Echoes of the ancestor

One of the most persuasive pieces of evidence of the common ancestry of all life on Earth is genetic overlap -- and the fact that the percent overlap gets higher when you compare more recently-diverged species.

What is downright astonishing, though, is that there is genetic overlap between all life on Earth.  Yeah, okay, it's easy enough to imagine there being genetic similarity between humans and gorillas, or dogs and foxes, or peaches and plums; but what about more distant relationships?  Are there shared genes between humans... and bacteria?

The answer, amazingly, is yes, and the analysis of these universal paralogs was the subject of a fascinating paper in the journal Cell Genomics last week.  Pick any two organisms on Earth -- choose them to be as distantly-related to each other as you can, if you like -- and they will still share five groups of genes, used for making the following classes of enzymes:

• aminotransferases
• imidazole-4-carboxamide isomerase
• carbamoyl phosphate synthetases
• aminoacyl-tRNA synthetases
• initiation facter IF2

The first three are connected with amino acid metabolism; the last two, with the process of translation -- which decodes the message in mRNA and uses it to synthesize proteins.

The fact that all life forms on Earth have these five gene groups suggests something wild; that we're looking at genes that were present in LUCA -- the Last Universal Common Ancestor, our single-celled, bacteria-like forebear that lived in the primordial seas an estimated four billion years ago.  Since then, two things happened -- the rest of LUCA's genome diverged wildly, under the effects of mutation and selection, so that now we have kitties and kangaroos and kidney beans; and those five gene groups were under such extreme stabilizing selection that they haven't significantly changed, in any of the branches of the tree of life, in millions or billions of generations.

The authors write:

Universal paralog families are an important tool for understanding early evolution from a phylogenetic perspective, offering a unique and valuable form of evidence about molecular evolution prior to the LUCA.  The phylogenetic study of ancient life is constrained by several fundamental limitations.  Both gene loss across multiple lineages and low levels of conservation in some gene families can obscure the ancient origin of those gene families.  Furthermore, in the absence of an extensive diagnostic fossil record, the dependence of molecular phylogenetics on conserved gene sequences means that periods of evolution that predated the emergence of the genetic system cannot be studied.  Even so, emerging technologies across a number of areas of computational biology and synthetic biology will expand our ability to reconstruct pre-LUCA evolution using these protein families.  As our understanding of the LUCA solidifies, universal paralog protein families will provide an indispensable tool for pushing our understanding of early evolutionary history even further back in time, thereby describing the foundational processes that shaped life as we know it today.

It's kind of mind-boggling that after all that time, there's any commonality left, much less as much as there's turned out to be.  "The history of these universal paralogs is the only information we will ever have about these earliest cellular lineages, and so we need to carefully extract as much knowledge as we can from them," said Greg Fournier of MIT, who co-authored the paper, in an interview with Science Daily.

So all life on Earth really is connected, and the biological principle of "unity in diversity" is literally true.  Good thing for us; the fact that we have shared metabolic pathways -- and especially, shared genetic transcription and translation mechanisms -- is what allows us to create transgenic organisms, which express a gene from a different species.  For example, this technique is the source of most of the insulin used by the world's diabetics -- bacteria that have been engineered to contain a human insulin gene.  Bacteria read DNA exactly the same way we do, so they transcribe and translate the human insulin gene just as our own cells would, producing insulin molecules identical to our own.

This is also, conversely, why the idea of an alien/human hybrid would never work.  Even assuming that some alien species we met was humanoid, and had all the right protrusions and indentations to allow mating to work, there is just about a zero likelihood that the genetics of two species that didn't have a common ancestor would line up well enough to allow hybridization.  Consider that most of the time, even relatively closely-related terrestrial species can't hybridize and produce fertile offspring; there's no way humans could do so with any presumed alien species.

Star Trek's claims to the contrary notwithstanding.

So that's our mind-blowing science news of the day.  The discovery of five gene families that were present in our ancestors four billion years ago, and which are still present today in every life form on Earth.  Some people apparently think it's demeaning to consider that we're related to "lower" species; me, I think it's amazingly cool to consider that everything is connected, that I'm just one part of a great continuum that has been around since not long after the early Earth cooled enough to have liquid water.  All the more reason to take care of the biosphere -- considering it's made up of our cousins.

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The viral accelerator

It's virus season, which thus far I've been able to avoid participating in, but seems like half the people I see are hacking and snorting and coughing so even with caution and mask-wearing I figure it's only a matter of time.  Viruses are odd beasts; they're obligate intracellular parasites, doing their evil work by hijacking your cellular machinery and using it to make more viruses.  Furthermore, they lack virtually all of the structures that cells have, including cell membranes, cytoplasm, and organelles.  They really are more like self-replicating chemicals than they are like living things.

Simian Polyoma Virus 40 [Image licensed under the Creative Commons Phoebus87 at English Wikipedia, Symian virus, CC BY-SA 3.0]

What is even stranger about viruses is that while some of the more familiar ones, such as colds, flu, measles, invade the host, make him/her sick, and eventually (with luck) are cleared from the body -- some of them leave behind remnants that can make their presence known later.  This behavior is what makes the herpes family of viruses so insidious.  If you've been infected once, you are infected for life, and the latent viruses hidden in your cells can cause another eruption of symptoms, sometimes decades later.

Even weirder is when those latent viral remnants cause havoc in a completely different way than the original infection did.  There's a piece of a virus left in the DNA of many of us called HERV-W (human endogenous retrovirus W) which, if activated, can trigger multiple sclerosis or schizophrenia.  Another one, Coxsackie virus, has an apparent connection to type-1 diabetes and Sjögren's syndrome.  The usual sense is that all viral infections, whether or not they're latent, are damaging to the host.  So it was quite a shock to me to read a piece of recent research that there's a viral remnant that not only is beneficial, but is critical for creating myelin -- the coating of our nerve cells that is essential for speeding up nerve transmission!

The paper -- which appeared last week in the journal Cell -- is by a team led by Tanay Ghosh of the Cambridge Institute of Science, and looked at a gene called RetroMyelin.  This gene is one of an estimated forty (!) percent of our genome that is made up of retrotransposons, DNA that was inserted by viruses during evolutionary history.  Or, looking at it another way, genes that made their way to us using a virus as a carrier.  Once inside our genome, transposons begin to do what they do best -- making copies of themselves and moving around.  Most retrovirus-introduced elements are deleterious; HIV and feline leukemia, after all, are caused by retroviruses.  But sometimes, the product of a retroviral gene turns out to be pretty critical, and that's what happened with RetroMyelin.

Myelin is a phosopholipid/protein mixture that surrounds a great many of the nerves in vertebrates.  It not only acts as an insulator, preventing the ion distribution changes that allow for nerve conduction to "short-circuit" into adjacent neurons, it is also the key to saltatory conduction -- the jumping of neural signals down the axon, which can increase transmission speed by a factor of fifty.  So this viral gene acted a bit like a neural accelerator, and gave the animals that had it a serious selective advantage.

"Retroviruses were required for vertebrate evolution to take off," said senior author and neuroscientist Robin Franklin, in an interview in Science Daily.  "There's been an evolutionary drive to make impulse conduction of our axons quicker because having quicker impulse conduction means you can catch things or flee from things more rapidly.  If we didn't have retroviruses sticking their sequences into the vertebrate genome, then myelination wouldn't have happened, and without myelination, the whole diversity of vertebrates as we know it would never have happened."

The only vertebrates that don't have myelin are the jawless fish, such as lampreys and hagfish -- so it's thought that the retroviral infection that gave us the myelin gene occurred around the same time that jaws evolved on our branch of the vertebrate family tree, on the order of four hundred million years ago.

So even some fundamental (and critical) traits shared by virtually all vertebrates, like the myelin sheaths that surround our neurons, are the result of viral infections.  Just proving that not all of 'em are bad.  Something to think about the next time you feel a sore throat coming on.

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Inner space

Donald Rumsfeld famously said, "There are known knowns.  These are things we know that we know.  There are known unknowns.  That is to say, there are things that we know we don't know.  But there are also unknown unknowns.  There are things we don't know we don't know."

At the time, much fun was made of his choice of words.  But although I wouldn't choose this as an exemplar of clarity, I have to admit the point he was making is valid enough.  Sometimes discovery starts with determining exactly what it is we don't yet know, with sketching out what astrophysicist Neil deGrasse Tyson (more eloquently) called "the perimeter of our ignorance."

This is the point of the Unknome Project, which is an effort to take our own genome and figure out what parts of it are, at present, unstudied and unexplained.  Cellular biologist Seth Munro and his colleagues at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, have developed a catalogue of thirteen thousand gene families found in humans (or other mammals that have been sequenced), coding for over two million proteins, and assigned each a "knownness score" -- a number describing to what extent the function of each is understood.  And three thousand of the families -- a little less than a quarter of them -- have a knownness score of zero.

That's a lot of genes that were (at least before Munro et al.) unknown unknowns.

[Image licensed under the Creative Commons Christoph Bock, Max Planck Institute for Informatics, DNA methylation, CC BY-SA 3.0]

What's even cooler is that the group is working to chip away at this bit of the perimeter of our ignorance, and to learn something about the mysteries of our own genetic inner space.  They found 260 genes with low knownness scores that are also present in fruit flies -- a much easier species to study -- and used a technique to suppress the expression of those genes.

Astonishingly, reducing the expression of sixty of these hitherto-unknown genes killed the flies outright.  Dampening others inhibited such important functions as reproduction, growth, mobility, and resistance to stress.

If these poorly-studied genes have analogous effects in humans -- and it's suspected that they do, given that they were evolutionarily conserved since the last common ancestor of humans and fruit flies, something like a half a billion years ago -- that's a lot of critical parts of our genome we don't yet understand.

What it got me wondering is how many of these are involved in diseases for which we haven't yet determined the causes.  There are so many disorders -- like, unfortunately, most mental illnesses -- for which the treatments are erratic at best, in part because we don't know for sure what the underlying origin of the condition is.  In my own case, I know for sure that depression and anxiety run in both sides of my family -- my mother and maternal grandmother both suffered from major depression, and a paternal great-grandmother committed suicide after (according to the newspaper article that reported it) "becoming mentally unbalanced by the illness of her husband."  Part of the problem with these sorts of things is, of course, that it's hard to tease apart the genetic from the environmental factors.  Growing up with mental illness in the family certainly doesn't make for an easy childhood; as my wise grandmother once said, "Hurt people hurt people" -- something that was certainly true enough within her own family.

It's fantastic that Munro and his colleagues are working to try and elucidate the functions of these mysterious genes, and I hope that perhaps some of them might turn out to be good targets for medications to alleviate conditions that have heretofore been resistant to treatment.  Certainly, anything we can do to reduce the perimeter of our own ignorance -- to eliminate some of those unknown unknowns -- is a good thing.

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