Recorded: 08 May 2012
We are really going through a revolution in molecular evolution, because for the first time we can actually study the evolution of entire genomes. Up until now we’ve developed a population genetics to understand the frequencies at which various variants of genes segregate in the population, how do they become fixed, how natural selection influences that process and it’s a basically a study of one site in the genome at a time. We have elaborate models for how a particular basis can drift by neutral evolution and how selection might change the rate but we don’t really understand how whole genomes change, so there is really an exciting opportunity to have a mathematical model of the actual neutral process of genome configuration change…
When we sequence whole genomes we discover that there are a number of mechanisms of genetic variation that operate at a very large scale, at a genome wide scale, one of them is transposition. So transposons occupy an enormous fraction of the genome, at least half and probably more like eighty percent of genomes are the relics of transposons. Essentially, dead and for the most part useless DNA that is just filling up our genome, but given that there are so many of them and that they make so many copies of themselves it turns out that the host has actually taken some of that material and used it for specific purposes. In particular many gene regulation networks have evolved and evolved very quickly into complex large-scale regulatory networks within the genome with the help of transposons; transposons can take material that is either already functional or nearly functional and make copies of it all over the genome. And then you can suddenly have transcription factors used to regulate fifty genes, now they regulate five hundred genes and you do have enormous growths. We looked at this with P-53, the very important cancer gene and other, we heard about it at this time and this meeting in the context of the estrogen receptor gene, it’s also known that nanog and other very important genes are hubs of activity within the gene regulatory networks and they are such large hubs with many spokes to different genes because transposons have spread their binding sites all around the genome. This was actually first predicted by, essentially by Barbara McClintock, when she called these transposons controlling elements, she had it right and then people switched over to the theory of junk DNA and that got forgotten. But, it was Eric Davidson who is also at this meeting. Eric Davidson and Roy Britain wrote the seminal paper in which they said ‘look these large gene networks in which one transposon – sorry one transcription factor – is actually regulating hundreds of genes would not evolve if you were just waiting for random mutations to create binding sites in those hundred spots, it’s better to take one template and spread it around.’ And there is now, at the time in 1969 talking about being ahead of his time, of course Barbara McClintock was writing in 1950, but Davidson and Britain wrote in 1969, 1970, 1971, some very seminal papers about how evolution can use this copy and paste mechanism to speed up and accelerate the development of complex networks, now we understand that that actually took place. And that’s one of the exciting topics that’s being discussed at this meeting. Of course, there are other methods of evolution: there’s segmental duplications of large segments of DNA, Evan Nightclare and others have discovered incredible hot beds of rapid genetic evolution within these regions; there are other retro-transposition mechanisms in which a mature spliced transcript, messenger RNA transcripts, gets copied back into DNA by reverse transciptase and now you’ve got what is often a pseudo-gene but actually could be a functional piece of DNA back in the genome, so there are rich variety. These are just a few of the types of changes that are structural changes, not a point, not at a single base changing to another base, but structural changes that are affecting our genome.
David Haussler (born 1953) is an American bioinformatician known for his work leading the team that assembled the first human genome sequence in the race to complete the Human Genome Project and subsequently for comparative genome analysis that deepens understanding the molecular function and evolution of the genome. He is a Howard Hughes Medical Institute Investigator, professor of biomolecular engineering and director of the Center for Biomolecular Science and Engineering at the University of California, Santa Cruz, director of the California Institute for Quantitative Biosciences (QB3) on the UC Santa Cruz campus, and a consulting professor at Stanford University School of Medicine and UC San Francisco Biopharmaceutical Sciences Department.