This article was written as a rather more technical (but still quite readable) “sidebar” to “Evolution and the Illusion of Randomness”, and can best be read in conjunction with that essay. Both pieces are part of a larger work in progress entitled: Toward a Biology Worthy of Life. Original publication: November 10, 2011. Date of last revision: July 9, 2012. Copyright 2011, 2012 The Nature Institute.
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In her 1983 Nobel address, geneticist Barbara McClintock cited various ways an organism responds to stress by, among other things, altering its own genome. “Some sensing mechanism must be present in these instances to alert the cell to imminent danger”, she said, adding that “a goal for the future would be to determine the extent of knowledge the cell has of itself, and how it utilizes this knowledge in a ‘thoughtful’ manner when challenged” (McClintock 1983). Subsequent research has shown how far-seeing she was.
It is now indisputable that genomic change of all sorts is rooted in the remarkable expertise of the organism as a whole. By means of endlessly complex and interweaving processes, the organism sees to the replication of chromosomes in dividing cells, maintains surveillance for all sorts of damage, and repairs or alters damage when it occurs — all with an intricacy and subtlety of well-gauged action that far exceeds, at the molecular level, what the most skillful surgeon accomplishes at the tissue level. But it’s not just a matter of preserving a fixed DNA sequence. In certain human immune system cells, portions of DNA are repeatedly cut and then stitched together in new patterns, yielding the huge variety of proteins required for recognizing an equally huge variety of foreign substances that need to be rendered harmless. Clearly, our bodies have gained the skills for elaborate reworking of their DNA — and, we will see further, in many different ways.
Depending on stage of development, cell type, and state of health, among other things, our cells convert millions of their genomic “letters” (most often the letter ‘C’, standing for the cytosine base) to an altered letter in a process known as “DNA methylation”. The new letter, 5-methylcytosine, is often referred to as the “fifth base” of the genome, and it has profound implications for gene expression that are far too extensive to survey here. The organism also contrives to effect several other kinds of DNA letter changes. The DNA sequence, it turns out, is subject to intense revision through its participation in the life of the larger whole.
More emphatically, and with remarkable nuance, the organism contextualizes its genome, and it makes no sense to say that these powers of contextualization are under the control of the genome being contextualized. Thus, the human genome yields itself to a radical and stable “redefinition” of its meaning in the extremely varied environments of some 250 different cell types found in brain and muscle, liver and skin, blood and retina. It is well to remember that the genes in your stomach lining and the genes in the cornea of your eye are supposed to be the “same” genes, and yet the immediate context makes very different things out of them. An especially revealing case of contextualization occurs when a genome fit for the needs of all the varied cells of a worm-like larva is subsequently pressed into perfectly adequate service for the entirely different cell types — and different bodily organization and different overall functioning — of a graceful, airborne butterfly. The genome, it appears, is to one extent or another like clay that can be molded in many different ways by the organism as a whole, according to contextual need.
Jumping for Change. Quite aside from such contextualization, it has long been known that the organism generates altogether new genetic material by duplicating entire genes, modifying them, and supplying them with regulatory elements. This can occur through direct duplication of genes or even larger chromosomal segments, and also through reverse transcription, whereby messenger RNA molecules, produced from DNA, are transcribed back into new DNA, which can then be modified. But “the array of mechanisms underlying the origin of new genes is compelling, extending way beyond the traditionally well-studied source of gene duplication”, writes Henrik Kaessmann of the Center for Integrative Genomics in Switzerland.
In a broad overview of the relevant studies, Kaessmann documents a dizzying variety of techniques by which the organism diversifies and enlarges its genetic repertoire. For example, two duplicated genes can, via a number of different pathways, fuse into a single chimeric gene. And not only protein-coding RNAs, but also small, regulatory RNAs, can be reverse transcribed into DNA and their functions diversified. And again, various repetitive and mobile elements called “transposons” can move around in the genome, often being duplicated in the process and then co-opted either as new protein-coding genes or new regulatory genes (Kaessmann 2010).
Let’s pause for a moment to look a little more closely at these transposons. “It now is undeniable”, writes a team of researchers from the U.S., Canada, Spain and the U.K., “that transposable elements, historically dismissed as junk DNA, have had an instrumental role in sculpting the structure and function of our genomes” (Beck et al. 2011). Directly and indirectly, transposable elements are being found crucial to many aspects of genome organization and renovation. And the diverse means by which the cell employs and regulates them have only begun to be delineated.
These transposons, also known as “jumping genes” (whose discovery led to Barbara McClintock’s Nobel prize), may hold the key to a puzzle about inbred mice. Such mice, with their perfectly matched genes, are sometimes reared in the laboratory under the strictest and most identical conditions possible. The frustration for researchers, according to Fred Gage, a neuroscientist at the Salk Institute for Biological Studies in San Diego, is that “you control for everything you can, and in behavioral tests, the variance is enormous”. Even within a single litter, “one mouse will be unusually smart, another below average”. Gage and others are proposing that jumping genes help account for this otherwise mysterious diversity (Vogel 2011).
Whatever may be going on with the mice, it has now been shown that transposons move around in the developing mammalian brain, altering the genome from cell to cell. They provide enough diversity among neurons, according to Gage, so that “you can optimize your response to the variety of environments you might encounter throughout life”. And now it’s being found that transposons also “jump” in other cell types much more readily than was previously thought. This particularly includes various cells of the early embryo, in which case each genetically altered cell propagates its changes into a subset of the mature organism’s tissues, making them genetically distinct from other tissues. “Given how often this may happen in the early embryo, there may be much more genomic variation within individuals than most researchers had assumed,” writes one reporter in Science (Vogel 2011).
None of this looks particularly haphazard. In embryonic stem cells the regulatory DNA elements known as enhancers of gene expression contain an elevated number of transposons. And germ cells (of which I will have more to say in a moment) are also especially susceptible to these mutable, or mobile, elements (Teng et al. 2011). The cell-type-specific and DNA-element-specific nature of transposon activity points to a meaningfully orchestrated process. In general, there is a bias for many transposable elements to insert themselves upstream of transcription start sites, which “prevents damage to functional coding elements and enhances the potential for a constructive regulatory change” (Shapiro 2006).
Are transposons mere parasites? An extraordinarily profound role for jumping genes has just recently come to light with the announcement by Yale University researchers that the evolution of placental development (and hence prolonged pregnancy) in mammals was intimately bound up with the regulatory role of transposons. The Yale team found that a network of 1532 genes recruited for expression in the human uterus (but not in marsupials, a mammalian group whose members give birth to undeveloped young a mere two weeks after conception) is coordinated by transposons. “We used to believe that changes only took place through small mutations in our DNA that accumulated over time”, remarked the lead researcher in the project, Günter Wagner. “But in this case we found a huge cut-and-paste operation that altered wide areas of the genome to create large-scale morphological change” (Hathaway 2011).
The study authors say that their findings “strongly support the existence of transposon-mediated gene regulatory innovation at the network level, a mechanism of gene regulation first suggested more than forty years ago by McClintock . . . Transposable elements are potent agents of gene regulatory network evolution” (Lynch et al. 2011).
It is no wonder, then, that when genomic researcher David Haussler of the University of California, Santa Cruz, was asked by the journal Cell what has been most surprising about the human genome, one of the things he cited was “mounting evidence” that transposons “play a critical role” in the turnover and reinvention of regulatory elements in DNA (Page et al. 2011). And, responding in Science to a report about the work on jumping genes in mammalian brains, Southern Illinois University neuroscientist, David King, wrote that the “dismissive dictum, ‘Mutations are accidents’, has grown obsolete”, adding that protocols for “the spontaneous, non-accidental production of genetic variation are deeply embedded in genomic architecture” (King 2011).
One other remark about transposons. They exemplify a growing (and, for biologists, embarrassing) class of cellular constitutents that were initially dismissed as more or less functionless simply because they didn’t fit into a kind of neat (but now hopelessly outmoded) digital coding schema linking DNA as Master Cause, to RNA as precisely programmed mediary, to protein as definitive final result. Making up a sizable portion of the human genome, transposons are to this day often referred to as “junk” or “parasitic” elements. Because they play a particularly prominent (and still barely explored) role in the germline, one often hears about the germ cell’s “defensive mechanisms” to protect itself from these highly mobile, “selfish” elements, with their genome restructuring potentials. How this kind of thinking could go on for many years without most biologists suspecting a positive role for transposons as genome remodelers with potentially powerful implications for evolution is, for me, a great mystery. Certainly transposons, like everything else in the cell, are subject to intense oversight by their larger context — and viruses may indeed have played a role in their origin, as many suppose — but this hardly makes them mere parasites in the organisms that have so intently taken them up and put them to use.
Out of thin air? With transposons the organism reshapes its genome through elaborately organized and synchronized processes often affecting considerable stretches of DNA. But even more striking, Kaessmann notes, is the recent discovery of protein-coding genes being composed “from scratch” — that is, from non-protein-coding genomic sequences altogether unrelated to pre-existing genes or transposable sequences. He cites a famous paper by the preeminent French biologist, François Jacob (1977), to the effect that the probability for creation of new protein-coding genes de novo (from scratch) by random processes “is practically zero”. Such creation was widely thought to be virtually impossible. And yet, Kaessmann goes on, “recent work has uncovered a number of new protein-coding genes that apparently arose from previously noncoding (and nonrepetitive) DNA sequences”.
If we take seriously Jacob’s “practically zero” probability for random, de novo assembly of functional, protein-coding genes from noncoding DNA sequences, then, given that such assembly does in fact somehow occur, the obvious thing to suspect is that the process is not random. Nor does the scale of the problem, as it is now emerging, look trivial. There is, we’re told by two biologists working in Germany — one at the Max Planck Institute for Evolutionary Biology and one at Christian Albrechts University — “accumulating evidence that de novo evolution of genes from noncoding sequences could have an important role” in a class of genes representing “up to one-third of the genes in all genomes” (Tautz and Domazet-Lošo 2011). The seemingly unbridgeable gap between “practically zero” and this recent, extraordinary claim invites evolutionary geneticists to do a lot of soul-searching.
Concerted change in the germline. There is nothing in the picture so far to suggest that, when turning our attention to genetic change in reproduction, we will find much evidence of randomness. Everything we’ve looked at so far occurs in germline cells as well. But in these cells we witness additional powers of change that could hardly be exceeded. Nowhere, for example, do we see the genome more concertedly re-shaped than in the two meiotic cell divisions leading to the formation of gametes in sexual reproduction — a choreography we hear described in the accompanying article as the “meiotic ballet”.
One of the central features of this ballet, referred to as “chromosomal crossover” or “genetic recombination”, involves an insistent re-shuffling of stretches of DNA between chromosomes, resulting in genetic variation in the offspring. You could hardly imagine a more carefully and delicately staged dance than the one resulting in chromosomal crossover — and, with researchers speaking of “recombination hotspots” and all sorts of regulation, we can be sure it is not at all random. As usual in the cell, many different factors within the larger whole come to bear on any specific point:
As is the case for transcription, no single type of DNA site, transcription factor, or histone modification can account for the regulated positioning of all recombination. Instead, these elements function combinatorially (with potential for synergism, antagonism and redundancy) to establish preferential sites of action by meiotic recombination protein complexes (Wahls and Davidson, 2010).
Context, as always, figures strongly (and nonrandomly) in shaping and directing local activities.
Kaessmann further points to studies in animals showing that the testes play a “potentially central role in the process of gene birth and evolution”. For example, there is an “overall propensity” of young retrogenes — genes copied back into DNA by reverse transcription from RNA — to be expressed in the testes. “The testis may represent a crucible for new gene evolution, allowing novel genes to form and evolve, and potentially adopt functions in other (somatic) tissues with time”.
Likewise, pluripotent cells such as stem cells, which bear certain similarities to germline cells, possess genomes that are “amazingly plastic”: “The incredible plasticity of pluripotent genomes is a notable discovery, and reveals the view of an unexpectedly dynamic mammalian genome for many of us” (Blasco et al. 2011).
Powers of change converging from all sides. In sum, recent work in genomics has laid bare
an astounding diversity of mechanisms underlying the birth of more recent genes. Almost any imaginable pathway toward new gene birth seems to have been documented by now, even those previously deemed highly unlikely or impossible. Thus, new genes have arisen from copies of old ones, protein and RNA genes were composed from scratch, protein-coding genes metamorphosed into RNA genes, parasitic genome sequences were domesticated, and, finally, all of the resulting components also readily mixed to yield new chimeric genes with unprecedented functions. (Kaessmann 2010)
None of this is yet to mention the way the organism massively structures, restructures, and regulates its genome through the intricate remodeling of chromatin (the DNA/protein/RNA complex comprising our chromosomes), or the way it shapes the dynamic, three-dimensional organization of the cell nucleus, which in turn has a great deal to do with how genes get expressed. (See the earlier article in this series, “Getting Over the Code Delusion”.) Even regarding the bare DNA sequence in the narrowest sense, Italian geneticist Vittorio Sgaramella, after noting the various alterations of the sequence throughout the cells of our bodies, was led to ask, “Which is our real genome. . . ?” And he adds, “The human genome seems more complex but less autonomous than originally believed” (Sgaramella 2010). Less autonomous because so many concerted activities of the organism are brought to bear on it.
And there is still much more we could have spoken about. For example, there is a consensus today that entire organelles of the cell originated in evolutionary history through a kind of cooperative fusion of distinct microorganisms, a process requiring an almost unimaginable degree of intricate coordination among previously independent life processes. Likewise, hybridization involving distinct species — with a corresponding merger of genomes — is being found to play an unexpectedly significant role in evolution. There is also the well-demonstrated reality of lateral gene transfer, which looks like invalidating the image of an evolutionary “tree,” especially at the level of simpler organisms: repeated horizontal exchanges of genetic material between distinct species make large portions of the tree look more like a complex web. Then, again, there is good evidence that viruses have played a major role in contributing to the genomes of more complex organisms, including mammals and humans. In all this we find organisms bringing their separate, highly coordinated life processes to bear upon each other in a symbiotic or other interactive manner that can no more be described as “random” than can, say, the complex and elaborately orchestrated mating processes we see among sexually reproducing organisms. "Our standard model of evolution is under enormous pressure," says John Dupré, philosopher of biology at the University of Exeter, UK. "We’re clearly going to see evolution as much more about mergers and collaboration than change within isolated lineages" (quoted in Lawton 2009).
We could also have looked at convergent evolution and the way it commonly involves changes to corresponding genes in widely different organisms, which “implies a surprising predictability underlying the genetic basis of evolutionary changes” (Nadeau and Jiggins 2010). And there is the rapidly rising interest in a kind of neo-Lamarckian, epigenetically mediated inheritance of acquired characteristics. But we have already seen enough to realize that, by one means or another, the organism pursues its own genomic alterations with remarkable insistence and subtlety.
Where is randomness? All these revelations about coherent genomic change have prompted University of Chicago geneticist James Shapiro to speak of “natural genetic engineering”. “We have progressed from the Constant Genome, subject only to random, localized changes at a more or less constant mutation rate, to the Fluid Genome, subject to episodic, massive and non-random reorganizations capable of producing new functional architectures” (Shapiro 1997). Crucially, “genetic change is almost always the result of cellular action on the genome” (Shapiro 2009).
Likewise, two geneticists from the University of Michigan Medical School, writing in Nature Reviews Genetics, remember how “it was previously thought that most genomic rearrangements formed randomly”. Now, however, “emerging data suggest that many are nonrandom, cell type‑, cell stage- and locus‑specific events. Recent studies have revealed novel cellular mechanisms and environmental cues that influence genomic rearrangements” (Mani and Chinnaiyan 2010).
Bear in mind that we’ve been looking at the one aspect of organismal functioning — the mutational aspect — where we are assured most confidently that “blind chance”, or randomness, becomes visible within the evolutionary process. Certainly from the organism’s side we see nothing to suggest any fundamental role for randomness. The accompanying article explores the question in a larger context, where our understanding of evolutionary fitness becomes crucial.
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Steve Talbott :: Natural Genome Remodeling