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Analysis of epistasis within nematodes


'Leaky' mutants may give clues to the evolution of development
Sydney Brenner Scientist
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The mutants of the nervous system, I started to look at very early on, and found that many of those that were not muscle mutants had very large deviations... in the organisation of their neurones. That is, we could find differences very easily. Now, of course what you would hope for is that you could find a very specific difference, so that you could identify a process that corresponded to this gene. And many of the mutants, all we could say is they made a mess. And the interesting thing is how many of them made the same mess, and how many of them made a mess which was different in... in this. And of course we could find various classes of this, so we found one... we found a number of mutants that made exactly the same mess, every time. And then of course another mutant made different messes in different organisms. That in itself is quite important, because according to many theoretical models of how you build things, you should be able to deduce something about the system, about the correspondence of the genes to this. And during this time... and again it's not something that has been ever formalised anywhere... but you can ask yourself is the genetic program in very general terms, say build this, build this, build this, build this? Or does it come... or does it say well, there's a big part that says build this, build a sort of a leg, and then we have all this tinkering that goes... that goes on... which evolution has added, to build a proper leg, an accurate leg? And one's guess is that there will be sort of leg programs and there will be a second level which will be called refining programs. Now, what those do is give you totally different... results when you start to break the system. Everybody knows that it's very unlikely that if you smashed a television set randomly that it would turn from a black and white television set into a colour television set, or even the reverse, that it'd go from colour television to black and white. And that's because a television set is... is atomistically specified there's a wiring diagram and you join this to this. And the most likely thing is that if you tinker with that wiring diagram — which is different from hitting it with an axe, by the way — tinkering with the wiring diagram in the factory is like changing the genetic program, hitting it with an axe is like doing surgery on... on a person... if you tinker with the wiring diagram you're most likely to just break it, to get a defective one. But if you have a system that says well I've got a program to... to build sort of television sets, and then in this particular one we will fix this value here so that we get something that isn't tilted, or isn't... is... is magnified correctly, then you can see that when you hit those refining programs you take away the... the sharpening of the system and you're left with this mess. So the one thing would say if you tried to work with insect legs, and insects have six legs, that one program would say you either get no legs at all or no insects, but another one would say well, maybe we'll get some with five and some with four, some with eight and some with nine, and this number six has been fixed. I don't think this has been very carefully studied at all. Because I think all of these mutations have been very deliberately thrown away by the geneticists. They are called mutants of low penetrance... or low expressivity, or variable phenotypes, or leaky, and they're not studied. I'm... I am fairly certain that these contain a lot of information about how actually developmental programs evolved, and rather from the kind of view that people have now that you know, you either have no legs or six legs, I think we're going to see that there's a very different thing. So that evolution might actually be viewed as, you know, one step backwards, two steps forward in another direction. However, that's the sort of thing that... that I think will eventually emerge as we understand these programs. Through all this work going on, which ranged from being interested in Hubel's work on vision right down to how proteins fold up, through the whole gamut of biology, there seemed that this would be a long and painful task.

South African Sydney Brenner (1927-2019) was awarded the Nobel Prize in Physiology or Medicine in 2002. His joint discovery of messenger RNA, and, in more recent years, his development of gene cloning, sequencing and manipulation techniques along with his work for the Human Genome Project have led to his standing as a pioneer in the field of genetics and molecular biology.

Listeners: Lewis Wolpert

Lewis Wolpert is Professor of Biology as Applied to Medicine in the Department of Anatomy and Developmental Biology of University College, London. His research interests are in the mechanisms involved in the development of the embryo. He was originally trained as a civil engineer in South Africa but changed to research in cell biology at King's College, London in 1955. He was made a Fellow of the Royal Society in 1980 and awarded the CBE in 1990. He was made a Fellow of the Royal Society of Literature in 1999. He has presented science on both radio and TV and for five years was Chairman of the Committee for the Public Understanding of Science.



Listen to Lewis Wolpert at Web of Stories



Duration: 5 minutes, 50 seconds

Date story recorded: April-May 1994

Date story went live: 29 September 2010