Typically, when we think of Tyrannosaurus Rex, we envision a giant killing machine with titanic jaws and huge teeth that could crunch through bones as thick as our arms and legs. Or, if you’re a fan of Jack Horner, you’re probably thinking of a five ton scavenger roaming the badlands and terrifying every smaller predator [...]... Read more »
Ruxton, G., & Houston, D. (2003) Could Tyrannosaurus rex have been a scavenger rather than a predator? An energetics approach. Proceedings of the Royal Society B: Biological Sciences, 270(1516), 731-733. DOI: 10.1098/rspb.2002.2279
Carbone, C., Turvey, S., & Bielby, J. (2011) Intra-guild competition and its implications for one of the biggest terrestrial predators, Tyrannosaurus rex. Proceedings of the Royal Society B: Biological Sciences. DOI: 10.1098/rspb.2010.2497
A research team from the Center for Molecular Medicine of the Austrian Academy of Sciences in Lazarettgasse recently published a paper in the open access journal BMC Systems Biology characterizing what they termed “the human central proteome.” Whenever a study comes out that characterizes a “central” process, pathway, proteomic or genomic subset I am always [...]... Read more »
Thomas R Burkard, Melanie Planyavsky, Ines Kaupe, Florian P Breitwieser, Tilmann Buerckstuemmer, Keiryn L Bennett, Giulio Superti-Furga, & Jacques Colinge. (2011) Initial characterization of the human central proteome. BMC Systems Biology. info:/
Sexual assault is no laughing matter - unless, of course, the would-be rapist isn't human. Who doesn't giggle when they see a small dog humping someone's leg? But what many people don't realize is that reverse bestiality - where an animal makes unwanted sexual advances on a person - is a true problem for scientists working in the field where the actions of wild animals are completely unpredictable.... Read more »
Brian Bowen. (2007) Sexual Harassment By A Male Green Turtle (Chelonia mydas). Marine Turtle Newsletter, 10. info:/
There’s been a little flurry of papers from UCSF recently about using chemical and environmental perturbations to ask when and why you need the function of a particular gene. I originally thought I might try to write about all of them at once, but no — there’s more here than I can do justice to [...]... Read more »
Yeah, you heard me right. We all have various ways of attempting to get rid of the hiccups. Drinking a glass of water backward, eating a spoonfull of sugar, getting surprised or scared, holding your breath. The list goes on. But what if those DON’T WORK? What if even medications don’t work!? Wherever shall you [...]... Read more »
Odeh M, Bassan H, & Oliven A. (1990) Termination of intractable hiccups with digital rectal massage. Journal of internal medicine, 227(2), 145-6. PMID: 2299306
In my second year of graduate school, I was in a study group with a few other grad students: in particular I remember a white female student and an Asian-American female student. Somehow we got on the topic of admissions, where we all admitted, jokingly, to feeling like impostors. Then the white female student stated that she didn't believe in affirmative action, and expressed her view with quite a bit of anger. "Besides," she finished, "I just don't see race."I was completely paralyzed, and felt like I had no way to articulate what was wrong with what she just said. She happened to leave the room shortly after her statement. I turned to my Asian-American friend."Doesn't see race?" She almost shouted. Tears sprang to her eyes. "When she says that, she doesn't see ME." I looked at her, mute, wanting to cry myself for the shame of not knowing how to be a better friend.* * *I haven't always been the best ally. At times, I probably haven't been an ally at all. The story I related above was the only one I dared share where I could sufficiently pseudonymize the characters. It was not the first, nor was it the last, time I was struck dumb by racism.I did learn to speak up and interrupt racism, and slowly have figured out ways to make the elimination of racism and sexism priorities in my life. But I have a long way to go.The MLK, Jr Memorial panel at Science Online 2011, like the women scienceblogging panel, was up against some stiff competition: Defending Science Online, Standing out: Marketing yourself in science, Blogging networks and the emerging science communications ecosystem and Not All Marketing is Evil: Getting Life Science Companies to Support Science Online. I'll admit to sitting near the back with the thought I might divide my time between this session and one other. Yet within the first few minutes I sat there, I knew I was in the right place. David Kroll, who you know all over the internet because of his great blogs Terra Sigillata and Take as Directed, opened by playing the guitar and singing Bob Marley. Within a few bars, about a third of the audience was singing along with him. I was too busy trying not to cry to join in.I was emotional for a number of reasons... because of the wonderful contradiction of David sitting up there and singing, because of the warmth of the room, where it felt like we had a shared mission. David contradicted the paralysis a lot of allies face, because we are so afraid of doing it wrong, of making the mistake that exposes the racism and privilege we are working so hard to cover up.In addition to discussing Martin Luther King, Jr's history in Durham and the surrounding area, David shared with us the following quote from Irving Epstein (which it turns out David wrote about a year ago here):In 2005, more than two-thirds of the American scientific workforce was composed of white males. But by 2050, white males will make up less than one-fourth of the population. If the pipeline fails to produce qualified nonwhite scientists, we will, in effect, be competing against the rest of the world with one hand tied behind our backs.Danielle Lee of Urban Science Adventures, and Alberto Roca of Minority Postdoc, were also panelists. Danielle was engaging and smart: she talked about issues of underrepresentation in science, as well as access and trust of science in minority communities. Alberto, who I had also heard speak as an audience member at a few other panels, also talked about underrepresentation issues in science, the invisibility and isolation of being a person of color in science, and how to operate against that isolation. Here are a few of their broader points (any butchered or incomplete thoughts are my fault only):People of color and from underrepresented groups often have to pass in order to survive in science.People have to be mentored all the way up the chain: several stories were mentioned where women and people of color were not adequately prepared or professionalized for their jobs and suffered for it.Impostor syndrome is universal.You act like a role model when you have a voice, so if you aren't speaking up you aren't a role model. Also, if you are invisible or are ignored/underappreciated, you will have a harder time being an effective role model. So the knife cuts both ways.As Danielle says, science needs a new PR campaign. The African American community has serious trust issues with science and with good reason: this community has been exploited, undervalued, ignored.Related to the above, there was some discussion of issues of religion and science; namely, that it is a mistake to completely discount or scoff at those with religion. Religion, faith, and religious practices have an important cultural component for many minority communities in the United States and beyond, and to write off their beliefs is to write them off as people. Even if that's not what is intended, that is certainly what is heard.The entire session was moving -- all three panelists were so thoughtful and kind to one another, they answered audience questions so well, and the audience was committed to the issue of underrepresentation in science. I have a few last thoughts of my own that I'd like to share, as a way to extend the conversation about women scienceblogging to be more inclusive.First, I don't think white people or people with privilege should shy away from conversations about underrepresentation, race, or ethnicity. It is time to just be comfortable with the fact that we are going to make mistakes. If we are well-meaning and want to eliminate racism and other oppressions, then the mistakes we are going to make will not be as bad as the worst ones faced by those to whom we're trying to be allies. Those of us in this community who are academics tend to encourage our students to make mistakes, because we know they will learn from them. But the stakes feel so high in this situation that we are paralyzed. Guess what? Being paralyzed is actually worse than making a mistake. You can apologize for a mistake. There isn't much you can do to fix things if you stay out of an important fight.Second, you know the isolation we talk about as women scientists and science writers? Multiply that times a million and you probably have the isolation of being a person of color in the sciences. There are some different ways in which sexism and racism play out in the public sphere, at least in the US: people might be a bit more willing to make sexist comments than racist ones. However, the impact of racism is at least as harmful, probably more harmful in most ways, because it leads to social disparities in education, health, salaries, living conditions. There are people out there who study the effects of social disparities and internalized racism on health, and folks, it's not good. For instance, the mortality rates of blacks are significantly higher than for whites in heart disease, cancer, unintentional injury, flu and pneumonia, HIV, cirrhosis and homicide (Williams 1999). Measures of internalized racism are correlated with a higher waist circumference, abdominal obesity and insulin resistance (Tull et al 1999, Chambers et al 2004). Issues of acculturation plague immigrant women, especially second-generation women, who experience more explicit instances of racism in their lives through acculturation (Viruell-Fuentes 2007).Finally, science will be a richer, more interesting topic when there is more diversity. And I don't just mean it in the Small World sense: I mean that while I love the scientific method, I know the process of science to be strongly biased by who performs it, and so it is absolutely necessary that we have many different people doing and thinking about science in order to have the best possible perspective on it.Back when I was a union organizer in grad school, my organizer and mentor told me that graduate school doesn't weed out the weak, it weeds out the strong: it weeds out those with strong senses of self who don't want to be exploited, who realize there are other things to do in the world and other ways to live a meaningful life. I think that is true for a lot of people who leave academia and science, and unfortunately most of the ones I know who left were women and people of color.Here's the problem. I want them back, I miss them: they were my dear friends. Those are the kinds of people we need to lead science, do science, communicate science, encourage and excite young people to be scientists.Reach out for people. Be an ally. Interrupt racism and sexism. Implement changes where you work to better recruit and retain people of color. Put people of color in positions of power: they probably know how to fix this mess much better than you do. Risk making mistakes; say you're sorry once you realize it.But whatever you do, don't just sit there.References... Read more »
Chambers EC, Tull ES, Fraser HS, Mutunhu NR, Sobers N, & Niles E. (2004) The relationship of internalized racism to body fat distribution and insulin resistance among African adolescent youth. Journal of the National Medical Association, 96(12), 1594-8. PMID: 15622689
Tull SE, Wickramasuriya T, Taylor J, Smith-Burns V, Brown M, Champagnie G, Daye K, Donaldson K, Solomon N, Walker S.... (1999) Relationship of internalized racism to abdominal obesity and blood pressure in Afro-Caribbean women. Journal of the National Medical Association, 91(8), 447-52. PMID: 12656433
Viruell-Fuentes EA. (2007) Beyond acculturation: immigration, discrimination, and health research among Mexicans in the United States. Social science , 65(7), 1524-35. PMID: 17602812
Williams DR. (1999) Race, socioeconomic status, and health. The added effects of racism and discrimination. Annals of the New York Academy of Sciences, 173-88. PMID: 10681897
This is a great big week for anthropology coverage. The sequencing of the orangutan (Pongo species) genome made the cover of Nature. It's grant-writing-dissertation-formulating-prelim-studying time for me so I haven't had a chance to read this one yet. Science has a couple paleoanthropology-related stories, including two by Ann Gibbons. The first is about recent research on ancient DNA, and how this informs the debate about 'modern human' origins. But there's also a short blurb on what the eff "species" means.
This is a great effing question! The textbook species definition is that proffered by Ernst Mayr: populations of actually or potentially interbreeding individuals, capable of producing viable (and fertile) offspring. Cool, so a dog and a cat are different species because if they mated (ew) no ungodly animal would come from this monstrous union. Expensive high-tech multivariate Scientific reconstruction simulations show the abomination would probably look like this:
But there are many "good" plant and animal species that do mate and reproduce successfully ('hybridize'). Very often these hybrids are sterile, but then very often they're not. This has led researchers to come up with scores of other ways to define species (Holliday (2003) has a great discussion on the matter).
Worse, there's no way to measure, genetically or morphologically, just how different things should be before they can be called different species. The late Morris Goodman and others (Wildman et al. 2003) argued that humans and chimpanzees are so genetically similar that chimps, now in the genus Pan, should be moved to our genus Homo to denote how similar we are. But any other, non-genetic comparison would put our chimp cousins in a very different group from us. Moreover, the effects of hybridization seem, to me at least, to be fairly unpredictable, at least superficially. That is, the outcome of hybridization is highly contingent on what animals are hybridizing, and on these lineages' own evolutionary histories (this is the intractable problem that made me abandon doing hybrid work for my dissertation. Some day though...).
A major issue relates to what I blogged about yesterday: both 'species' and 'hybrid' are terms we've found ourselves with, but they have no inherent meaning in themselves, other than whatever we give them. So it's funny to read this from Gibbons' story:In the real world, [Jean-Jacques Hublin] says, Mayr's concept doesn't hold up: "There are about 330 closely related species of mammals that interbreed, and at least a third of them can produce fertile hybrids."But is it Mayr's species concept that's flawed, or was it misguided to have put these hybridizers into different species in the first place? Should we delineate species based on our a priori conception about whether two things are different, or should a definition of 'species' determine what we call them? Or does it even matter?
To this end, Gibbons's other story describes the morphologically-unremarkable Denisova fossils as belonging to "a new type of human." Well, now what the eff does that mean? We're back to "The Species Problem" (the title of Gibbons's article), but with a new term. And pretend for a moment that the Denisovan fossils didn't yield DNA: the pinky and tooth probably would not have made headlines. Pretend they did have diagnostic cranial remains - would we have recognized them as being so distinct as their genes indicate?
For that matter, I wonder how many arguably 'modern' human fossils would still retain the modern moniker if we could analyze their genes...
ReferencesGibbons, A. (2011). The Species Problem Science, 331 (6016), 394-394 DOI: 10.1126/science.331.6016.394
Gibbons, A. (2011). A New View Of the Birth of Homo sapiens Science, 331 (6016), 392-394 DOI: 10.1126/science.331.6016.392
Holliday, T. (2003). Species Concepts, Reticulation, and Human Evolution Current Anthropology, 44 (5), 653-673 DOI: 10.1086/377663
Wildman, D. (2003). Implications of natural selection in shaping 99.4% nonsynonymous DNA identity between humans and chimpanzees: Enlarging genus Homo Proceedings of the National Academy of Sciences, 100 (12), 7181-7188 DOI: 10.1073/pnas.1232172100... Read more »
Holliday, T. (2003) Species Concepts, Reticulation, and Human Evolution. Current Anthropology, 44(5), 653-673. DOI: 10.1086/377663
Wildman, D. (2003) Implications of natural selection in shaping 99.4% nonsynonymous DNA identity between humans and chimpanzees: Enlarging genus Homo. Proceedings of the National Academy of Sciences, 100(12), 7181-7188. DOI: 10.1073/pnas.1232172100
To say that paleontologists can’t make heads or tails of the Tully Monster would be untrue. The claw-tipped proboscis on the front end and the arrow-shaped rear fins at the posterior end can be easily identified in complete specimens. Beyond that, though, this 300 million year old invertebrate remains one of the most vexing fossil [...]... Read more »
Richardson, E. (1966) Wormlike Fossil from the Pennsylvanian of Illinois. Science, 151(3706), 75-76. DOI: 10.1126/science.151.3706.75-a
Chen, J., Huang, D., & Bottjer, D. (2005) An Early Cambrian problematic fossil: Vetustovermis and its possible affinities. Proceedings of the Royal Society B: Biological Sciences, 272(1576), 2003-2007. DOI: 10.1098/rspb.2005.3159
Ralph Gordon Johnson, Eugene S. Richardson. (1969) The Morphology and Affinities of Tullimonstrum. Fieldiana: Geology, 12(8), 119-149. info:/
One of the major thrusts of the research I've involved with in the last few years is in the world of "domestic introgression." Some times, when we move animals around, there will be a pre-existing wild form of that species. For reindeer transplanted to Alaska, it's the endemic caribou. Some mink farms are in areas that already have a wild mink population. And a dog is nothing, if not a very ... Read more »
SACKS, B., MOORE, M., STATHAM, M., & WITTMER, H. (2011) A restricted hybrid zone between native and introduced red fox (Vulpes vulpes) populations suggests reproductive barriers and competitive exclusion. Molecular Ecology, 20(2), 326-341. DOI: 10.1111/j.1365-294X.2010.04943.x
The enzyme imidazole glycerophosphate synthase (IGPS) can be a bit of a lump. If you bind just one substrate it doesn't do anything, even though its two active sites are separated by more than 30 Å. Only if the second substrate also binds does catalysis actually go at anything like a respectable rate. In a recent paper in Structure researchers from Yale report evidence that this change of pace results from a change in dynamics.
Apo- IGPS from Thermatoga maritima
PDB code: 1GPW
IGPS consists of two different protein subunits, HisH and HisF (right). HisH performs a relatively standard hydrolysis of glutamine, producing ammonia and glutamic acid. The ammonia molecule is then used by HisF as part of a cyclization reaction involving a weird nucleotide called PRFAR (with an IUPAC name that's just too long to bother with). The products of this reaction feed into the biosynthesis of histidine (as you might guess from the name) and the purines. In an example of poor planning, however, the active sites for these two reactions are separated by a great distance. Glutamine hydrolysis takes place near the interface between the proteins (which bind to each other with nM affinity), while PRFAR cyclization takes place at the far end of HisF (near the bottom of the image). This is too far for the ammonia to be efficiently transferred by any direct action of the enzyme itself. Therefore, the reaction proceeds when the NH3 travels down the β-barrel of HisF to its distant active site (see image below left). The upside of this system is that ammonia gets where it needs to go. The downside of it is that unless the hydrolysis reaction only occurs when PRFAR is in position, this enzyme will be a little ammonia factory, costing the cell a fortune in nitrogen. Therefore, the cleavage reaction must be tightly regulated.
Enzymes can deal with this kind of demand in two ways. The first is to make the binding of one substrate depend on another. This is called K-type allostery because what is changed is the affinity (KD) of the enzyme for its substrates. Alternatively, the rate of catalysis can be altered, which is called V-type allostery because the velocity (Vmax) of the reaction is changed. IGPS uses the latter approach. When glutamine binds, NH3 gets eliminated at a stately pace of about 10-3 /s. If PRFAR also binds, however, HisH starts firing NH3 down the barrel at about 5 /s, which may not win many races but is a substantial enhancement. The question, then, is how the HisF active site lets the HisH active site know that PRFAR has arrived, when they are separated by more than 30 Å. Examining the enzyme complex in the presence of various ligands, James Lipchock and Pat Loria find evidence that changes to the dynamics of HisF are responsible for this communication.
A rotated view, looking through the barrel
towards the HisH active site.
The authors start by examining the energetics of PRFAR binding to IGPS. This event is endothermic, with an unfavorable enthalpy of binding. However, the entropic contribution is sufficiently large to overwhelm this effect. This could indicate a major increase in conformational entropy upon binding, or it could just be related to the behavior of water. Lipchock and Loria found that PRFAR binding to form the ternary complex had similar energetics. Of course, you can't form a ternary complex with actual substrates for very long, because catalysis would occur and change the affinities. They dealt with this using acivicin, a glutamine analogue that binds covalently to the active C84 of HisH.
Unfortunately, these thermodynamic data aren't particularly illuminating, so the authors proceeded with a high-resolution examination of the system. Because IGPS is a bit over 50 kDa in size, they chose to use methyl groups as their primary probes. Most of the remaining work in the paper uses ILV (Isoleucine, Leucine, Valine) labeling, which takes advantage of the favorable relaxation properties of the methyl groups of those side chains.
Lipchock and Loria started by examining the enzyme in its apo- state using relaxation-dispersion experiments. As I've mentioned before, these experiments detect exchange between different conformations on the microsecond to millisecond timescale. If this represents motion between two well-defined states, then the apparent relaxation rate at a given refocusing field strength will be a function of total process rate (kex = kab + kba), the populations of the two states (pa and pb), and the chemical shift difference between them (Δω). If the exchange rate is fast on the NMR timescale (meaning that kex >> Δω), the last three parameters can be combined into a factor called φex.
This is how the authors fit their data, a choice they justified by stating that fitting the data to the full Carver-Richards formula (SI equations 8-18) gives similar answers for kex but yields large errors in the populations and chemical shift differences. However, most of the dispersion curves look like data from slower exchange regimes. Unfortunately, I'm having trouble reconstructing their fitted curves from the parameters in any convincing way, in part because the equations in SI contain a few errors, so it's difficult to discuss where the vulnerabilities in this fitting procedure lie.
Using their approach, Lipchock and Loria find that only a few residues are experiencing conformational exchange, and they believe that the motions are primarily local. I'm not so certain on that point: a quick examination of SI Table 1 indicates that all but two methyls have kex within error of 150 /s or so, which may indicate that most residues belong to a single process. However, most of the residues with similar fluctuation rates don't physically group in any obvious way (although V100 and V79 are adjacent).
Regardless of the particulars, it's clear that in the apo- state, few of the methyl groups in HisF are experiencing any kind of µs - ms fluctuation. Binding of acivicin to HisH doesn't change this too much. Within the bounds of the fitted error, the extracted dynamics parameters are the same for many residues. The exceptions are the adjacent residues V79 and V100, and L153δ1, which has an odd halving of both rate and the combined parameter.
Also, as you can see in SI Table 2, the R2° values in this state are significantly lower than apo- IGPS. This is difficult to interpret without knowing exactly how the experiment was performed; they could represent additional ns fluctuations, the removal of some very fast global process, or simply different deuteration efficiency. However, some methyls do not appear to have large changes in their R2° values (e.g. V56γ2, I73δ1, L94δ1). Most of the spurious factors that would give rise to the observed changes in R2° should affect all residues more or less equally; the lack of uniformity suggests this may be worth following up on.
When Lipchock and Loria added PRFAR to the system, all hell broke loose. Many of the amide groups in the protein had their signals broadened beyond the detection limit, indicating conformational exchange on the intermediate timescale. In addition, a large number of methyl groups showed evidence of conformational exchange.
Here the fluctuation is obviously a genuinely incoherent one. Not only do the fitted kex values vary wildly across the protein, they also have poor fitting characteristics (including fitted errors greater than 100%), and enormous differences between adjacent methyls on a side-chain (e.g. L153δ1,2). This suggests that the two-state mode... Read more »
Lipchock, J., & Loria, J. (2010) Nanometer Propagation of Millisecond Motions in V-Type Allostery. Structure, 18(12), 1596-1607. DOI: 10.1016/j.str.2010.09.020
Francis Thicke, agronomist and organic dairy farmer in Iowa, asks: Do you think there are unanswered questions about the health effects of GE foods? I have heard GE critiques frequently contend that there have been very few feeding trials on the health effects of GE foods, and that in the feeding trials that have been done, the results have raised questions about the safety of GE foods. For starters, what is your opinion Continue reading...... Read more »
Ewen SW, & Pusztai A. (1999) Effect of diets containing genetically modified potatoes expressing Galanthus nivalis lectin on rat small intestine. Lancet, 354(9187), 1353-4. PMID: 10533866
Citrus fruits are delicious. Their delicate balance of sweetness and tartness is a biochemical masterpiece. It's no wonder that they, of all nature's tasty options, are the highest value fruit crop in terms of international trade, with over 105 million tons produced annually. But these tempting produce face a persistant villain that seeks to destroy their roots; a menace known, cleverly, as the citrus root weevil.
The weevil's grubby larvae feed like maggots on the vital roots of citrus plants. Native to the Caribbean, this crop-destroying pest wreaks havoc on citrus farms in Florida and California, causing approximately $70 million in damage annually in the US. Farmers have tried a variety of control methods, including ants, parasitic wasps, and even a virus, but they simply don't keep up with the birth rate of the pesky weevils. A female weevil can lay up to 5,000 eggs at a time, each of which burrows into the roots of its host plant, depriving it of water and nutrients and making it vulnerable to infection by deadly fungi.
But the citrus plants don't just sit idly and allow the weevil larvae to eat their tender roots: they call for backup, emitting chemical signals that attract weevil larvae-killing nematodes. Read the rest of this post... | Read the comments on this post...
... Read more »
Ali, J., Alborn, H., & Stelinski, L. (2010) Subterranean Herbivore-induced Volatiles Released by Citrus Roots upon Feeding by Diaprepes abbreviatus Recruit Entomopathogenic Nematodes. Journal of Chemical Ecology, 36(4), 361-368. DOI: 10.1007/s10886-010-9773-7
Africa has a new, old wolf. An animal that was previously called a subspecies of the golden jackal in Egypt has now been found to be a very rare relict species hiding in plain sight — an ancient gray wolf line still living today. Previously, it was thought that the Ethiopian wolf (Canis simensis) was [...]... Read more »
Eli Knispel Rueness, Maria Gulbrandsen Asmyhr, Claudio Sillero-Zubiri, David W. Macdonald, Afework Bekele, Anagaw Atickem, Nils Chr. Stenseth. (2011) The Cryptic African Wolf: Canis aureus lupaster Is Not a Golden Jackal and Is Not Endemic to Egypt . PLoS ONE, 6(1). info:/10.1371/journal.pone.0016385
Normal 0 false false false EN-GB X-NONE X-NONE ... Read more »
Mason, P.G., Appleby, M., Juneja, S., Allen, J., & Landry, J.-F. (2010) Biology and Development of Acrolepiopsis assectella (Lepidoptera: Acrolepiidae) in Eastern Ontario. The Canadian Entomologist 142(4):393-404. 2010 , 142(4), 393-404. info:/10.4039/n10-026
So, we've already discussed the fact that genomic imprinting is mediated through epigenetic differences between the maternally and paternally inherited gene copies. That is, at an imprinted locus, the maternally inherited allele will have one pattern of epigenetic modifications, while the paternally inherited allele has a different pattern. These differences are first established in the male and female germ lines, when the alleles that will eventually become maternally and paternally derived are in physically different locations. It is not hard to imagine, then, how these differences could be established. One pattern of gene expression in spermatogenesis results in the paternal-specific epigenetic modifications. A different pattern of gene expression in oogenesis results in maternal-specific epigenetic modifications.
But what are these epigenetic modifications, and how do they change the expression pattern of the gene?
There are a number of modifications involved in imprinting, but for the moment, we're going to focus specifically on the simplest and best-understood mechanism: DNA methylation.
The two horizontal lines in this picture represent the two copies of a gene. The big, solid box is the part of the gene that actually codes for the protein. The open box is the promoter region, which is the part of the DNA sequence responsible for regulating expression of the gene. The lollipop things indicate DNA methylation on cytosine residues (the "C" of the A, C, G, T alphabet that makes up DNA).
In this simplest type of scenario, the DNA sequence in the promoter region binds to a variety of proteins that recruit the molecular machinery that will transcribe the gene, leading eventually to production of the corresponding protein. The addition of methyl groups to the DNA changes its binding properties, so that it no longer binds to this machinery, and that copy of the gene is not transcribed.
If you're not a molecular biologist, you can think of it like this. The transcription machinery is a bit like a Xerox machine, and the gene is like the master copy of some document. The promoter region is like a lock that has to be unlocked before you can copy this particular document. There are a number of proteins called "transcription factors" that function like a key to this lock. These transcription factors fit nicely on the promoter region, unlocking the gene and resulting in the production of many copies of the gene product.
Adding methylation to the promoter region is a bit like squirting epoxy into the lock. The presence of the methyl groups actually changes the physical shape and chemical properties of the DNA. So, when you try to put the key in, it no longer fits right, and the gene can not be copied.
In the top part, we see the red transcription factor binding to the black promoter region, which will activate transcription from the gene. In the bottom part, methyl (CH3) groups have been chemically added to the promoter region, preventing binding, and thereby preventing transcription.
So, these relatively subtle chemical changes are able to completely alter the functional properties of the gene.
Next time, we'll talk about how these methylation patterns are maintained through development, and how the two gene copies are able to maintain distinct epigenetic states across multiple rounds of cell division and DNA replication. Make sure to tune in, because it's really slick!
The two references represent the first proposals that DNA methylation might be the thing that permits the stable transmission of patterns of gene expression across cell divisions.
Holliday, R., & Pugh, J. (1975). DNA modification mechanisms and gene activity during development Science, 187 (4173), 226-232 DOI: 10.1126/science.1111098
Riggs, A. (1975). X inactivation, differentiation, and DNA methylation Cytogenetic and Genome Research, 14 (1), 9-25 DOI: 10.1159/000130315
... Read more »
Holliday, R., & Pugh, J. (1975) DNA modification mechanisms and gene activity during development. Science, 187(4173), 226-232. DOI: 10.1126/science.1111098
Riggs, A. (1975) X inactivation, differentiation, and DNA methylation. Cytogenetic and Genome Research, 14(1), 9-25. DOI: 10.1159/000130315
I was surprised to discover the paper I’m about to present to you came out over a week ago. It didn’t cause much of a splash, yet it details a novel treatment for HIV. Ok, that’s overstating it a little bit, but it’s not far off. In order to explain exactly how this “aptamer-siRNA chimera” [...]... Read more »
Neff, C., Zhou, J., Remling, L., Kuruvilla, J., Zhang, J., Li, H., Smith, D., Swiderski, P., Rossi, J., & Akkina, R. (2011) An Aptamer-siRNA Chimera Suppresses HIV-1 Viral Loads and Protects from Helper CD4 T Cell Decline in Humanized Mice. Science Translational Medicine, 3(66), 66-66. DOI: 10.1126/scitranslmed.3001581
Just when you think you understand how a gene works…BAM! Alternative splicing shows up and reminds us that there is so much yet to learn, even about a gene as well-studied as formin. Genes get transcribed into RNA, which gets translated into proteins. After transcription of a gene, different regions of RNA called exons and introns are either connected together (exons) or removed (introns) in a process called splicing. Some genes undergo a process called “alternative splicing” that allows one single gene the ability to splice, or connect, the exons in multiple ways that result in different protein isoforms. A recent paper describes a previously-unidentified isoform of FHOD3 formin, an actin-nucleating protein found at high levels in the heart. This new isoform includes an alternative exon in certain muscle tissues, and this exon contains a phosphorylation site that allows an additional level of regulation of FHOD3. Images above are of neonatal rat heart cells with or without this alternative exon. The presence of the alternative exon (bottom cell) directs formin (left images, green in merged) to myofibrils (middle images, red in merged), which are the repetitive and contractile structures in muscle cells. Without the alternative exon, formin is found in aggregates in the cytoplasm (top cell).Iskratsch, T., Lange, S., Dwyer, J., Kho, A., Remedios, C., & Ehler, E. (2010). Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance originally published in The Journal of Cell Biology, 191 (6), 1159-1172 DOI: 10.1083/jcb.201005060... Read more »
Iskratsch, T., Lange, S., Dwyer, J., Kho, A., Remedios, C., & Ehler, E. (2010) Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance. originally published in The Journal of Cell Biology, 191(6), 1159-1172. DOI: 10.1083/jcb.201005060
Stem cells are often hailed for their medical potential, but the cells surrounding them can be just as important and may offer an alterative therapeutic strategy. Professor Andrea Brand and Dr James Chell of the Gurdon Institute, Cambridge, have uncovered the key role of glial cells in controlling stem cell division in the brain. [...]... Read more »
Chell JM, & Brand AH. (2010) Nutrition-responsive glia control exit of neural stem cells from quiescence. Cell, 143(7), 1161-73. PMID: 21183078
In this week's Science, Greg Miller describes recent uproar about a study that claims to have scientific support for the existence of extrasensory perception (ESP). Of course, ESP being in the realm of the paranormal, it ought to be somewhat outside the purview of Big Science.But who cares about ESP?! What comes under scrutiny is statistics, the mathematical theory underlying hypothesis testing. And inference. The brief story is worth a read, as it cites statisticians on what these statistical tests actually tell us, as well as the ups and downs of Bayesian stats.An important thing to keep in mind is that no matter how mathematical, statistics is nevertheless like everything else in science - a human endeavor. No matter how creative and insightful humans can be, there's always a limit to our ability to decipher the world around us. I'm certainly not decrying statistics, but it's important to keep in mind that these aren't just handed down to us from on high. We human beings play a critical (and often subjective) hand in how we apply statistics to address our research questions.Along these lines, just last night I was reading about body mass variation in the Gombe chimpanzees (Pusey et al. 2005), and the authors provide a very insightful quote from statistician George Box:All models are wrong; some models are useful.As I added to this on Facebook, "... some models can be hott."ReferencesMiller G (2011). Statistics. ESP paper rekindles discussion about statistics. Science (New York, N.Y.), 331 (6015), 272-3 PMID: 21252321Pusey, A., Oehlert, G., Williams, J., & Goodall, J. (2005). Influence of Ecological and Social Factors on Body Mass of Wild Chimpanzees International Journal of Primatology, 26 (1), 3-31 DOI: 10.1007/s10764-005-0721-2... Read more »
Miller G. (2011) Statistics. ESP paper rekindles discussion about statistics. Science (New York, N.Y.), 331(6015), 272-3. PMID: 21252321
Pusey, A., Oehlert, G., Williams, J., & Goodall, J. (2005) Influence of Ecological and Social Factors on Body Mass of Wild Chimpanzees. International Journal of Primatology, 26(1), 3-31. DOI: 10.1007/s10764-005-0721-2
Some protective bacterial strains help defend against a dangerous bacterial infection in mice by producing acetate, which hinders toxin transport into the blood.... Read more »
Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura, K., Tobe, T., Clarke, J. M., Topping, D. L., Suzuki, T.... (2011) Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature, 469(7331), 543-547. DOI: 10.1038/nature09646
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