preference for aligning to reference over alternate?

[efoss]

Has anyone seen a systematic preference for alignment to the reference sequence over the alternate sequence? It seems like your sequences should preferentially align to the reference genome. Therefore if you have a heterozygous SNP in an RNA seq experiment, more of the reference sequences might align than the alternates, giving you the false impression that reference was transcribed more. One could always create an alternate genome in addition to the reference genome and align to both, but I wonder how much of an issue this is in practice.

Thanks.

Eric

[efoss]

And a related question: Has anyone seen a sample in which the base calls at sites with both reference and alternate calls going overwhelmingly in favor of reference calls? These are situations where the alternate calls aren't so small as to be just an occasional missed call at what is actually a homozygous site.

Thanks.

Eric