When the paper on genome-wide copy-number polymorphism came out, I noted something interesting–the MAPT locus, known to be in an inversion under selection, was also the site of a copy-number polymorphism. I suggested this might provide an explanation for why the H2 haplotype was under selection.
A new paper adds another bit of data to the story–the H1 haplotype shows significantly greater expression of MAPT than the H2 haplotype. MAPT is a protein known to form deposits that are characteristic of neurodegenerative diseases like Parkinson’s and Alzheimer’s. So now the hypothesis is clear: the H1 haplotype has an duplication of the MAPT locus, which leads to subtly higher levels of MAPT, which in turn lead to subtly higher levels of neurogenerative disease in carriers. Thus, the H2 haplotype has a selective advantage.
Things that would provide support for this hypothesis:
1. Proof that the duplication of the MAPT locus is on the H1 haplotype (the technology used to identify the copy-number polymorphism can’t properly phase the haplotypes).
2. Evidence that the change in copy number is indeed the cause of the change in gene expression at the MAPT locus.
3. A large association study between MAPT copy number and neurodegenerative disease.
A story to watch…