The missing heritability puzzle
"The "missing heritability" problem can be defined as the fact that individual genes cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on "the combined effect of all the genes in the background than on the disease genes in the foreground" [Wikipedia].
I've discussed the issue here: http://goo.gl/2sQjsW
In summary, there are the following hypothesis:
1) some variants are too rare and we simply don't have the power to find them (I'm not convinced this is the case, but that's personal opinion);
2) there are epistatic effects and genes don't work "solo" but rather in concert, hence every time we look at single genes we miss the big picture; more here: http://goo.gl/5MvOS5
3) the mutations could be happening at the RNA level, not the DNA;
4) since the discovery that epigenetic changes are inheritable, a lot of interest has been focused in finding mutations in the epigenome rather than the genome; more on epigenetics and how we could possibly inherit changes that are not encoded in the DNA here: http://goo.gl/uF2Q5H
I wonder if the missing heritability puzzle has lost interest now that much of the focus has shifted on epigenetics. I want to bring the debate back because of something I recently discovered: amyloids
are proteins that don't fold properly. Proteins can take different 3D structures (conformations) that change as their function changes. These structures are essential for the protein to function properly. If a protein fails to fold and reach the necessary conformation, then it won't function properly.
Amyloids arise when proteins don't fold properly into their 3D structure. They start accumulating and they become toxic to the cell. This toxic accumulation of amyloids has been associated to many diseases -- diabetes, parkinson and alzheimer in particular.
Now, here is the intriguing bit. While in some cases this misfolding is caused by one mutated gene allele that eventually takes over, in many cases the misfolding can happen without any mutation in the DNA.
So, my question for the experts is: could this misfolding explain some of the missing heritability? Has anybody looked at that? I searched on PubMed for both "missing heritability" and "protein misfolding" but found nothing.
Since this is not my field, but I'd love to know more about it, I wanted to share my thoughts with +ScienceSunday
and see if somebody in the community has some references to suggest.
Thank you and a happy holiday to all!+Allison Sekuler
, +Buddhini Samarasinghe
, +Rajini Rao
, and +Robby Bowles