Alternative genetic codes in bcftools csq for mitochondrial variant annotation

[etwatson]

Hello,

I’ve been using snpEff for variant effect prediction and find it very useful. However, I have noticed some instances of multi-nucleotide polymorphisms that nullify effect predictions based on single nucleotides - so I have become very interested in using bcftools csq in order to perform this analysis in a haplotype-aware manner.

I frequently analyze mitochondrial variants, which often require the use of alternative genetic codes. Fun mitochondria in fungi that contain mobile introns! From what I can tell, bcftools csq does not currently support specifying different genetic codes for annotation.

Would it be possible to add an option to allow users to specify an alternative genetic code when running bcftools csq? This would be particularly helpful for those working with mitochondrial genomes, where the standard nuclear genetic code does not apply.

If there is already a workaround for this, I would appreciate any guidance. Otherwise, I’d love to hear if this could be considered as a feature request.

Thanks for your time, and I appreciate all the work that goes into maintaining bcftools!

[pd3]

It is not supported but we can think about it, if you can provide detailed descriptions with specific examples.

[etwatson]

That is excellent. There are 33 well established alternative genetic codes as described by Anjay Elzanowski and Jim Ostell at the National Center for Biotechnology Information (NCBI). Anyone working on these organisms, especially on mitochondrial or chloroplast genetics, would be very appreciative.

As I mentioned, in snpEff, you can set the mitochondrial codon table in the config file, and even make changes to it, since there are some lineage specific codon tables. For example AUA and AUU are initiation codons in human mitochondria, while AUC also acts as an initiation codon in mice mitochondria. However, as you know, snpEff is limited to single nucleotide effect predictions, so it would be excellent if we could use bcftools csq for predicting variant effects.

For some examples here are a few of the major differences from the standard code:

Codon	Alternate	Standard	Taxonomy	Translation Table
AGA	Ter *	Arg R	Human mito	2
AGG	Ter *	Arg R	Human mito	2
AUA	Met M	Ile I	Human mito	2
UGA	Trp W	Ter *	Human mito	2
AUA	Met M	Ile I	Yeast mito	3
CUU	Thr T	Leu L	Yeast mito	3
CUC	Thr T	Leu L	Yeast mito	3
CUA	Thr T	Leu L	Yeast mito	3
CUG	Thr T	Leu L	Yeast mito	3
UGA	Trp W	Ter *	Yeast mito	3
UGA	Trp W	Ter *	Mold/Fungi/Protozoan mito	4
AGA	Ser S	Arg R	Invertebrate mito	5
AGG	Ser S	Arg R	Invertebrate mito	5
AUA	Met M	Ile I	Invertebrate mito	5
UGA	Trp W	Ter *	Invertebrate mito	5