Seoul, Korea and Stanford, CA, USA. Scientists have created a new computational model that can be used to predict the function of previously uncharacterized plant genes with unprecedented speed and accuracy.

Plants, animals and other organisms share a number of the same or similar genes — particularly those that arose early in evolution and were retained as organisms differentiated over time. Despite significant progress in functional characterization of plant genomes, over 30% of the 30,000 Arabidopsis genes have not been functionally characterized yet. Another third has little evidence regarding their role in the plant.

The computational network, dubbed AraNet, has over 19,600 genes associated to each other by over 1 million links and can increase the discovery rate of new genes affiliated with a given trait tenfold. The new work, based on plant and agricultural research, provides a boost to fundamental biology.

Arabidopsis
thaliana

... a favorite of many plant biologists and commonly used to test genetic questions.

Plants, animals and other organisms share a number of the same or similar genes — particularly those that arose early in evolution and were retained as organisms differentiated over time.

A. thaliana is widely used by scientists as an easily manipulated model organism because it is simple to grow in the laboratory, has a short life cycle, and a comparatively small genome.

Compared to corn, which might have as many as 2.5 billion base pairs of DNA and the human genome with roughly 3 billion pairs, Arabidopsis only has about 120 million base pairs of DNA.

Faster growth, darker leaves, and a different way of branching — wild varieties of this small mustard plant, Arabidopsis thaliana, are often substantially different from the laboratory strain.

Moreover, plants from different geographical origins differ in many traits.

Research teams have investigated which detailed differences distinguish the genomes of strains from a wide variety of locations (the polar circle or the subtropics, from America, Africa or Asia).

The plant is self-pollinating and can produce many genetically identical offspring. Current reports date the start of this reproduction mode ("selfing") to at least a million years ago.

Investigators have been surprised by the results: the extent of the genetic differences far exceeds expectations for such a streamlined genome.

These identical plants still have subtle individual differences (just like human twins).

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Image courtesy of Max Planck Institute for Developmental Biology.

"We call it guilt by association. Based on over 50 million scientific observations, AraNet contains over 1 million linkages of the 19,600 genes in the tiny, experimental mustard plant Arabidopsis thaliana. We made a map of the associations and demonstrated that we can use the network to propose that uncharacterized genes are linked to specific traits based on the strength of their associations with genes already known to be linked to those characteristics."

The network allows for two main types of testable hypotheses.

• The first uses a set of genes known to be involved in a biological process such as stress responses, as a "bait" to find new genes ("prey") involved in stress responses. The bait genes are linked to each other based on over 24 different types of experiments or computations. If they are linked to each other much more frequently or strongly than by chance, one can hypothesize that other genes that are as well linked to the bait genes have a high probability of being involved in the same process.
  
  
• The second testable hypothesis is to predict functions for uncharacterized genes. There are 4,479 uncharacterized genes in AraNet that have links to others that have been characterized, so a significant portion of all the unknowns now get a new hint as to their function.

The scientists tested the accuracy of AraNet with computational validation tests and laboratory experiments on genes that the network predicted as related. The researchers selected three uncharacterized genes.

• Two of them exhibited phenotypes that AraNet predicted. One is a gene that regulates drought sensitivity, now named Drought sensitive 1 (Drs1).
  
  
• The other regulates lateral root development, called Lateral root stimulator 1 (Lrs1). The researchers found that the network is much stronger forecasting correct associations than previous small-scale networks of Arabidopsis genes.

Lead and corresponding author Insuk Lee at Yonsei University of South Korea. "AraNet not only contains information from plant genes, it also incorporates data from other organisms. We wanted to know how much of the system's accuracy was a result of plant data versus non-plant derived data. We found that although the plant linkages provided most of the predictive power, the non-plant linkages were a significant contributor."

AraNet network. Each line represents a functional link between two genes.

Click Pic for Details

"AraNet has the potential to help realize the promise of genomics in plant engineering and personalized medicine," remarked Rhee.

"A main bottleneck has been the huge portion of genes with unknown function, even in model organisms that have been studied intensively. We need innovative ways of discovering gene function and AraNet is a perfect example of such innovation.

"Food security is no longer taken for granted in the fast-paced milieu of the changing climate and globalized economy of the 21st century. Innovations in the basic understanding of plants and effective application of that knowledge in the field are essential to meet this challenge. Numerous genome-scale projects are underway for several plant species.

However, new strategies to identify candidate genes for specific plant traits systematically by leveraging these high-throughput, genome-scale experimental data are lagging. AraNet integrates all such data and provides a rational, statistical assessment of the likelihood of genes functioning in particular traits, thereby assisting scientists to design experiments to discover gene function.

AraNet will become an essential component of the next-generation plant research."

CitationRational association of genes with traits using a genome-scale gene network for Arabidopsis thaliana. Insuk Lee, Bindu Ambaru, Pranjali Thakkar, Edward M Marcotte & Seung Y Rhee. Nature Biotechnology 2010; ePub ahead of print. doi:10.1038/nbt.1603

Abstract

We introduce a rational approach for associating genes with plant traits by combined use of a genome-scale functional network and targeted reverse genetic screening. We present a probabilistic network (AraNet) of functional associations among 19,647 (73%) genes of the reference flowering plant Arabidopsis thaliana. AraNet associations are predictive for diverse biological pathways, and outperform predictions derived only from literature-based protein interactions, achieving 21% precision for 55% of genes. AraNet prioritizes genes for limited-scale functional screening, resulting in a hit-rate tenfold greater than screens of random insertional mutants, when applied to early seedling development as a test case. By interrogating network neighborhoods, we identify AT1G80710 (now DROUGHT SENSITIVE 1; DRS1) and AT3G05090 (now LATERAL ROOT STIMULATOR 1; LRS1) as regulators of drought sensitivity and lateral root development, respectively. AraNet (http://www.functionalnet.org/aranet/) provides a resource for plant gene function identification and genetic dissection of plant traits.

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