Next-generation sequencing yields fundamental insights
Hypertension, or chronic high blood pressure, is a serious health risk that affects more than 25% of all adults. Despite its prevalence in the population, the molecular basis of the disease is not yet well understood. “[It is] a problem that has proved remarkably difficult to study in humans directly,” notes the CSC’s Tim Aitman, Head of the Physiological Genomics and Medicine Group.
The most widely studied animal model of human hypertension is the spontaneously hypertensive rat (SHR) – a model that has yielded a great deal of insight into the human condition. Without a complete sequence of the SHR genome, however, it has been difficult to resolve many of the molecular consequences of the genomic variations in SHR, and this is exactly what Professor Aitman and coworkers have delivered.
Using next generation sequencing technology, the team have sequenced the first genome of a mammalian disease model. They have generated a nearly complete catalogue of SHR genomic variants that may contribute to hypertension and other phenotypes. In the SHR genome, the team found 788 genes mutated enough to cause a major disruption of protein function. Affected proteins encode calcium and potassium ion channels, and may have a role in regulating blood pressure.
Rat vs. Mou
Interestingly, the study revealed that the rat has a clear advantage over other animal models, such as the mouse: genome variability within the species is more similar to that in humans. The team compared the SHR genome with that of the Brown Norway, the first rat to have had its genome sequenced in 2004. They looked at the number of single DNA base pair differences between the two strains and found that about 15 in every 10, 000 base pairs was different. This is remarkably similar to the variability between humans (also 15/10,000). However, from 11 commonly used inbred laboratory mouse strains, average variability was only about 7 per 10, 000 base pairs. Having a genomic variability that more closely matches that seen in humans is another factor that makes the rat a better model for human disease than the mouse.
The new genome sequence offers a direct path to establishing the causes of high blood pressure in the hypertensive rat and of corresponding genes that correspond to the causes of high blood pressure in humans.
Atanur, S. S., Birol, I., Guryev, V., Hirst, M., Hummel, O., Morrissey, C., Behmoaras, J., Fernandez-Suarez, X. M., Johnson, M. D., McLaren, W. M., Patone, G., Petretto, E., Plessy, C., Rockland, K. S., Rockland, C., Saar, K., Zhao, Y., Carninci, P., Flicek, P., Kurtz, T., Cuppen, E., Pravenec, M., Hubner, N., Jones, S. J., Birney, E., Aitman, T. J. (2010). The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome research. doi: 10.1101/gr.103499.109