trioPhaser: Using Mendelian inheritance logic to improve genomic phasing of trios

Mendelian inheritance logic can be used to determine phase for the majority (67-83%) of variant nucleotide positions (Choi et al. 2018 & Roach et al. 2011). However, when both parents and the child are heterozygotic (A/G), Mendelian inheritance alone cannot be used to determine phase. When such scenarios are present, phasing programs that rely on population-based haplotype reference panels can be used.

Available software that directly uses trios and Mendelian inheritance logic during phasing have limitations. For example, some software require multiple input sources (resulting in extensive storage requirements), or do not support current genome builds. To address these challenges, we have developed trioPhaser.

trioPhaser can increase the total number of correctly phased positions by using Mendelian inheritance logic in conjunction with SHAPEIT4 [insert manuscript doi here].

Usage

Installation (requires Docker installation)

docker pull dmill903/triophaser:latest

Run trioPhaser on the included example data (see here for how we generated the files and for more details on how to run trioPhaser)

Here we provide example code on how to execute trioPhaser. In this example, the input files are provided within the container. Under normal circumstances, the input files will be on your local machine. This example implies the following:

There is a directory called /Data on the local machine.
We attached and called this directory /proj within the container.
We set /proj as our working directory within the container.
The haplotype_references directory has been created and is located at /Data/haplotype_references (*this is where trioPhaser will store the haplotype reference data).
The output file will be written to /Data/phased_output.vcf.gz
The container ID will be stored at /Data/trio_phaser.out upon execution.

Update /Data and haplotype_references with the directories you want to use on your local machine. For example, if you want the output to be stored at /tmp and within /tmp you have a folder called references, you would change /Data to /tmp and haplotype_references to references.

Use docker run -t dmill903/triophaser:latest python3 /trio_phaser.py -h learn more about trioPhaser's arguments and how multiple trios can be used as input.

docker run -d -v /Data:/proj -w /proj -t dmill903/triophaser:latest \
  python3 /trio_phaser.py \
  -c /trioPhaser/validate/son_ashkenazim_GRCh38_chr22.g.vcf.gz \
  -p /trioPhaser/validate/father_ashkenazim_GRCh38_chr22.g.vcf.gz \
  -m /trioPhaser/validate/mother_ashkenazim_GRCh38_chr22.g.vcf.gz \
  -o /proj/phased_output.vcf.gz \
  -r /proj/haplotype_references \
  > /Data/trio_phaser.out

*Note: The first time trioPhaser is run, it will download reference files, which may take a while depending on internet speed. Subsequent runs can use the cached reference files.

View log information output by trioPhaser

CONTAINERID="cat /Data/trio_phaser.out"
docker logs `$CONTAINERID` >> /Data/trio_phaser.out

References

Choi Y, Chan AP, Kirkness E, Telenti A, Schork NJ: Comparison of phasing strategies for whole human genomes. PLoS Genet. 2018, 14:e1007308.

Roach JC, Glusman G, Hubley R, Montsaroff SZ, Holloway AK, Mauldin DE, Srivastava D, Garg V, Pollard KS, Galas DJ, Hood L, Smit AFA: Chromosomal haplotypes by genetic phasing of human families. Am. J. Hum. Genet. 2011, 89:382–397.

dmiller903 / trioPhaser