Thursday, April 29, 2010

The Complexity of a Complex Disorder

A group of researchers led by Timothy Aitman of the MRC Clinical Sciences Centre and Imperial College London used the SHR (spontaneously hypertensive rat) to identify the few genes they thought predisposed this strain to hypertension (several genes had already been identified but the group knew or felt a few others remained to be discovered). Sequencing this SHR rat with the NextGen approach and comparing those data to the rat reference genome, led to quite a surprise. 788 genes are mutated in SHR compared to the reference genome, including 60 that are deleted altogether.

My take on this is many genes are likely involved in a complex disorder and many genes - with specific variants - may work in concert to produce the disease phenotype – either via gene-gene interactions or affecting interconnecting pathways.

This type of result is very likely to be repeated with other metabolically sensitive disorders and afflictions such as dyslipidemia, obesity and type 2 diabetes. A series of variations in genes combined with deviations from a standard environment - both in terms of diet and microbiome - are likely to combine to tip the balance and enhance onset and/or progression of said affliction.



EurekAlert: Hypertensive rat genome sequence expected to uncover genetic basis of human hypertension

Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, Morrissey C, Behmoaras J, Fernandez-Suarez XM, Johnson MD, McLaren WM, Patone G, Petretto E, Plessy C, Rockland KS, Rockland C, Saar K, Zhao Y, Carninci P, Flicek P, Kurtz T, Cuppen E, Pravenec M, Hubner N, Jones SJM, Birney E, Timothy J. Aitman TJ. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Res. (in press).


  1. This is interesting - although I don't have access to full paper. 788 genes is a lot - one question is how many genes are mutated in other rat strains compared to the reference - i.e. how many of these 788 are really linked to hypertension? Is there any discussion of this in the paper?

  2. In my opinion one question is how realistic is any definition of a 'reference genome'?. Speccially now that next gen of genome sequencers are coming to hospitals!

    Thats is very important for designing complex diseases aproach.
    With no 'realistic standard genome' (in my opinion there is no sense for using 'consensus genome' in the future), my propose is to use phenotypes (phenomes) as multiple references to study a single complex disease such hypertension.
    genome 1: obese+CVD+inflammatory arthritis
    genome 2: Rheumatic arthritis+gota+hypertension
    genome 3: Healthy
    genome 4: Healthy
    genome 5: colon cancer+hypertension+obese
    genome 6: pneumonia+VIH infection+Hodgkin Disease+obesity

    All these information (genome sequences and phenotypes-via text mining from hospitals' reports) in a public (?) repository.

    ...and 'blasting' genome-phenome 'strings'.

    Much more complicate, of course.

    Hi Larry, now a follower!
    Bests from Spain

  3. ...

    Similar to the idea of this paper...

    Campillos M, Kuhn M, Gavin AC, Jensen LJ, Bork P. Drug target identification using side-effect similarity. Science. 2008 Jul 11;321(5886):263-6.

    ...where side-effect profiles (phenotype) helps to find molecular drug target -protein and/or pathway- (complex disease associate genes).

  4. ...

    and this communication (only change OMIM/GO terms by 'individual' clinical diagnostic and mouse/rat gene expression profiles by 'personal' genome sequence)...

    ...with one single repository or multilocated data accessed via Semantic Web Workflow (still no clear future for this last well-known text-mining project?!).