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Variant Discovery in High-Throughput Sequencing Data

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Developed in the Data Sciences Platform at the Broad Institute, the toolkit offers a wide variety of tools with a primary focus on variant discovery and genotyping. Its powerful processing engine and high-performance computing features make it capable of taking on projects of any size. Learn more

Picard LiftOver behaviour for multiallelic positions


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    Chris Kachulis

    Hi Adeline,

    One thing to note, Liftover only knows about the REF and ALT in the input (in your case hg19) and the REF in the output (in your case hg38) references.  It does not know anything about common ALT alleles in archaic vs modern human populations, since the reference sequence only defines the reference, not possible ALTs.  The ALT allele is coming from the vcf, which contains that additional information (unlike the reference on its own).

    Liftover will check that the REF allele matches between the two genomes.  If it doesn't, you can set RECOVER_SWAPPED_REF_ALT to attempt to rescue sites where the ref and alt alleles are swapped.  This procedure is only available for biallelic sites, not multialleleics.

    However, I think you are asking about sites where the REF has stayed the same, but modern humans and archaic humans tend to have different alt alleles, leading to multiallelic sites in a vcf which contains both modern and archaic humans.  In these cases, Liftover will lift the site over fine, which I don't think should be a problem.  It will still be clear that the variant in an archaic human is different from the variant in a modern human, because the alleles indicated by the genotypes will be different (for example 0/1 in archaic humans but 0/2 in modern humans.  Or split into two separate sites with different alt alleles.).  As long as your method for comparing modern and human genomes is aware of the alt alleles and genotypes, this should not artificially increase the resemblance between archaic and modern humans.

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