I wonder if anyone has a good feeling for how confident we are in the available sets of germline D genes?
We talk a lot about our (lack of) confidence in the Vs, and the Js don’t mutate much and seem to have pretty low diversity, so they’re probably ok.
But the Ds seem like a problem. We’re frequently telling our experimental colleagues “this is the naive sequence for this clonal family, go and synthesize this to see how good it is”. And within the V, there’s at most a few bases of uncertainty. But in the cdr3 our dependence on the completeness and correctness of the D germline set is a bigger problem, largely because of the lack of homology among D genes.
As I’m sure you’re familiar, sometimes there’s a D that aligns quite confidently, and sometimes there isn’t. In the latter case, it’s usually just a highly mutated cdr3 – but what about when it isn’t, and there’s a D we don’t know about? There’s a growing body of germline inference algorithms for V, but it’s hard to imagine these extending even in principle to D, so my impression is we’re stuck with germline sequencing. Does anyone have a good feeling for the state of this? Or any plans to do more?