If you have gotten the impression from the above discussion that one gene with dozens of introns could create thousands of different but related proteins through differential splicing, then you would be correct, at least in the case of Dscam. The current champion at making multiple proteins from the same gene is the Drosophila Dscam gene.1 This gene encodes a membrane adhesion protein that prevents dendrites from the same neuron from touching (Wu et al. 2012). Dscam contains 115 exons. Moreover, a dozen different adjacent DNA sequences can be selected to be exon 4, and nearly 3 to 4 dozen mutually exclusive adjacent DNA sequences can become exons 6 and 9 (Figure 1A; Schmucker et al. 2000). If all possible combinations of exons are used, this one gene can produce 38,016 different proteins, and random searches for these combinations indicate that a large fraction of them are, in fact, made. The pre-mRNA of Dscam has been found to be alternatively spliced in different neurons, and when two dendrites from the same Dscam-expressing neuron touch each other, they are repelled (Figure 1B; Wu et al. 2012). This repulsion promotes the extensive branching of the dendrites and ensures that axon-dendrite synapses occur appropriately between neurons. It appears that the thousands of splicing isoforms are needed to ensure that each neuron acquires a unique identity (Figure 1C; Schmucker 2007; Millard and Zipursky 2008; Miura et al. 2013). Moreover, the combination of expressed Dscam1 isoforms can change in a given neuron with each new round of RNA synthesis. Such timely changes in alternative splicing may be in response to neuron-neuron interactions during the process of dendritic arborization. The Drosophila genome is thought to contain only 14,000 genes, but here is a single gene that encodes nearly three times that number of proteins!
1 DSCAM (Down syndrome cell adhesion molecule) is a gene found in humans within the “Down syndrome” region of chromosome 21. It encodes a cell adhesion molecule that functions through homophilic binding and is important for axon guidance.
About 92% of human genes are thought to produce multiple types of mRNA. Therefore, even though the human genome may contain about 20,000 genes, its proteome—the number and type of proteins encoded by the genome—is far larger and more complex. “Human genes are multitaskers,” notes Christopher Burge, one of the scientists who calculated this figure (Ledford 2008). This fact explains an important paradox. Homo sapiens has about 20,000 genes in each nucleus; so does the nematode C. elegans, a tubular creature with only 959 cells. We have more cells and cell types in the shaft of a hair than C. elegans has in its entire body. What’s this worm doing with approximately the same number of genes that we have?
Millard, S. S. and S. L. Zipursky. 2008. Dscam-mediated repulsion controls tiling and self-avoidance. Curr. Opin. Neurobiol. 18: 84–89.
Miura, S. K., A. Martins, K. X. Zhang, B. R. Graveley and S. L. Zipursky. 2013. Probabilistic splicing of Dscam1 establishes identity at the level of single neurons. Cell 155: 1166–1177.
Schmucker, D. 2007. Molecular diversity of Dscam: Recognition of molecular identity in neuronal wiring. Nat. Rev. Neurosci. 8: 915–920.
Schmucker, D., J. C. Clemens, H. Shu, C. A. Worby, J. Xiao, M. Muda, J. E. Dixon, and S. L. Zipursky. 2000. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101: 671–684.
Wu, W., G. Ahlsen, D. Baker, L. Shapiro, and L. Zipursky. 2012. Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. Neuron 74: 261–268.
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