Worms and death

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If you’ve seen BladeRunner, you know the short soliloquy at the end by one of the android replicants, Roy, as he’s about to expire from a genetically programmed early death.

“I’ve seen things you people wouldn’t believe. Attack ships on fire off the shoulder of Orion. I watched c-beams…glitter in the dark near Tanhauser Gate. All those…moments will be lost…in time, like tears…in rain. Time…to die.”

There’s an interesting idea here, that death can be an intrinsic property of our existence, a kind of internal mortality clock that is always ticking away, and eventually our time will run out and clunk, we’ll drop dead. There is a germ of truth to it; there are genetic factors that may predispose one to greater longevity, and in the nematode worm C. elegans there are known mutants that can greatly extend the lifetime of the animal under laboratory conditions.

However, in humans only about 25% of the variation in life span can be ascribed to genetic factors to any degree, and even in lab animals where variables can be greatly reduced, only 10-40% of the life span variation has a genetic component. There is a huge amount of chance involved; after all, there aren’t likely to be any genes that give you resistance to being run over by a bus. Life is like a long dice game, and while starting with a good endowment might let you keep playing for a longer time, eventually everyone craps out, and a run of bad luck can wipe out even the richest starting position rapidly.

In between these extremes of genetic predetermination and pure luck, though, a recent paper in Nature Genetics finds another possibility: factors in the organism that are not heritable, yet from an early age can be reasonably good predictors of mortality.

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Evolving motors

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As we are so often reminded by proponents of Intelligent Design creationism, we contain molecular “machines” and “motors”. They don’t really explain how these motors came to be other than to foist the problem off on some invisible unspecified Designer, which is a poor way to do science—it’s more of a way to make excuses to not do science.

Evolution, on the other hand, provides a useful framework for trying to address the problem of the origin of molecular motors. We have a theory—common descent—that makes specific predictions—that there will be a nested hierarchy of differences between motors in different species. Phylogenetic analysis of variations between species allows us to reconstruct the history of a molecule with far more specificity than “Sometime between 6,000 and 4 billion years ago, a god or aliens (or aliens created by a god) conjured this molecule into existence by unknown and unknowable means”.

Richards and Cavalier-Smith (2005) have applied tested biological techniques to a specific motor molecule, myosin, and have used that information to assemble a picture of the phylogenetic history of eukaryotes.

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This one is for the bearded mo-bio types out there

The rest of you might be totally lost. Here’s a soon-to-be-classic paper on the characterization of the Hoho2 gene (292K pdf)—the Santa phenotype seems to represent an optimization for an arctic niche. They suggest the allele might have had an origin in Neandertal populations, but then they also show its effect in reindeer and E. coli (yes, they have beardy bacteria). It’s a very confused paper.

In this paper we unequivocally identify and characterize the genetic determinant of the famous white beard of Santa Claus to be the ortholog of human KRT6B. The newly discovered gene is named Hoho2 for Human ortholog for hair ougmentation 2. The Santa gene Hoho2 is synthesized and codon optimized for codon expression. Successful heterologous protein expression is shown in three separate systems; E. coli, reindeer, and human. We further show that the bearded phenotype is tissue specific in mammalians, but not in prokaryotes. A Hoho2 specific RNAi knockout was constructed and shown to specifically disrupt the facial beard phenotype. Trans-complementation of the gene could be achieved using a synthetic RNAi resistant variant, indicating that the phenotype is truly a direct consequence of the Hoho2 gene and not due to indirect or off-target-effects on the phenotypic display.

The profile photo of that Wilkins guy looks like he might be a carrier—I just know he’ll gag over Figure 4, though.

P.S. I’ve categorized this one as “Molecular biology” and “Humor”. Do you know how rarely those two come together?

P.P.S. Everyone who reads the paper is probably going to come back and tell me why they don’t go together very often.

Claes S, Reindeer R, Nicolas S, Tomte NE, Sridhar D, Elf J (2006) Heterologous expression and functional characterization of the Santa Hoho2 gene. Proc. Natl. Acad. Sci. Northpole 12:25-31.

Spongeworthy genes

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What are the key ingredients for making a multicellular animal, or metazoan? A couple of the fundamental elements are:

  • A mechanism to allow informative interactions between cells. You don’t want all the cells to be the same, you want them to communicate with one another and set up different fates. This is a process called cell signaling and the underlying process of turning a signal into a different pattern of gene or metabolic activity is called signal transduction.

  • Patterns of differing cell adhesion. But of course! The cells of your multicellular animal better stick together, or the whole creature will fall apart. This can also be an important component of morphogenesis: switching on a particular adhesion molecule (by way of cell signaling, naturally) can cause one subset of cells to stick to one another more strongly than to their neighbors, and mechanical forces will then sort them out into different tissues.

These are extremely basic functions, sort of a minimal set of cellular activities that we need to have in place in order to even begin to consider evolving a metazoan. Fortunately for our evolutionary history, these are also useful functions for a single celled organism, and while the metazoa may have elaborated upon them to a high degree, there’s nothing novel about the general processes in our make-up. The principles of signaling and transduction were first worked out in bacteria, and anyone who has a passing acquaintance with immunology will know about the adhesive properties of bacteria, and their propensity for modulating that adhesion to build complexes called biofilms.

So let’s take a look at the distribution of signaling and adhesion molecules in single-celled organisms, multicellular animals, and most interestingly, a group that is close to the division between the two (although more on the side of multicellularity), the sponges.

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Evolution of vascular systems

Once upon a time, in Paris in 1830, Etienne Geoffroy St. Hilaire debated Georges Léopole Chrétien Frédéric Dagobert,
Baron Cuvier on the subject of the unity of organismal form. Geoffroy favored the idea of a deep homology, that all animals shared a common archetype: invertebrates with their ventral nerve cord and dorsal hearts were inverted vertebrates, which have a dorsal nerve cord and ventral hearts, and that both were built around or within an idealized vertebra. While a thought-provoking idea, Geoffroy lacked the substantial evidence to make a persuasive case—he had to rely on fairly superficial similarities to argue for something that, to those familiar with the details, appeared contrary to reason and was therefore unconvincing. Evolutionary biology has changed that — the identification of relationships and the theory of common descent has made it unreasonable to argue against origins in a common ancestor — but that difficult problem of homology remains. How does one argue that particular structures in organisms divided by 600 million years of change are, in some way, based on the same ancient organ?

One way is sheer brute force. Characterize every single element of the structures, right down to the molecules of which they are made, and make a quantitative argument that the weight of the evidence makes the conclusion that they are not related highly improbable. I’ll summarize here a recent paper that strongly supports the idea of homology of the vertebrate and arthropod heart and vascular systems.

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Notch

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One of my favorite signal transduction pathways (what? You didn’t know that true nerds had favorite molecular pathways?) is the one mediated by the receptor Notch. Notch is one of those genes in the metazoan toolkit that keeps popping up in all kinds of different contexts—it’s the adjustable wrench of the toolbox, something that handles a general problem very well and therefore gets reused over and over again, and the list of places where it is expressed in Drosophila is impressive.

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MADS boxes, flower development, and evolution

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I’ve been writing a fair amount about early pattern formation in animals lately, so to do penance for my zoocentric bias, I thought I’d say a little bit about homeotic genes in plants. Homeotic genes are genes that, when mutated, can transform one body part into another—probably the best known example is antennapedia in Drosophila, which turns the fly’s antenna into a leg.

Plants also have homeotic genes, and here is a little review of flower anatomy to remind everyone of what ‘body parts’ we’re going to be talking about. The problem I’ll be pursuing is how four different, broadly defined regions of the flower develop, and what that tells us about their evolution.

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The eye as a contingent, diverse, complex product of evolutionary processes

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Ian Musgrave has just posted an excellent article on the poor design of the vertebrate eye compared to the cephalopod eye; it’s very thorough, and explains how the clumsy organization of the eye clearly indicates that it is the product of an evolutionary process rather than of any kind of intelligent design. A while back, Russ Fernald of Stanford University published a fine review of eye evolution that summarizes another part of the evolution argument: it’s not just that the eye has awkward ‘design’ features that are best explained by contingent and developmental processes, but that the diversity of eyes found in the animal kingdom share deep elements that link them together as the product of common descent. If all we had to go on was suboptimal design, one could argue for an Incompetent Designer who slapped together various eyes in different ways as an exercise in whimsy (strangely enough, though, this is not the kind of designer IDists want to propose)…but the diversity we do see reveals a notable historical pattern of constraint.

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The sea urchin genome

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Oh happy day, the Sea Urchin Genome Project has reached fruition with the publication of the full sequence in last week’s issue of Science. This news has been all over the web, I know, so I’m late in getting my two cents in, but hey, I had a busy weekend, and and I had to spend a fair amount of time actually reading the papers. They didn’t just publish one mega-paper, but they had a whole section on Strongylocentrotus purpuratus, with a genomics mega-paper and articles on ecology and paleogenomics and the immune system and the transcriptome, and even a big poster of highlights of sea urchin research (but strangely, very little on echinoderm development). It was a good soaking in echinodermiana.

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Granpappy was a Neandertal

Fascinating stuff…read this paper in PNAS, Evidence that the adaptive allele of the brain size gene microcephalin introgressed into Homo sapiens from an archaic Homo lineage, or this short summary, or John Hawks’ excellent explanation of the concepts, it’s all good. It’s strong evidence for selection in human ancestry for a gene, and just to make it especially provocative, it’s all about a gene known to be involved in brain growth, and it’s also showing evidence for interbreeding between Homo sapiens and Neandertal man.

The short short explanation: a population genetics study of a gene called microcephalin shows that a) it arose and spread through human populations starting about 37,000 years ago, b) this particular form of the gene (well, a small cluster of genes in a particular neighborhood) arose approximately 1.1 million years ago in a lineage distinct from that of modern humans, and c) the likeliest explanation for this difference is that that distinct lineage interbred with modern humans 37,000 years ago, passing on this particular gene variant that was then specifically selected for, a process called introgression.

The work looks sound to me, and I’m convinced. The one thing to watch for, though, is that there will be attempts to overreach and couple possession of this gene to some kind of intellectual superiority. We don’t know what this particular variant of the gene does yet! All we can say at this point is that some abstract data shows that a particular allele spread through the human population at a rate greater than chance would predict, that the gene itself has as one of its functions the regulation of brain growth, but that it is highly unlikely that that particular function is affected by the variant. Whatever it does, I expect the role is more along the lines of subtle fine-tuning rather than simply making people smart.