Monday, March 23, 2009

JAK2 haplotype promotes JAK2 mutation

An interesting trio (Klipivaara et al, Jones et al, Olcaydu et al) of abstracts from the Nature Genetics Advance Online Publications site (alas, I don't have fulltext access without traipsing in to MIT or Harvard to use the library, but more on that soon).

JAK2 (Janus Kinase 2) is a protein kinase important in hematopoeitic cell function, and a particular mutation was shown several years ago to result in several distinct but related myeloproliferative disorders.

In these papers, particular haplotypes (given only the abstracts, its impossible to determine if there is complete agreement on which ones) lead to a higher risk of the disease-causing V617F mutation. What is quite striking is that the mutation occurs in cis to the haplotype, that is to say the same chromosome with the haplotype tends to be the one bearing the mutation.

The explanation favored by the papers appears to be that the haplotype somehow creates a favorable DNA context for causing the mutation. If the mutations showed up in trans (on the other chromosome) just as often, one might contemplate a mechanism whereby the haplotype somehow increases the selective advantage of V617F -- perhaps, for example, by causing incorrect JAK2 expression.

It will be fascinating to see this story play out -- of what DNA mutational or repair mechanism does the haplotype shift the balance? And, now that this is precedented you can be sure there will be a lot of searching for other examples. A quick screen would be to look for mutational haplotypes which contain known oncogenic mutations, and then go screening somatic samples for those haplotypes. Of course, with sequencing getting so cheap, the not too distant future will have lots of paired somatic and tumor complete genomes to compare.

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