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We've been working on these experiments for a year. They are more difficult than I expected, but they will probably be the subject of our third paper (after the Hardy-Weinberg results). Lots more discussion of this on PR.

@Trish It's true that the original group of 20 in Ron Davis' OMF-funded big data study were identified as severely ill. But we now have sequence data for 66 ME/CFS patients covering the entire spectrum of disease severity, and every one of them has at least one damaging mutation in IDO2. The...

Right. You probably remember that I was looking only for common variants because I felt (and still believe) that common variants are required to account for the existence of ME/CFS epidemics or outbreaks.

It is intrinsic, but only to nonlinear systems. Of course, as you point out, almost every interesting system is regulated, and typically that makes them nonlinear. There are three interesting features of nonlinear systems that are never seen in linear systems: 1) bistability, 2) sustained...

It's thought that IDO2 is the ancient gene and IDO1 evolved from it by duplication and divergence. They are next to one another on chromosome 8. You are correct that the trap could exist in the absence of IDO2. The trap is inherent in the substrate inhibition of IDO1 and my seeing the high Km...

I think I've read all that Craig has written on catastrophe theory and ME/CFS, but I haven't seen a particular part of cell biology or physiology identified as the site of the catastrophe. There is a lot in common between catastrophe theory and bistability, so if anyone knows what part of...

First, in case it's not already clear to anyone, I'm the author of the IDO metabolic trap hypothesis. I think most S4ME members are aware of this, but I just want to be sure. This is already a long thread. If asked to summarize what Chris has said, I'd list two main points. 1) there are no IDO2...

@strategist This is why I asked Chris if the Biobank data we see online are filtered in any way. As for the IDO2 sequencing method, it is Peidong Shen's multiplexed PCR (mPCR) method, which he developed for other projects (at least two published) and which he simply adapted to target the IDO2...

@wigglethemouse In your table from Biobank, there is a column labeled HWE, which I imagine is an abbreviation for Hardy-Weinberg equilibrium. Can you tell me what the numbers in that column signify? Or just a link to the Biobank explanation? Thanks.

Chris, Does "Variant annotation dubious" mean that the Broad investigators think the existence of the variant is dubious or do they mean that someone's interpretation of the significance of the variant is dubious? Rob

I used this phrase because the strategy we employed was to search for genes coding for enzymes or transporters with common damaging mutations. Using our most conservative criteria, we still found 208 such genes. I liked IDO2 because it catalyzes the first reaction in an important metabolic...

@Chris Ponting I'm always going to defer to your expertise on genomics. But I am going to ask questions. First question is this. Some people tell me they find no mutations in IDO2 when they look at WGS data and I find this very unlikely since the R248W and the Y359X are so common in the CEU...

Yes. I suggested all of those as reviewers. Also Travis Craddock in the Broderick group.

This question can be seen as a variant of your sudden vs. progressive onset question. Trapping more cells of a given cell type or trapping new additional cell types both could lead to increased disease severity. Good questions. Thanks for your interest.

An upper limit on cellular Trp? Certainly there is the limit of solubility, but below that the level achieved in any cell will depend on the kinetic properties of the LAT1 transporter bringing Trp into the cell and the kinetic properties of the enzymes that consume Trp. An amazing feature of...

To answer @Robert1973, your post includes many questions. I'll do my best. The IDO metabolic trap hypothesis does predict a stable steady state after cellular tryptophan (Trp) has increased to the point where cellular uptake of Trp equals the sum of degradation (by the kynurenine pathway) and...

Thanks to @Michiel Tack, I now have a PDF of the Streeten (Bell) (2000) paper on erythrocyte volume in ME/CFS. Table 4 of that paper shows that neither plasma volume nor total blood volume is altered significantly in the 12 women with CFS studied. This goes some way toward answering the gender...

This topic has interested me so, like Michiel, I've tracked down some of the published work. I think Michiel is correct that David Bell often spoke of CFS patients with dramatically decreased blood volume. I believe I saw this in a YouTube video of a talk he gave in Australia years ago. If this...

As Chris points out there are many SNVs in IDO2. The IDO metabolic trap hypothesis, however, is not based on a GWAS approach to the data. The hypothesis originates from a need to explain both genetic predisposition and the existence of ME/CFS epidemics or outbreaks. I'm thinking one cannot...

This is an interesting and important question. I'll look into it. I will, however, be greatly surprised if all our CFS patients (now n=66) acquired ME/CFS following infection because our criterion is diagnosis by a physician who sees a large number of ME/CFS patients, and uses the appropriate...