Monday, June 17, 2013

Alternative Genetic Splicing – What is its Significance?

There exists a seeming paradox among the many species that constitute vertebrates – animals with backbones.  The fact is that although so many of these species share similar families of protein-coding genes, they are very distinct in terms of their physical characteristics – their phenotypes.  There is no clear explanation of how this phenomenon can be defined on the molecular level.

What has been well established is the fact that over the evolutionary time scale for these various species – approximately 350 million years – significant changes have occurred in their respective transciptomes.  A transcriptome represents the entire set of all RNA molecules within a cell including Messenger RNA (mRNA), Ribosomal RNA (rRNA) and Transfer RNA (tRNA) and the so-called “non-coding” RNA.  It can either be used to represent the complete set of transcripts for an entire organism or for a particular cell type – for a particular organ, for example.  The transcriptome, in essence, is a quantitative measure of the genes that are actually being expressed at any given time and as such can very dependent upon the particular set of environmental conditions that the organism is subjected to.

From the accumulated data, it seems unlikely that changes in gene expression can account for the diversity of characteristics found among members of the vertebrate family.  It seems more likely that changes in alternative splicing (AS) may be responsible for the species-specific differences found in nature.  AS is a process in which a single gene can, in fact, result in the production of more than one protein.  This is a regulated process that determines what exons – that portion of a gene that that has coding information for the final protein product - will be included or excluded in the final m-RNA.  It is this mechanism that accounts for the fact that far more proteins are produced from the ~ 20,000 protein-coding genes found in the human genome than would ordinarily be expected.

Given these assumptions arrived at from well-supported evidence, Dr. Nuno L. Barbosa-Morais and colleagues, from the Banting and Best Department at the Donnelly Centre of Medical Research at the University of Toronto, Canada, conducted a genome-wide investigation of AS differences among equivalent organs from vertebrate organisms encompassing all vertebrates higher on the evolutionary scale than fishes – tetrapods.  The organs that they used for the investigation were whole brain, forebrain cortex, cerebellum, heart, skeletal muscle, liver, kidney, and testis.  This approach engendered a significant amount of precise and demanding work

From this exhaustive study, they found significant differences in the complexity of AS between the various lineages studied with the highest complexity found within primates.  The species examined spanned ~ 350 million years in the evolutionary time scale.  Furthermore, within 6 million years the splicing patterns of the individual organs studied diverged to the extent that they were more closely correlated with the identity of the species than to the organ type.

These results add significantly to the understanding of the underlying genetic mechanisms that account for the diversity of characteristics found within the vertebrate family of organisms.

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