September 23, 2005 | David F. Coppedge

Alternative Gene Splicing May Be Common

Scientists at MIT publishing in PNAS1 detected instances of alternative splicing in over 1,000 genes of stem cells.  They also computed possible isoforms of mRNA transcriptions and found 80% of them in the cells.  Not only that, the isoforms (alternatively spliced versions of exons from the same gene) appeared to be functional: “We find that alternative splicing can modify multiple components of signaling pathways important for stem cell function,” they say.  In short, alternative splicing, in which exons from genes are recombined in different ways, expands the information content of the genome:

We also analyze the distribution of splice variants across different classes of genes.  We find that tissue-specific genes have a higher tendency to undergo alternative splicing than ubiquitously expressed genes.  Furthermore, the patterns of alternative splicing are only weakly conserved between orthologous genes in human and mouse.  Our studies reveal extensive modification of the stem cell molecular repertoire by alternative splicing and provide insights into its overall role as a mechanism of generating genomic diversity. (Emphasis added in all quotes.)

They took note that “different mRNA isoforms from a single gene can often encode proteins with distinct, sometimes opposite functions.”  In fact, they point to earlier research that said, “Numerous biological processes ranging from sex determination to apoptosis depend on the alternative splicing of specific genes.”  Later, they said, “alternative splicing was found to extensively affect components of signaling pathways that are functional in stem cells, suggesting an important role of splice variations in self-renewal and differentiation.”  Thus, their work adds to a growing body of research showing that “alternative splicing is a general mechanism to increase the coding capacity and diversity of the genome in metazoans.”
    What regulates how the exons are spliced?  “Previous studies of individual genes have shown that splicing is coupled to transcription by protein-protein interactions between components of the transcription and splicing complexes.”  Their work suggested that tissue-specific genes seem to undergo the most alternative splicing, and ubiquitously-expressed genes less so.  They offered an “evolutionary argument” that tissue-specific genes could afford more experimentation: “ubiquitous transcripts responsible for crucial and general cellular processes have evolved not to be modified, whereas diversification is advantageous for tissue-specific gene products.”  This hypothesis, they felt, was reinforced by the finding that “patterns were conserved for only 20% of the examined orthologous genes in the human and mouse species, despite the general conservation of their exon-intron boundaries.”  This, they feel, could lead to rapid evolution of alternatively spliced exons, and subsequently to functional differences in otherwise analogous cell types between distant species.

1Pritzker et al., “Diversification of stem cell molecular repertoire by alternative splicing,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0502132102, published online before print September 23, 2005.

These findings add to the growing realization that the genome contains much more embedded information than mere gene count would suggest (see 09/08/2005 entry).  If the introns themselves (02/18/2005, 02/02/2005) transcribe into RNA regulatory elements, then nothing is wasted, and nothing is junk.  If all parts of the system can be shown to produce function, it becomes harder to claim evolution built this tight ship.  These authors’ weak attempt to produce an “evolutionary argument” did not demonstrate that any heritable, functional advantage derived from mistakes in alternative splicing, but only that it could have.  Did they demonstrate an example of a new function arising from a mistake?  No; they just expressed faith that randomness creates the possibility space for order.  This is a doctrine of pantheism (a religion).
    On the other hand, the high degree of conservation found in ubiquitously-expressed genes and at intron-exon boundaries are anti-evolutionary observations.  To argue evolution out of this data is to rely again on slippery homology vs. analogy arguments (see “Homology for Dummies,” 05/05/2004).  Because such arguments depend on embedded evolutionary assumptions, they are inherently circular.  It is just as logical to conclude that a common Designer built the system around two principles: (1) modular construction, wherein commonly-needed functions are coded similarly between different organisms, and (2) robustness, in which regulatory networks can maintain stability in changing environments.  The design inference has the added advantage of an adequate cause for the high degree of information involved.
    Whatever geneticists continue to uncover about the particulars, the system works.  Somehow, a human genome gives rise to a human, and a mouse genome gives rise to a mouse.  Unless mutations disrupt the program, the mouse will have all the parts in the right places.  It will be covered with the right kind of fur, have the right teeth in the right order, have feet and muscles and eyes and a brain and every organ necessary for its little life.  The molecular processes may seem disorganized to us.  We see that one gene can be alternatively spliced into several products, some which can produce opposite functions.  How does the right one get selected at the right time it is needed?  There are wonderful mysteries here that could be illuminated by a scientist looking for intelligent design.  If the DNA is not the master controller of its own transcription, what is?  What controls the spliceosome? (09/17/2004).  Can protein-protein interactions really be responsible for regulating the splicing, or is there another layer of genetic information directing their interplay?  What do all those short non-coding RNAs do?  How can so many competing processes and such a multiplicity of molecules guarantee a working mouse at the end of the assembly line?  We see only glimpses of how the plethora of processes at the molecular level leads invariably to the right result.  There may be more information and more design operating than we can possibly imagine.

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Categories: Genetics

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