The consequences of alternative splicing on biological pathways

Higher-order eukaryotes present biologists with complexities not found in simpler organisms. One such complexity is alternative splicing. 7179 of 22218 human genes in ENSEMBL [1] encode two or more different proteins, with 2229 genes encoding proteins with different Pfam [2] domain compositions. We evaluated how these changes in domain composition may alter biological network behavior, a phenomenon suggested to be frequent in prior work [3]. First, in regulatory networks, alternative splicing can change the DNA-binding affinity of transcription factors by altering the number of DNA-binding domains, a pattern also observed by others [4]. For instance, in 265 of 563 genes producing zinc finger proteins, alternative splicing alters the number of zinc fingers. In extreme cases, this can lead to a complete loss of DNA-binding. For example, the Icaros gene can produce a dominant negative transcription factor protein: it cannot bind DNA but binds other co-factors, thus competing for low copy-number co-factors and consequently acting as a transcriptional repressor [5]. Additionally, when a domain is spliced out of a protein, some protein-protei