Genotype Interpretation and Possible bugs

[anh151]

Hello,
I have several questions about Aldy genotypes and a possible bug report. I am using the latest version of Aldy with the default ILP solver. I have WGS samples that I am using to call CYP2D6.

I have a few genotype results that I need help interpreting.

1. *2/*41+rs368858603 - what does the + rsID mean?
2. *2/*68:2 - what does the ":2" mean?
3. *4+*4/*4.021.ALDY - what does the ".ALDY" mean?
4. *1+*94/*10 and *1+*2/*17 - For these last two my question is about the "*1+other" haplotype. *1 is generally defined as the lack of a variant/allele. In these two scenarios, is Aldy saying that one of the suballeles within *1 was detected plus *94 on the same haplotype?

I have a few samples where the stdout call from Aldy is *5/*5. However, the output .tsv file is blank. Why would this be the case? Example is shown below.

🐿  Aldy v4.3.1 (Python 3.9.15 on Linux 5.15.65+-x86_64-with-glibc2.31)
   (c) 2016-2022 Aldy Authors. All rights reserved.
   Free for non-commercial/academic use only.
Genotyping sample 1004207.bam...
Potential CYP2D6 gene structures for 1004207:
   1:  (confidence: 100%)
Potential major CYP2D6 star-alleles for 1004207:
   1:  (confidence: 100%)
Best CYP2D6 star-alleles for 1004207:
   1: *5 / *5 (confidence=100%)
      Minor alleles: 
CYP2D6 results:
  - *5 / *5
    Minor: [*5] / [*5]
    Legacy notation: [*5] / [*5]
Preparing debug archive...

I can provide a debug report for anything shown here if needed.

[inumanag]

Hi @anh151

*2/*41+rs368858603 - what does the + rsID mean?

This means that you have *2 and *41 with an extra SNP rs368858603 that is not part of either *2 or *41 definition.

*2/*68:2 - what does the ":2" mean?

This is *68; :2 is just an internal distinction between two *68 variants present in the database.

*4+*4/*4.021.ALDY - what does the ".ALDY" mean?

This means that you have *4.021 augmented with some extra SNPs (or, in some cases, with some SNPs removed). Such alleles were observed in some of our samples (see aldy query "CYP2D6*4.021.ALDY" and aldy query "CYP2D6*4.021" for the full list of differences). In general, all alleles ending with .ALDY are specific to Aldy and are not part of the PharmVar.

*1+*94/*10 and *1+*2/*17 - For these last two my question is about the "*1+other" haplotype. *1 is generally defined as the lack of a variant/allele. In these two scenarios, is Aldy saying that one of the suballeles within *1 was detected plus *94 on the same haplotype?

This means that you have 3 copies of CYP2D6: *1, *94 and *10. Each copy has a distinct star-allele.

*5/*5

This is a complete gene deletion on both chromosomes.

[anh151]

Hi @inumanag
Thanks for the responses.

For the *5/*5 scenario my question was related to the .tsv output from Aldy. The stdout contains the *5/*5 call, but the .tsv file is empty. Is this intentional or is this a bug?

[inumanag]

Hi @anh151

That is expected... right now. I can address this in the next release (the file will be still empty, but I can add a comment--- would that work?)

[anh151]

Hi @inumanag
Are there any other scenarios for CYP2D6 or other genes where the .tsv file would be blank, but a call is made within the stdout? If not, then the existing implementation is fine. I am using Aldy to call CYP2D6 for a large dataset and I am not monitoring the stdout.

Thanks,
Andrew

[inumanag]

It should only happen if you have two deletion alleles (*5/*5 in CYP2D6 case; for other genes, the * number might differ).

[anh151]

Sounds good. Thanks for the help.