The genome wars that have shaped us

(Written by  By Mikel Zaratiegui, Assistant Professor. Department of Molecular Biology and Biochemistry. Rutgers, the State University of New Jersey)

 Our genome, and the genomes of all present-day species, shows the scars of a war that has been ravaging them since the origin of life: the fight against parasite genes. This war has shaped us in ways that we are only now beginning to understand.

The concept of a parasite gene may be counterintuitive. After all, aren’t genes the building blocks of all biological systems? But not all genes contribute to the function of the cell. Some genes may act in “selfish” ways, to enhance their own inheritance without regard for the well-being of the organism that harbors them. This is a very ancient way of doing things. In artificial life simulations, where digital replicating “life forms” are left to compete and evolve in a computer, the first novel life strategy to arise is that of the parasites: short programs that take advantage of the more complex “autonomous” programs by latching on to their function. In the case of our chemically defined life, we suspect that molecular parasites probably evolved alongside the very earliest life forms.

As flu season approaches, everyone is familiar with one form of molecular parasites: Viruses. This is probably an extreme form of parasitism, where the parasite hijacks the host organism to replicate new copies of itself, leaving it behind after completing the viral life cycle, exhausted if it’s lucky, dead if it’s not. But all parasites need to be careful not to be too harsh on their host, because if it goes extinct due to an excessive disease burden it’s very likely that the parasite will follow it to the same fate, after losing their replication platform. Successful parasites become attuned to their hosts, maximizing their reproductive success, but making sure they don’t impact the fitness of their hosts so much that it starts to affect their own. Some of our molecular parasites have taken up permanent residence in our genome, and have been with us for millions of years. They have been evolving with us, fighting for their survival, and perhaps even contributing to ours.

Photo: Wikipedia.org. Waterloo Battle

These resident molecular parasites are commonly known as Mobile Elements, or Transposons, because they were discovered due to their unique ability to change their localization in the genome. There are many families of Mobile Elements, reflecting their diverse origins. Some are viruses that have lost their extracellular stage of their life cycle, becoming stuck in the host genome, resigned to be transmitted down generations. Others are descendants from ancestral molecular parasites. Strikingly, some of them are cellular genes that went rogue when they acquired the capacity to move and multiply by using the enzymatic machinery of other Mobile Elements, parasitizing the parasite. Mobile Elements are present in virtually every species, and contribute a large amount of sequence to the genomes of higher eukaryotes; for example, 85% of the maize genome is composed of Mobile Elements. As a consequence, the Transposase family of genes, which mediates the mobility of these parasitic elements, is the most abundant gene class found in the biosphere.

In the human genome, 40% of the DNA clearly belongs to multiple families of Mobile Elements, present from fully functional and active copies to barely recognizable mutated remnants. Using more sensitive sequence identification methods we see that as much as 70% of our genome may be of Mobile Element origin. In fact, most of our genome is constituted by the decomposing bodies of these invading armies. Considering that cellular protein-coding genes take up only 2% of the space, it is easy to understand that the impact of Mobile Elements in the evolution of our genome has been profound.

But beyond the purely cosmetic structural aspect, Mobile Elements may be contributing to a much more important process affecting genome function: the regulation of cellular genes. The 2% protein-coding fraction of the genome is controlled by non-coding sequences, where proteins bind to organize transcription. Non-coding regulatory sequences therefore determine when, where and with what intensity each gene is expressed. This very precise control of genes turning on and off in a coordinated manner is necessary for development.

We now know that a large fraction of regulatory sequence is derived from Mobile Elements. It is easy to understand why: being parasites that have to pack a lot of punch in a small stretch of DNA, they are often chock-full of regulatory sequences that guide their own transcription. They can even acquire new regulatory sequence into their movable unit, and disperse it across the genome as they multiply within it. As they insert near protein coding genes, they contribute this new sequence to their regulation. In this way, Mobile Elements can rapidly rewire gene regulatory networks, adding a new layer of plasticity to the evolution of the host that probably increases adaptability. Through this process Mobile Elements probably can, over evolutionary time, contribute to the fitness of their host genome.

 However, excessive Mobile Element activity can be very detrimental to the host in the short term. If they insert within a protein-coding gene, they can mutate it beyond repair. Also, having multiple copies of the same sequence in different parts of the genome can lead to chromosomal rearrangements by a process called non-allelic Homologous Recombination. We have seen this happen; the causing mutation of some cancers can be traced back to a Mobile Element, and it is suspected that non-allelic recombination underlies much of the structural variability that is observed in humans. To prevent these processes, all organisms have evolved genome defense mechanisms that keep Mobile Elements in check. When we look at our genome we are looking at a well-worn battlefield, the result of a delicate balance between counteracting forces of stability and plasticity that has contributed to our blind stumbles around the evolutionary landscape.