Saturday, December 15, 2012

Genome junk: the history and usefulness of transposons

Why do we have so much, and bacteria so little? Because a junkyard has its uses.

The role of junk in the human genome continues to fascinate, since there is so much of it- perhaps 98% of the total. I reviewed some recent work that described how active much of this junk is, getting transcribed to RNA and bound by proteins of various sorts, though honestly, this may be more smoke than fire.

Another way to understand junk DNA is from a broader evolutionary perspective, which is what Nina Fedoroff offers in a fascinating recent review (sorry, not even a free abstract). The problem is that many workers (e.g. Richard Dawkins) have thought of this junk as parasitic, such as transposons of various sorts which carry protein-encoding genes and other sequences needed to replicate and pop themselves around the genome. (Much of the junky DNA arises more straightforwardly as errors in replication that pile up as boringly repetitive sequence.)

Transposons certainly have this capacity of propagation, but what Fedoroff focuses on is that eukaryotes have had these transposons and related junk from the very beginning. Bacteria are afflicted by them too. In addition, eukaryotes have had, from the beginning, various mechanisms inherited from bacteria which counteract transposon proliferation, such as the recently discovered micro-RNA mechanisms. One simple mechanism is homologous DNA recombination, which can delete duplicated DNA segments, even as it can also create them.

(Incidentally, introns, which are the junk that lie between the exons that encode our proteins, also were there from the very beginning, and possibly before, being descended from primordial transposable RNAs.)

So it has all been an ecosystem present from the beginning, and the reason why eukaryotes such as ourselves have a lot of junk (and plants have even more) is not that DNA transposons have become more infectious or diabolical, but that advanced organisms have relaxed their surveillance over this aspect of their genomes, for other reasons.

Sizes of genomes, from various species. Bacteria occupy a distinctly tiny range, (bottom), while genome size increases roughly with organismal complexity. Some plants (and amphibians) have allowed another order of magnitude amount of DNA in their genomes. The actual gene content of these genomes is much less variable than the gross DNA size shown here, ranging from about 3,000 genes to perhaps 45,000 genes. So the gross size at the higher end reflects "junk" elements almost exclusively.

One reason is that active shuffling of genomic elements can be highly advantageous, enabling faster evolution for larger organisms with longer generation times than bacteria. Unlike the highly compact arrangement in bacteria, our genes are modular pastiches of broken-up exons and far-flung regulatory elements whose duplications and rearrangements sometimes lead to cancer, but can more rarely also lead to the evolutionary innovation we are so familiar with from economic theory- Marx's "creative destruction".

Plants are a prime example of this. Barbara McClintock was amazed to see the variegation of maize, as shown by stunning varieties all over the American landscape.

Well, some of this variegation is driven by transposons, which hop in and out of the relevant pigmentation genes and their regulatory regions with abandon, and earned McClintock an Nobel prize for her assiduous, astonishing work bringing this to light in the 1940's and 50's, long before the molecular revolution in biology.

Now we know some of the molecular details, and they are pretty hard to believe. Fedoroff  offers a diagram of one locus of about six genes, from various maize strains (each row is a different strain). Each of the colored triangle insertions are transposons, and one can see in some cases they have piled up with time, one inserting within another.

A dramatic history of transposon (colored triangles) insertion into a six-gene segment of the maize genome. (The bronze locus, encoding an anthocyanin pigment in kernels.) Each row shows a different strain, from widely varying origins. Coding regions are the crayons in yellow, with exons dark, and the introns light. Click to see at full magnification.

There is a direct connection between the apparent physical plasticity of plants, including an ability to respond to many environmental conditions, and their genomic plasticity. Maize was clearly selected by prior generations of Americans to have additional flexibility to meet a variety of aesthetic and functional needs.

The only question then is why all life forms have not availed themselves of such genomic plasticity. Plants have a particular need, not being able to respond to the world via nervous systems or locomation. But wouldn't bacteria be in the same boat? Yes, but they are trapped in a world of even more cut-throat competition, where the margins of victory and defeat are razor-thin, proportional to their microscopic size and especially their infinitesimal cell volume. A maize plant can lose a few seeds to mutation and still succeed, but a mutation in a bacterium presents a much more immediate threat.

Additionally, any extra DNA spent on junk is a metabolic cost- a cost high enough to prevent bacteria from accumulating much of it. A maize plant can gain large amounts of DNA without it being a significant metabolic load- due to its high cell volume, its DNA is a tiny fraction of its biomass. And this in turn, combined with a lack of recombination via sex and lack of modular gene units like exons, limits bacteria's ability to adapt to environmental challenges via genomic change. Instead, they rely on a great deal of promiscuous quasi-mating, infection, and DNA transfer from related and unrelated microorganisms to acquire new codes and traits, like antibiotic resistance. If evolution had stopped with bacteria, our planet would have an ocean alive with a bacterial soup, (and an atmosphere of oxygen), but few other signs of life.

It is a sort of ironic comment on this world of maximal competition and insufficient cooperation that bacteria have to resort to infecting and stealing from each other to advance even a small amount in evolutionary terms. We, on the other hand, are blessed with a much richer fund of internal diversity to draw on, which has (slowly) contributed to the development of multicellularity, terrestrial colonization, skeletons, (both animal and plant), cognition, sociality, and so many other complex biological bequests.

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