December 8, 2004
Organizing Genes into an Entire Ecosystem
Less can be more, at least with regard to how genes organize themselves into an entire ecosystem. Two new studies reveal how genes maintain control and don't run wild in a single organism, and then how few genes it may take to predict new branches on the tree of life.
Astrobiology Magazine -- It is tricky enough to get a soccer team of eleven players to cooperate and work as one - but what would it be like if there were 25,000 players on the field? What would the rules be like, and how many referees would it take to make sure that the rules were followed?
As it happens, our genomes consist of networks of roughly 25,000 interacting genes, and these networks are obviously very stable and resilient to changed conditions. Out of billions of cells, not a single one falls into chaos. How can order be maintained?
A question that scientists have been pondering since the 1960s may now have been answered by theoretical physicists at Lund University.
In the most recent issue of the Proceedings of the National Academy of Sciences USA, professor Carsten Peterson and his collaborators Björn Samuelsson and Carl Troein demonstrate how this is possible. Stuart Kauffman - a pioneer in the field, who formulated and attempted to solve the problem as early as 1967 - is their co-author.
At any given time, each of the 25,000 genes in a cell may or may not be producing a protein - each gene is 'on' or 'off', to use language from the world of computers. A gene can affect other genes, turning them 'on' or 'off'. A simple case is that two genes are controlling a third gene. To activate this third gene, both the controlling genes might need to be active, or maybe only one or the other.
"In such a simple subsystem, sixteen different rules are possible in the interaction between the genes, and a large number of different solutions can emerge for the entire network," says professor Peterson. It was systems like this that Dr. Kauffman started working with; he assumed that the different solutions corresponded to different cell types. This would also explain how the DNA can be the same in all types of cells. Unfortunately, real systems are vastly more complicated. More than two genes may be involved in activating a single gene. In the case of three controlling genes, there are already 256 different rules. And in a system of 25 genes, the number of possibilities is greater than the number of atoms in the known universe.
To find those solutions that would produce stable systems, Peterson and his collaborators have primarily used literature knowledge from the foremost guinea pig of genetics: the fruit fly. More is known about the details of the genetic network here than in humans.
"In the fruit fly one can find almost 200 rules that are canalyzing, and this property is most likely general and applicable to genetic networks in other organisms," Carsten Peterson notes. "With 'canalyzing' we mean that there is a controlling gene that decides the value of the gene it activates by being either on or off. In that case, other controlling genes don't have any effect on the activated gene. It doesn't matter whether they are on or off.
With canalyzing rules, it turns out that the networks become stable regardless of the number of controlling genes, the size of the networks and the initial state of the system." It might be added that when Stuart Kauffman first started working on this problem, he was using punch cards. Now that the problem has been solved, it was not thanks to simulations on a powerful computer - it has been sufficient with observations, logical thinking and mathematical labor.
One Tree Falls in Search for Tree of Life
Finding such high degree of order in the genome of a single species is only part of the problem. The remainder is to understand what is responsible for some of the needed adaptability, which means to understand the organism's surroundings and environment. A new study carries on the ambitious task to build a tree of life for all species on Earth.
A tree of life shows how living things have evolved since the origins of life billions of years ago, grouping related organisms on the same branch. Such trees provide an organizing framework for biology. They can be used for predicting the properties of poorly known species and are powerful tools for tasks such as drug discovery, said Michael Sanderson, professor of evolution and ecology at UC Davis and senior author on the paper.
Comparing protein and DNA sequences is a powerful tool for creating trees, because large amounts of data can be generated quite easily. But existing databases contain big gaps, because some organisms have been studied very heavily while many others are represented by single entries or not at all.
Postdoctoral researcher Amy Driskell and colleagues from Sanderson's laboratory analyzed over 300,000 protein and DNA sequences deposited by scientists in the GenBank and Swiss-Prot public databases. They found that even though there were big gaps in the data, with many groups of organisms represented by a single sequence, it was still possible to construct useful trees starting from samples of 16,000 green plants and 7,500 plants and animals.
"It's pretty surprising that you can draw conclusions from such a small amount of information, compared to how much there would be if the databases contained a better sample of biodiversity," Sanderson said.
Researchers can now take the same approach and add more information from sequence databases, increasing the resolution of phylogenetic trees, he said.
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