15 July 2005

Do We Really Understand Gene Transfer?

By Rusty Rockets

New research has cast doubt on our understanding of how DNA and genes are prioritized for replication and eventual inclusion in an organism's genetic composition. The European Bioinformatics Institute (EBI) study amends years of scientific wisdom that uses the "tree of life" perspective to illustrate how gene transfer functions between organisms. In this particular instance, the EBI researchers looked long and hard at microbial evolution and came up with some surprising findings. Christos Ouzounis, the man at the center of the study, says that gene transfer hierarchies occur not only vertically, from one organism to its progeny, but also horizontally, through the exchange of genetic material between distantly related organisms. These recently observed webs that link the various branches of microbial evolution could help us to further our understanding of how disease-causing bacteria manage to stay one step ahead of us in our battle to tackle antibiotic resistance. Although there is no direct link between this latest study and an understanding of our own genetic material, it may cast some light on the question of how DNA is passed on to subsequent generations through evolution, and what factors contribute to such changes.

Richard Dawkins states that: "When we have served our purpose we are cast aside. But genes are denizens of geological time: genes are forever." Whether we like it or not it seems that we are merely a vessel or host for genes. And who are we to complain or intervene in this evolutionary chain of rival genes? The process has served us well, it has protected us, well most of us, from all sorts of nasty little bugs and environmental hazards during our species continuing evolution. Dawkins uses the example of blood group resistances that have developed over millions of years of evolution that remain with the human species today, stating that: "Astonishingly, our ABO polymorphism is present in chimpanzees. It could be that we and chimps have independently 'invented' the polymorphism (the various possible 'types', or alleles, that a single gene could be), and for the same reason. But it is more plausible that we have both inherited it from our shared ancestor and independently kept it going during our six million years of separate descent because the relevant diseases have been continuously at large throughout that time. This is called trans-specific polymorphism, and it may apply to far more distant cousins than chimpanzees are to us." This, in essence, explains the 'tree' version of gene transfer between generations of species, which includes many overlaps and, at least theoretically, reaches as far back as two ancestral bacterium.

But now, Ouzounis and his team of researchers have discovered that microbes can do this on a horizontal level, passing on the genes that can lead to antibiotic resistance, for example. By using a method called GeneTrace, a technique developed by Victor Kunin, the team observed more than 600,000 vertical transfers, coupled with 90,000 gene loss events and approximately 40,000 horizontal gene transfers. This does not mean that the 'tree' becomes conceptually redundant, as it forms the framework or skeleton for Ouzounis and his team's research. It just makes it far more complicated than was previously thought. "We used these trees as the scaffold of the net, on which we looked for the evidence of horizontally transferred genes," explains Kunin, previously a PhD student in Christos Ouzounis's group.

So, at the microbial level, at least, gene transfer is a complicated and messy process, with microbes throwing genes to one another as necessity demands. Ouzounis suspects that this is how certain organisms become antibiotic resistant so quickly, and have the potential to cause human populations so much trouble. "It's entirely possible that apparently harmless organisms are quietly spreading antibiotic resistance under our feet," said Ouzounis. He explains that rapid, horizontal gene transfer between small organisms is made possible because of the nature of the networks involved. Kunin and Ouzounis noticed that the network of connections behaved in a 'scale-free' manner, a term used to describe networks that exhibit some intriguing properties. Scale-free networks typically have an uneven distribution of connectivity and a small number of hubs that are far more connected than other nodes. Neuron clusters in the human brain are an example of a scale-free network.

Scale-free networks have been of interest to scientists for some time now, and further research into the mathematics of such networks has provided insights into how many complex systems like the Internet and air-travel connections operate. One property of scale-free networks is their 'small-world' nature: travelling from one node to any other is very fast. Scientists at the Max Planck Institute of Colloids and Interfaces have observed that these scale-free networks can also be used to store and retrieve a large number of fixed patterns (PNAS, 8 July 2005). These same pattern structures can be used to map social networks or microbial gene transfer, as Kunin and Ouzounis did.

For the mathematically inclined, the Planck institute explains the term 'scale-free' by considering the probabilities P(10), P(100), P(1000), and P(10000) to find a node with 10, 100, 1000, and 10000 connections, respectively. A scale-free network has the property that the probability ratio P(100)/P(10) is equal to the ratio P(1000)/P(100) which is equal to the ratio P(10000)/P(1000) etc. The logarithm of this constant ratio defines the decay exponent 'gamma'. The degree of connectedness between nodes in a scale-free network is critical for it to function properly. It turns out that a value between 2 and 2.5 (average number of connections per node) is required for the network to be scale-free.

Putting aside the mathematics of probability, the thing to remember about scale-free networks is their ability to transform from a random state to an ordered state in a very short amount of time, regardless of how small or large the network is. This means that the structure of a scale-free network allows the distribution of information - genes, bits, people or the latest fashion advice - over the entire network very rapidly, irrespective of the size of the network. For Ouzounis' microbes, it means that highly connected nodes forming the scale-free network are connected to a hub that is in effect a gene bank that provides a medium to acquire and redistribute genes in microbial communities. "This has important implications for our understanding of horizontal gene transfer because, in small-world networks, the shortest path between any two network nodes is relatively small: in other words, a gene can rapidly be disseminated from organism to organism through very few horizontal gene transfer events," explains Ouzounis.

Considering the properties of scale-free networks, together with any gene's determination to be replicated, a valid argument may be whether human societies, and the hierarchies that they are comprised of, contribute to the fate of human genetic composition. While people can quibble over whether life has any intrinsic meaning, the ability for humans to speak and hear, for example, must have some biological function: a function that is solely designed to propagate some genes over others. Our own scale-free networks of social interaction spread information and knowledge among a vast number of social networks that are all competing for prominence and recognition for themselves. As Dawkins states, however, it is the genes that are the real competitors, we just like to pretend that we have a say. The question is how much these social networks, driven by our initial genetic structure, ultimately alter our future genetic composition, and more interestingly how quickly? Billions of years? Generations? Or less?

Read more about scale-free networks at the Max Planck Society.

Read more about Ouzounis' work at the European Molecular Biology Laboratory.

Ref: The net of life: Reconstructing the microbial phylogenetic network
V. Kunin, L. Goldovsky, N. Darzentas, and C. A. Ouzounis
Genome Res, 1 July 2005