(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.
