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.

Who do you love more… mom (species 1) or dad (species 2)?

The latest blockbuster ‘Jurassic World’ brings to our theaters a hybrid dinosaur. In their quest for the most terrifying creature ever, the movie’s ‘scientists’ combine traits of different dinosaur species to create the ultimate predator, which turns out to be big, insatiable… and intelligent. Quite obviously, the movie goes far beyond the state of the art of genetic engineering. That said, hybrids actually can be found everywhere in the real world. And some of them are ‘designed’ by us.

A hybrid is an individual that results from the combination of genomes of different species. Mankind has been raising hybrids from old, by controlled pairings of animals and plants to obtain desired traits in crops and cattle. For example, farmers have long been using mules (the hybrid offspring of a male donkey and a mare) to help laboring the fields, and lots of fruits, cereal crops and garden trees are hybrids selected by us to better suit our needs. Have you ever eaten frog legs? Yes, you’re right! Edible frogs are hybrids too.

Here in the Iberian Peninsula, we also have hybrid frogs. When an Iberian green waterfrog, or  Pérez’s frog (Pelophylax perezi) mates with an individual of other European species (P. ridibundus), a hybrid is formed: Pelophylax klepton grafi.  These three species together compose a hybridogenetic complex. This is because ADN of hybrid frogs contains 50% of each parental species but, amazingly, the eggs or sperm they produce contain exclusively P. ridibundus DNA. They can thus perpetuate a hybrid lineage just by mating with another P. perezi (see figure). If you think about it, they are certainly a mixture of two species but, when they mate, they genetically mimic just one of the parentals, so they perform as a ‘sexual parasite’ for the other parental species. That’s why they are called ‘klepton’ (from Greek, ‘robber’).

Example of the origin and perpetuation of a hybridogenetic lineage of Pelophylax klepton grafi. Matings may involve different sexes of each species than those in the figure. Note that, although adult hybrids are RP (2n chromosomes, half of them are from P. perezi and the other half are from P. ridibundus), they only produce R gametes, thereby discarding the whole P. perezi chromosome dotation in their germinal line. 

When hybrid frogs enter the ecosystem, they may outperform parental species, potentially leading them to extinction. Therefore, understanding the processes of hybridization and delineation of ranges of parental species and contact zones is critical for the conservation of involved species. This is challenging because all these species look extremely alike, and thus morphological identification is very difficult. For this reason, molecular tools are necessary to solve biological questions involving hybridization in water frogs.

A group of researchers from the University of Navarra, the Natural History Museum of Madrid and the Doñana Biological Station (CSIC) are developing sets of molecular tools to answer questions such as: ‘What is the distribution range of P. kl. grafi? Did this hybrid klepton originate naturally or as a result of human introductions? Can hybrids mate themselves and produce P. ridibundus offspring? Is the klepton displacing native P. perezi? These genetic markers have proven useful to distinguish among the three species within the complex and, by using them, we can assess the genetic variability of individuals to trace the history of hybrid lineages and solve these and other key issues.

So don’t panic in the theater. If a mad hybrid threatens you, we’ll be ready for it… as long as it is a frog!

Gregorio Sánchez-Montes

PhD Student

Department of Environmental Biology, University of Navarra

Genomic Editing à la carte

The recent decades have witnessed what has been named as a Genomic Revolution. The most recent discovery in this revolution is called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 (an RNA-guided endonuclease) system, a breakthrough new form of DNA editing. The system was originally discovered in bacteria and archae in the late 80’s. Microbiologists found in the genome of these organisms patterns of interspersed DNA whose function had remained elusive for many years. Several decades after, through sequencing of bacterial genomes, researchers discovered that these repeats were flanking DNA sequences of virus origin that the bacteria had incorporated into their chromosome. Moreover, these elements (CRISPR) were found to be in close proximity to genes that coded for proteins (Cas enzymes) involved in DNA cleavage and repair (Bolotin et al., Microbiology 2005; Mojica et al., J Mol Evol 2005; Pourcel at al., Microbiology 2005). Over the following years it was found that these viral sequences inserted at these specific loci constituted an immune memory that allowed bacteria fighting invading nucleic acids –such as virus- and blocking their propagation, and was the first evidence of an acquired immunity used by bacteria to adapt against foreign DNA. 

Unravelling the evolution of the human brain

There is no doubt that one of the big scientific challenges ahead is to understand how brain activity is translated into specific mental states. If we are to solve this question, we must first obtain a deeper knowledge of the outer layer of the brain, made up of billions of neurons, which is known as the neocortex. The neocortex is organized into functional areas associated with movement, perception and with higher cognitive abilities typical of humans. In Homo sapiens, the neocortex amounts roughly to 80% of the total mass of the brain, an evolutionary leap compared to other primates and even great apes. How was such innovation achieved?