Variable window binding for mutually exclusive alternative splicing.
BACKGROUND
Genes of advanced organisms undergo alternative splicing, which can be mutually exclusive, in the sense that only one exon is included in the mature mRNA out of a cluster of alternative choices, often arranged in a tandem array. In many cases, however, the details of the underlying biologic mechanisms are unknown.


RESULTS
We describe 'variable window binding'--a mechanism used for mutually exclusive alternative splicing by which a segment ('window') of a conserved nucleotide 'anchor' sequence upstream of the exon 6 cluster in the pre-mRNA of the fruitfly Dscam gene binds to one of the introns, thereby activating selection of the exon directly downstream from the binding site. This mechanism is supported by the fact that the anchor sequence can be inferred solely from a comparison of the intron sequences using a genetic algorithm. Because the window location varies for each exon choice, regulation can be achieved by obstructing part of that sequence. We also describe a related mechanism based on competing pre-mRNA stem-loop structures that could explain the mutually exclusive choice of exon 17 of the Dscam gene.


CONCLUSIONS
On the basis of comparative sequence analysis, we propose efficient biologic mechanisms of alternative splicing of the Drosophila Dscam gene that rely on the inherent structure of the pre-mRNA. Related mechanisms employing 'locus control regions' could be involved on other occasions of mutually exclusive choices of exons or genes.
Anastassiou
Dimitris
D
Center for Computational Biology and Bioinformatics, and Department of Electrical Engineering, Columbia University, New York, NY 07670, USA. anastas@ee.columbia.edu
Liu
Hairuo
H
Varadan
Vinay
V
D000465:Algorithms; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015815:Cell Adhesion Molecules; D017124:Conserved Sequence; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA
D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; C491736:Dscam1 protein, Drosophila