Beyond the Genome

10/01/2012

This past July marked the 8th anniversary of the posting of the first draft of the dog genome sequence into free public databases for use by biomedical and veterinary researchers around the globe. On the occasion of this anniversary it is important to take stock of our progress and our future in canine health research. We are now in our third iteration of the canine genome, CanFam3.1, and much progress has been made by the Dog Genome Sequencing Consortium.

The genome refers to all DNA present in the cells of an organism and is the blueprint that determines the genetic makeup of an individual. Segments of DNA encode genes, which, when turned on, lead to transcription of RNA and ultimately synthesis of protein (Figure 1). Proteins help define cellular function and contribute to their roles in the tissues within a body. An excellent example of the power of the genome in canine health was the discovery of the mutation that causes Progressive retinal atrophy (PRA) in English Mastiff dogs. This disease is caused by a mutation in the RHO gene encoding Rhodopsin, a signaling protein in retinal cells. The end result of this mutation is the production of dysfunctional Rhodpsin protein that prevents the rods in the eye from responding to light properly, and ultimately leads to loss of vision.

Beyond
Figure 1

 

Beyond sections of DNA that code for genes, there is a vast amount of DNA that does not code for any functional protein. In fact, the amount of DNA in the genome that actually encodes protein is approximately 1%, and for a long time the remaining 99% was considered ‘junk’ DNA. Recently there has been a shift in this thinking, and there is now a growing respect for non-coding DNA and the role it may play in repression or activation of gene expression.

Beyond the genome, much progress has been made in our understanding of the regulation of health and disease. One such example are the events downstream of the genetic blueprint: RNA and protein, which ultimately define a disease phenotype and are the endpoints where severity of disease is recognized. New techniques have been developed to perform rapid, large volume (also known as “high throughput”) analysis of RNA (the transcriptome). Unlike the genome, the transcriptome can vary with external environmental conditions and reflects the genes that are turned on at any given time. High throughput analysis of the proteome, the entire set of proteins expressed by a cell or tissue, has advanced understanding of protein expression and modification.  Because protein expression does not necessarily reflect protein activity, we must often dig deeper and evaluate the activation state of protein (the phosphoproteome).

Finally, the importance of defining the factors that regulate gene expression is growing as well.  One of the most rapidly growing fields is epigenetics, which is the study of the heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. Epigenetic regulation explains how two identical genotypes can give rise to different phenotypes in response to the same environmental stimulus. There are four recognized epigenetic mechanisms by which gene expression is altered: modifications of histone proteins, DNA methylation, chromatin remodeling, and noncoding RNAs (microRNAs or miRNAs).  Aberrant DNA methylation has been identified in human and dog cancers and is found in two distinct forms, hypermethylation and hypomethylation, when compared to healthy cells.

Developing a greater understanding of all of these mechanisms of disease development in the dog is critical and will likely help solve some of our most complex health problems – not just in dogs, but in humans too.  The AKC Canine Health Foundation looks forward to supporting cutting edge research in these areas so that we can fulfill our mission to prevent, treat and cure canine disease.

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