The Distant Potential of Front-loading

The reach of the Alu domain may have extended much further into the future that the evolution of eukaryotes.  Shortly after the dawn of the primate lineage, the gene for the SRP RNA was duplicated and the Alu domain was freed of its SRP function.  A second round of duplication occurred and the two Alu domains were merged to form what is now known as the Alu element [55].

The Alu elements have played an important role in the evolution of the primate genome.  Since escaping from its SRP function, the number of Alu elements has expanded to 1.1 million copies in the human genome, making up 11% of human DNA [56].  Since Alu elements do not code for any protein, they were once considered a classic example of “junk DNA.”  In reality, they are retrotransposons.  A retrotransposon is a gene that is transcribed into RNA and an enzyme known as reverse transcriptase uses it to make a DNA copy that can be inserted some other place in the genome.  Since the Alu element does not code for reverse transcriptase, where does the enzyme come from?  When the Alu elements were born early in the primate lineages, they commandeered the reverse transcriptase from an older retransposon in the genome known as L1.

What is the purpose of spreading all these Alu elements around during the dawn of human evolution?

Biologist James Shapiro and Richard von Sternberg propose that they are one means of reformatting a genome [57].  Since Alu elements have the ability to influence the activity of the genes in their neighborhoods, by spreading such elements around, the regulatory activity of the entire genome is being reorganized.  For example, in one study of two human chromosomes, the Alu elements were far more likely to be clustered with genes involved in metabolism, transport across the cell membrane, and the signaling network inside the cell.  In contrast, the Alu elements were rarely found in the neighborhood of genes that coded for components of DNA replication, translation, or structural proteins [58].  It’s as if the Alu elements are tinkering with the processes that most closely interface with the environment while preserving the basic identity of the cell.  And while natural selection would act as the final editor to determine if the reorganization passes the fitness test, the actual reorganization is being driven by machinery intrinsic to the genome.  In other words, the Alu elements certainly look like they are part of a larger activated program that facilitates the front-loaded potential of the genome.

The most intriguing feature of the Alu elements is their apparent role in the evolution of the human brain.  In the 1980s, it was determined that one type of Alu element was expressed only in the brain [60].  Later it was shown that this Alu domain also binds to the SRP9 and SRP14 proteins inside the brain cells, forming a complex that is distinct from the SRP [61].  The function of this complex is not known, but it does tend to localize in the dendrites, which are extensions off the brain cell used to make connections to other brain cells.  All of this raises the intriguing possibility that this Alu/protein complex may actually be involved in learning and memory.  And what’s more, this appears to be another example of moonlighting among ribosomal components.

Another role Alu elements played during brain evolution revolves around the process of alterative splicing.  When a gene is transcribed in eukaryotes, the RNA is typically cut into pieces, where non-coding sequences known as introns are removed, while the coding sequences (exons) are spliced back together to form the mature RNA that will be translated by the ribosomes.  Alternative splicing occurs when different combinations of exons are spliced together, generating different versions of a protein from the same gene.  The process of alternative splicing is very important in the brain.  Diane Lipscombe, a neuroscientist from Brown University, notes that “alternative splicing might be the primary mechanism for generating the spectrum of protein activities that support complex brain functions” [62].  And the Alu elements may have played a significant role in generating many of the alternatively spliced proteins in the brain.  These elements contain sequence that is similar to a splice site (the region where the RNA is cut and spliced together) and there is growing evidence that they have spawned a good deal of the alternative splicing in the human genome [62].  Yet another role for the Alu elements involves a sugar known as sialic acid.  This sugar is attached to the surface of the cell in almost all animals.  In fact, the only mammal that doesn’t coat its cells with this sugar happens to be reading this sentence.  Very early in the human lineage, before brain size began to expand, an Alu element jumped into a gene needed for the synthesis of sialic acid and disrupted it [63].  As a result, human cells cannot synthesize this sugar.  What makes this loss so intriguing is that in all mammals, the expression of sialic acid in the brain is significantly dampened.   Perhaps the sugar acts as a brake that prevents significant brain size expansion, and by removing it from the genome with the help of the Alu elements, the human brain was uniquely released from this constraint and was freed to evolve into a more complex state.

Finally, if we turn our attention to the manner in which the Alu elements spread throughout the primate genomes, we’ll see a pattern that is quite friendly to the hypothesis of front-loaded evolution.  The million Alu elements that are found in the human genome can be categorized into 200 or so families and subfamilies [64] that in turn can be arranged in a hierarchy that reflects their evolutionary origin.  One such subfamily is known as AluYb.  This group is one of the largest and most active groups of retrotransposons in the human genome. It originated approximately 25 million years ago, just after the Old World monkeys split from the lineages that would lead to apes, chimpanzees, and humans [65].  During the subsequent twenty million years or so, the AluYb family would remain largely dormant.  For example, when the chimpanzee genome was searched, only 12 copies of AluYb were found [65].  In comparison, the human genome has over 2000 copies, indicating that this Alu subfamily underwent a burst of activity and expansion specific to the human lineage about 3-4 million years ago [65].  What is most striking is the very long span of dormancy, where the AluYb elements didn’t do much until it was time to evolve human beings.  Mark Batzer, from the Louisiana State University, is the one who discovered this pattern of Alu element evolution and has come up with a model to describe their evolution known as the ‘stealth driver’ hypothesis.  Essentially, the idea is that Alu elements have the ability to slowly and quietly propagate across deep time without having much of an impact on their genome.  However, periodically, they can spawn copies that in turn are much more active.  These progeny elements undergo rapid rates of retrotransposition and thus reformat the genome.  If the reformatting efforts fail the test of natural selection, those genomes go extinct.  Yet the stealth drivers remain in the genomes that didn’t actively evolve, waiting for another opportunity for to catalyze the evolution of their genome.  It’s is if the ability to radically evolve lies in waiting.  What makes this phenomenon even more interesting is that the ability to significantly reformat the genome may be a response to stress, as experiments have shown a higher level of Alu expression and activity as a consequence of stressing cells [66].  In other words, the bursts of reformatting activity may be homeostatic responses to environment stresses, as the Alu elements help the genome search for a program betters enables the organism to survive through some form of accelerated evolution.  In the human lineage, one such program may have been the further development of the brain.

matrix2How interesting this all is.  The Alu domain, which is completely unnecessary for the bacterial way of life, is nevertheless present in gram positive bacteria and archaebacteria.  In essence, it exists as a preadaptation that will help nudge the emergence of eukaryotic protein processing.  Then, its preadaptive potential lays dormant for billions of years, until it is unleashed through gene duplication to help facilitate not only primate evolution itself, but also the evolution of the human brain.

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6 responses to “The Distant Potential of Front-loading

  1. Pretty awesome

  2. Yes, very cool.

  3. ‘And while natural selection would act as the final editor to determine if the reorganization passes the fitness test, the actual reorganization is being driven by machinery intrinsic to the genome. In other words, the Alu elements certainly look like they are part of a larger activated program that facilitates the front-loaded potential of the genome.”

    Could a layer of code found in the genome unfold over time, independent of the environment, be one of the possibilities ?

    Put simply – when certain sequences became available, then there was this expansion of Alu sequences in the genome.

  4. Tim,

    That’s possible. There is a lot about evolution we still don’t understand. I should point out that a lot of Alu elements are simply neutral – they get tucked away in inactive regions of the genome.

    But here is a key thought that is pretty solid. Since Alu elements played multiple, important roles in the evolution of humans, would humans (or humanoids) have ever evolved without retrotransposons? without Alu elements?

  5. GoreBloodGore

    wow that is really cool. Mike Gene and front loading evolution +1. I just don’t even understand how it would be possible to go “stealth”

  6. Me thinks it is going to get much more cool (as if it wasn’t cool enough).

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