Faster methods for elucidating gene function

Research lead

Despite the sequencing of the human genome eight years ago the function of most human genes is still barely understood. Now, computational biologists Johannes Söding and Andreas Biegert of the Gene Centre of LMU Munich have developed a method that improves database searches for homologous gene sequences in other organisms. The method makes it easier to investigate gene sequences and is significantly more sensitive than existing methods, while being just as quick.

Instead of comparing sequences letter by letter, the method takes the neighbouring sequences into account during the comparison. The current best and most frequently used algorithms, such as BLAST (Basic Local Alignment Search Tool) evaluate the similarity between a pair of sequences by aligning them underneath each other in such a way that similar amino acids lie in the same columns. The sequence similarity is then calculated by adding the similarities of all aligned amino acids.

BLAST has been the most important method for sequence searching since its development in 1990 and is called up around 500,000 times a day from all around the world. But when evaluating the similarity of two amino acids, it ignores their neighboring amino acids. Now Söding and Biegert have developed “context-specific” BLAST, or CS-BLAST, which can sniff out twice as many relatives as BLAST.

When determining the similarity of an amino acid to the reference sequence, CS-BLAST includes the sequence context of every amino acid, namely its six left and six right sequence neighbors, in the analysis. “The idea is that the context says much more about how likely two amino acids are to mutate into each other,” says Söding, who heads the group for Protein Bioinformatics and Computational Biology.

The new method is just as fast despite its better sensitivity, explains the researcher, because the sequence search takes place in two steps. In the future, the scientists intend to apply the newly developed algorithm to genomic alignments as well, where not only individual genes, but entire segments of DNA are compared. “As with proteins, there are certain key regions in DNA that fulfill crucial regulatory functions,” explains Söding. “You can identify these regulatory regions, which are important for a deeper understanding of many diseases, by comparing the human genome with those of other mammals.”

http://www.en.uni-muenchen.de/news/research/soeding.html