutting and pasting stretches of DNA have been replaced by “biofabs” – correction – a “biofab industry” complete with consultants and marketing research firms. The DNA2.0 website even has an ominous “biosecurity compliance” message (just the kind of goofy touch a consultant would come up with) noting that all orders are screened against the CDC list of “select agents.” Am I missing something ? The chemical mis-incorporation error in DNA synthesis is seriously problematic and, as noted in the article, the error rates for long synthetic sequences is undesirable to put it mildly. Seems to me you’d have to sequence and re-sequence a multitude of these commercially purchased clones to be sure they contained the correct sequence. I imagine many a grad student, using traditional cloning and mutagenesis methods, would have easily finished the cutting and pasting long before then.
Posted in Uncategorized | Tagged New York Times | Leave a Comment »
August 14, 2007 by dendrite
As reported on the BBC, a recent call by Lord Justice Sedley, for universal inclusion (tourists too) in Great Britain’s national DNA database, has fanned longstanding civil rights debates. Given that the national DNA database carries disproportionate levels of ethnic minorities, it hardly seems fair to search or use the database within a legal framework or presumption that its contents generalize to the UK population at large. Some have concluded that there is much more genetic variation within ethnic and racial groups than between groups, making the ethnic composition of the database, a non-issue. In contrast, the article (free on Pubmed central) , “Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies,” led by Neil Risch and Nicholas Schork find that when many, many markers are used, clustering algorithms can reveal a strong correspondence between self-reported ethnicity and genetic background. This article was a good jumping-off point for me to learn more about this complex issue. I think its not to soon for me to start rehearsing what I’ll say to the cops when they pull me over for driving with an undesirable allele.
RELATED UPDATE … story on how US government insiders/lobbyists abuse public monies set aside for DNA testing.
Posted in Uncategorized | Tagged Civil rights, Genetic testing, law | Leave a Comment »
August 7, 2007 by dendrite
In a recent free and open BMC report on gene expression in non-smokers vs. current smokers vs. quitters, Chari and colleagues identify a class of genes whose expression “appears to be permanently altered despite prolonged smoking cessation.” Frighteningly, a number of genes encoding DNA repair enzymes are irreversibly altered … definitely not good to mutagenize your genome and then knock out the repairman. Worse yet, another gene that popped up was calcium binding tyrosine-(Y) phosphorylation regulated (CABYR) a gene that is found in the sperm flagellum, lung and brain (these are all tissues with cells that are rich in microtubules and dynein motors – so perhaps CABYR plays a smoking-related role in the lung in ciliary clearance of mucous). Wait a minute, did someone say sperm cell ? Ouch – no more cigarettes please. Although, the effects of smoking on CABYR expression were reversible, I don’t need a direct mutagenic hit there to make me wince, just thinking about that is enough.
Posted in acetylcholine, CABYR | Tagged Addiction, Gene expression, Nicotine | Leave a Comment »
July 28, 2007 by dendrite
Daniel Weinberger and company have a new installment in-press at Biological Psychiatry in their epic program to untangle the genetic basis of schizophrenia – “Heritability of Brain Morphology Related to Schizophrenia: A Large-Scale Automated Magnetic Resonance Imaging Segmentation Study.” Like all complex illness, schizophrenia is regulated by a variety of environmental sources (perinatal complications, stress & substance abuse are a few) and equally regulated by heritable factors. Although several specific genes for schizophrenia have been painstakingly identified, the genes are expressed widely throughout the brain – making it difficult to pinpoint where in the brain the gene interacts with the environment to exert its detrimental effects. To solve this problem, Weinberger and colleagues pioneered a method known as imaging-genetics where they look at how individual genetic differences correlate with differences in brain structure or functional activity (if you ever have a chance to volunteer for an fMRI brain imaging study – go for it – it’ll be one of the top 10 weirdest experiences of your life). In their latest report, the team pioneers a new “fully-automated whole brain segmentation” technique to show that the genetic factors that put individuals at risk may be functioning vis-a-vis the hippocampus and neocortex. This narrows the search space a lot! and is a major step forward in beginning to localize where in the brain the genetic risk originates.
Posted in Cingulate cortex, DLPFC, Frontal cortex, Hippocampus | Tagged Brain, Functional magnetic resonance imaging, Mental health, Neuroimaging, schizophrenia | Leave a Comment »
July 21, 2007 by dendrite
To me, phylogenetics is one of the coolest ways to use human sequence diversity. I’m not an expert, but roughly speaking, the method involves looking at sequences among ancestral populations and comparisons to sequences in groups that have migrated out over space and time. In these out groups, recombination and mutation have caused genetic sequences to diverge – in some cases new alleles have been naturally selected for, and in most cases, new alleles thrived or crashed due the size and mating structure of a population. The genome carries the historical record of this change – the ultimate history book !
I recently had my Y-chromosome analyzed by the Genographic Project and was intrigued to discover a southwest asian heritage. More recently, Kenneth Kidd and colleagues report a detailed analysis of sequences in the KIR receptor gene complex on chromosome 19q13 and variation in the human leukocyte antigen (HLA) class I gene complex on chromosome 6p23. It has long been known that these regions are hypervariable, which is a good thing since our immune system exploits this diversity to counter ever-changing pathogen invasions – but how do two parts of the immune system continue to work together (KIR receptors bind to HLA antigens) when the separate, unlinked genomic regions show hypervariability ? Worse yet, if the KIR-HLA interaction is too weak, we are susceptible to infection, but, if too strong, we are susceptible to autoimmune attack. Quite a tight-wire to walk, amidst a deluge of pathogen invasions ! Kidd and colleagues use the ALFRED database to reveal some clues to the historical record of this. Apparently, the co-evolution is selective, where activating receptor (19q13) -ligand (6p23) complexes were strongly negatively selected for but not inhibitory receptor-ligand pairs.
Posted in MHC loci | Tagged evolution, Genetic testing, Immune system | Leave a Comment »
July 15, 2007 by dendrite
Just quickly plugging the various feeds and discussions from the recent Health 2.0 conference. Thanks to the facebook group, folks like me, who did not attend, are getting great insights into the emerging issues in this exciting area. Doesn’t seem like too long before the open, consumer-directed, health management & care model is seamlessly knitted together with ‘omics’ of all molecular weights!
Posted in Uncategorized | Tagged Health care, Web 2.0 | Leave a Comment »
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Image via Wikipedia A look at almost any gene expression pattern in the brain will most certainly confuse you. This is in contrast to functional imaging studies that often show that the brain is organized into neat, aesthetically pleasing functional circuits. Why don’t genes show similar neat expression patterns that reflect a common functional organization ? Some clues to this can be found in the recent paper, “A survey of genetic human cortical gene expression” by Myers and company (DOI). Their joint analysis of individual variation at the level of genome sequence (Affy 500K array) and mRNA-expression (Illumina Refseq-8 Expression BeadChip) shows that most of the correlations between gene sequence and gene expression are between genetic variants that are far away from the genes whose expression they are correlated with (so-called, trans, effects). The team found 433 SNP-transcript pairs (99 transcripts) that showed a significant specific empirical cis association and 16,701 SNP-transcript pairs (2,876 transcripts) that showed a significant trans association. This result is similar to a previous study using mice DOI that found that the expression of the mouse strain-specific genes was driven mainly by cis-acting regulatory elements, whereas the brain region-specific genes were mainly regulated by trans-acting regulators. Thus, it seems that a given non-coding snp variant may be more likely to influence expression outside its local (50kb) neighborhood than close by. The authors generously provide access to this important data for folks who would like to query candidate snps. Manga !
Genes 2 Brains 2 Mind 2 Me 