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yhaplo | Identifying Y-Chromosome Haplogroups

David Poznik
23andMe
October, 2016

Overview

yhaplo identifies the Y-chromosome haplogroup of each male in a sample of one to millions. It does not rely on any particular genotyping modality or platform, and it is robust to missing data, genotype errors, mutation recurrence, and other complications. Although full sequences yield the most granular haplogroup classifications, genotyping arrays can yield reliable calls, provided a reasonable number of phylogenetically informative variants has been assayed.

Briefly, haplogroup calling involves two steps. The program first builds an internal representation of the Y-chromosome phylogeny by reading its primary structure from (Newick-formatted) text and importing phylogenetically informative SNPs from the ISOGG database, affiliating each SNP with the appropriate node and growing the tree as necessary. It then traverses the tree for each individual, identifying the path of derived alleles leading to a haplogroup designation.

yhaplo is available for non-commercial use pursuant to the terms of the non-exclusive license agreement, LICENSE.txt. To learn more about the algorithm, please see our bioRxiv pre-print:

Poznik GD. 2016. Identifying Y-chromosome haplogroups in arbitrarily large samples 
of sequenced or genotyped men. bioRxiv doi: 10.1101/088716

To learn more about the software, please see the manual, yhaplo.manual.<DATE>.pdf. For an overiew of command-line options, install the package and run: yhaplo -h

Installation

yhaplo is compatible with both Python 2 and Python 3.

To install:

git clone [email protected]:23andMe/yhaplo.git
cd yhaplo
pip install --editable .

To test-run on example data:

yhaplo -ex

The -ex option tells yhaplo to run on a subset of 1000 Genomes data and sets the --all_aux_output flag to produce all auxiliary output.

Caveats

Please note the following caveats before running yhaplo:

  • yhaplo does not check for sex status; it assumes all individuals are male.
  • yhaplo expects SNP coordinates consistent with the hg19/GRCh37 reference assembly.
  • yhaplo expects data at a reasonable number of ISOGG SNPs. This assumption is violated by:
    • variants-only sequence data
    • very low-coverage sequencing
    • genotyping arrays with few Y-chromosome probes

If, for a given individual, yhaplo observes no derived alleles at ISOGG SNPs on the upper branches of the Y-chromosome phylogeny, it will call the individual haplogroup "A," since all human Y-chromosome lineages are technically sublineages of A. Before concluding that the individual sample belongs to paragroup A (which includes haplogroups A00, A0, A1a, and A1b1), run with the -as option, and check the auxiliary output for ancestral alleles at haplogroup-BT SNPs. If you do not see any, your data set probably violates one or more of the assumptions listed above.

In particular, "variants-only" VCF files restrict to SNPs at which alternative alleles were observed, but ref/alt status is unimportant to yhaplo. What is important is ancestral/derived status. The reference sequence contains many derived alleles, and yhaplo will not be happy if you discard these valuable data. So please emit all confident sites when calling variants. To limit compute time and file size, you could safely restrict to positions in output/isogg.snps.unique.DATE.txt, as these are the only SNPs yhaplo considers. To generate this file, just run yhaplo with no arguments.

Input

Phylogenetic data

input/

  • y.tree.primary.DATE.nwk : primary structure of the Y-chromosome tree
  • isogg.DATE.txt : phylogenetically informative SNPs scraped directly from the ISOGG website. yhaplo resolves errors and formatting inconsistencies and emits cleaned versions (output/isogg.snps.cleaned.DATE.txt and output/isogg.snps.unique.DATE.txt; see yhaplo.manual.<DATE>.pdf for details).
  • isogg.correct.*.txt : corrections to ISOGG data
  • isogg.omit.*.txt : SNPs to drop due to inconsistencies observed in test data
  • isogg.multiallelic.txt : physical coordinates of multiallelic sites to be excluded
  • representative.SNPs.*.txt : SNPs deemed representative of corresponding haplogroups

Supported genotype formats

  • .genos.txt : sample-major genotypes
    • row 1: physical coordinates
    • column 1: individual IDs
    • cell (i, j): genotype for individual i at position j, encoded as a single character from the set { A, C, G, T, . }, with "." representing an unobserved value
  • .resid.txt : file with 23andMe research IDs in the first column
  • .vcf, .vcf.gz : snp-major VCF file. It is most efficient to restrict input VCF files to the Y chromosome.
  • .vcf4 : snp-major pseudo-VCF. differences include:
    • no "#" in header row
    • fewer header columns
    • GT values recorded as { A, C, G, T, . } rather than { 0, 1, . }

Output

All output file formats are described in detail in yhaplo.manual.<DATE>.pdf.

The two primary output files are:

  1. log.projectName.txt : log file containing details of the run
  2. haplogroups.projectName.txt : haplogroup calls. The 4 columns are:
    1. ID
    2. Haplogroup short form, with the name of a SNP observed in the derived state
    3. Haplogroup short form, with the name of a representative SNP
    4. Haplogroup long form, using Y-Chromosome Consortium nomenclature

yhaplo also produces a number of SNP tables, tree files, and auxiliary output files. Please see yhaplo.manual.<DATE>.pdf and yhaplo -h for details.

Code

Driver script

call_haplogroups.py

Main classes

  • Tree : knows root, depth, haplogroup-to-node mappings, etc.; parses a Newick file to build primary tree; parses ISOGG table to add SNPs to nodes and grow tree; finds the derived path leading from the root to an individual
  • Node : element of the tree. knows parent, children, snps, etc. represents the branch that leads to it
  • SNP : knows position, ancestral and derived alleles, node, etc.
  • PlatformSNP : knows position and ablock index
  • Sample : knows genotypes and haplogroup of an individual
  • Customer : (subclass of Sample) has 23andMe metadata and genotypes from ablocks
  • Path : path through a tree; stores the next node to visit, a list of SNPs observed in the derived state, the most derived SNP observed, and the number of ancestral alleles encountered
  • Page : 23andMe content page labels
  • Config : container for parameters, command-line options, and filenames

Utilities

  • utils.py : shared utility functions

Auxiliary scripts

  • convert_to_genos.py : converts data to .genos.txt format
  • plot_tree.py : plots a newick tree