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README.md

Hierarchical Alignment (HAL) Format API (v1.2)

Copyright (C) 2012 by Glenn Hickey (hickey@soe.ucsc.edu) Released under the MIT license, see LICENSE.txt

HAL is a structure to efficiently store and index multiple genome alignments and ancestral reconstructions. HAL is a graph-based representation which provides several advantages over matrix/block-based formats such as MAF, such as improved scalability and the ability to perform queries with respect to an arbitrary reference or subtree.

This package includes the HAL API and several analysis and conversion tools which are described below. HAL files are presently stored in HDF5 format, but we note that the tools and most of the API are format-independent, so other databases could be implemented in the future.

Citing

Glenn Hickey, Benedict Paten, Dent Earl, Daniel Zerbino, and David Haussler. HAL: A Hierarchichal Format for Storing and Analyzing Multiple Genome Alignments. (submitted).

Installation

Requirements

  • gcc 4.2 or newer
  • git

Downloading HAL

From the parent directory of where you want HAL installed:

 git clone git://github.com/glennhickey/hal.git

Installing Dependencies

HDF5 1.8 with C++ API enabled

  • Using MacPorts:

    sudo port install hdf5-18 +cxx

  • From Source:

    wget http://www.hdfgroup.org/ftp/HDF5/current/src/hdf5-1.8.9.tar.gz
    tar xzf hdf5-1.8.9.tar.gz
    cd hdf5-1.8.9
    ./configure --enable-cxx
    make && make install

  • Local install from source into DIR (do not need root)

    mkdir DIR/hdf5
    wget http://www.hdfgroup.org/ftp/HDF5/current/src/hdf5-1.8.9.tar.gz
    tar xzf hdf5-1.8.9.tar.gz
    cd hdf5-1.8.9
    ./confiugre --enable-cxx --prefix DIR/hdf5
    make && make install

    Before building HAL, update the following environment variables:

    export PATH=DIR/hdf5/bin:${PATH}
    export h5prefix=-prefix=DIR/hdf5

sonLib

From the same parent directory where you downloaded HAL:

  git clone git://github.com/benedictpaten/sonLib.git
  pushd sonLib && make && popd

If sonLib and HAL are not sister directories, update hal/include and change

sonLibRootPath=${rootPath}/../sonLib

to reflect the directory where you installed sonLib

Building HAL

From the hal/ directory:

  `make`  

Before using HAL, add it to your path:

 `export PATH=<path to hal>/bin:${PATH}`

HAL Tools

General Options

Detailed command line options can be obtained by running each tool with the --help option.

All HAL tools compiled with HDF5 support expose some caching parameters. Tools that create HAL files also include a chunking and compression parameters. In most cases, the default values of these options will suffice.

--cacheBytes <value>: The maximum size of each array cache. 3 such caches can be allocated per genome in the alignment.

--cacheRDC <value>: The number of slots in each cache. This number should be set to a prime number that is roughly 50 x [cacheBytes / chunk].

--cacheMDC <value>: Size of the metadata cache. There is presently no reason to touch this.

--chunk <value>: The chunk size for the hdf5 arrays. Unreasonable chunk sizes can adversely affect cache performance. Larger chunks can lead to better compression. [default = 1000]

--deflate <value>: Compression level. Higher levels tend to not significantly decrease file sizes but do increase run time. [0:none - 9:max] [default = 2]

Importing from other formats

MAF Import

The (MAF)[http://genome.ucsc.edu/FAQ/FAQformat.html#format5] is a text format used at UCSC to store genome alignments. MAF's are typically stored with respect to a reference genome. MAFs can be imported into HAL as subtrees using the maf2hal command.

To import primates.maf as a star tree where the first alignment row specifies the root, and all others the leaves:

 maf2hal primates.maf primates.hal

To import primates.maf using "chimp" has the root

 maf2hal primates.maf primates.hal --refGenome chimp

The more the underlying tree looks like a star tree, the less efficient HAL is as all genomes will be fragmented with respect to each other. If ancestral (or multiple reference) sequences are available, or if it is acceptable to use a non-reference species as a reference proxy, then trees of arbitrary typologies can be constructed using the --append option.

 maf2hal mammals.maf mammals.hal --refGenome mouse --targetGenomes human,rat,chimp,dog
  maf2hal mammals.maf mammals.hal --append --refGenome human --targetGenomes chimp,gorilla,orang
  maf2hal mammals.maf mammals.hal --append --refGenome dog --targetGenomes cow,horse

This will create a tree that looks like

 ((chimp, gorilla,orang)human, rat,(cow,horse)dog)mouse;

Progressive Cactus Import

HAL is most beneficial when consensus reference or ancestral sequences are available at the internal nodes of the tree. This is the type of information generated by progressive alignment pipelines. Progressive Cactus (manuscript in preparation) is our implementation of such a pipeline. A beta version is presently available on GitHub. A tool to convert from Cactus graphs to HAL graphs, cactus2hal, can be downloaded as well.

 cactus2hal.py mammals_cactusProject.xml mammals.hal

Exporting to other formats

MAF Export

MAF files can be generated from HAL alignments or sub-alignments. The reference genome and alignment scope (subsequence of the reference and/or phylogenetic distance) are chosen through command-line options.

Export the HAL alignment as a MAF referenced at the root

     hal2maf mammals.hal mammals.maf

Export a MAF with referenced at sequence chr6 in the human genome

     hal2maf mammals.hal mammals.maf --refGenome human --refSequence chr6

Export a MAF consisting of the alignment of human with respect to chr2 in chimp

     hal2maf mammals.hal mammals.maf --refGenome chimp --refSequence chr2 --targetGenomes human

Export a MAF consisting of the alignment of all apes referenced on gorilla

     hal2maf mammals.hal mammals.maf --rootGenome ape_ancestor --refGenome gorilla

By default, no gaps are written to the reference sequence. The --maxRefGap can be specified to allow gaps up to a certain size in the reference. This is achieved by recursively following indels in the graph that could correspond to reference gaps.

Summary Information

halValidate

It is a good idea to check if a hal file is valid after creating it.

halValidate mammals.maf

halStats

Some global information from a HAL file can be quickly obtained using halStats. It will return the number of genomes, their phylogenetic tree, and the size of each array in each genome.

  halStats mammals.maf

The --tree, --sequences, and --genomes options can be used to print out only specific information to simply iterating over the alignment in shell or Python scripts.

halSummarizeMtuations

A count of each type of mutation (Insertions, Deletions, Inversions, Duplications, Transpositions, Gap Insertions, Gap Deletions) in each branch of the alignment can be printed out in a table.

 halSummarizeMutations mammals.maf

Subtrees can be specified using the --targetGenomes or --rootGenome option. The --maxGap option is used to distinguish from small, 'gap' indels and larger indels. This distinction is somewhat arbitrary (but conventional). HAL allows gap indels to be nested within larger rearrangements: ex. an inversion with a gap deletion inside would be counted as a single inversion, but an inversion containing a non-gap event would be identified as multiple independent inversions.

 halSummarizeMutations mammals.maf --maxNFraction 0

Will prevent rearrangements with missing data as being identified as such. More generally, if an insertion of length 50 contains c N-characters, it will be labeled as missing data (rather than an insertion) if c/N > maxNFraction.

Analysis

Liftover

Annotations in BED, ie tab-delimited files whose first three columns are

 SequenceName     StartPosition    LastPosition+1

can be lifted over between genomes using halLiftover. halLiftover does a base-by-base mapping between any two sequences in the alignment (following paralogy relations as well).

 halLiftover mammals.hal human human_annotation.bed dog dog_annotation.bed

will map all annotations in human_annotation.bed, which must refer to sequences in the human genome, to their corresponding locations in dog (if they exist), outputting the resulting annotations in dog_annotation.bed

Mutation Annotation

Annotation files, as described above, can be generated from the alignment to provide the locations of substitutions and rearrangements. Annotations are done on a branch-by-branch basis, but can be mapped back to arbitrary references using halLiftover if so desired. The produced annotation files have the format

 SequenceName     StartPosition    LastPosition+1  MutationID  ParentGenome ChildGenome

The ID's refer to the types of mutations described above, and are explained in the header of each generated file. To generate tables of rearrangement mutations between human and its most recent ancestor in the alignment, run

 halBranchMutations mammals.hal human --refFile ins.bed --parFile del.bed

Two bed files must be specified because the coordinates of inserted (and by convention inverted and transposed) segments are with respect to bases in the human genome (reference), where as deleted bases are in ancestral coordinates (parent).

Point mutations can optionally be written using the --snpFile <file> option. The '--maxGap' and '--maxNFraction' options can specify the gap indel threshold and missing data threshold, respectively, as described above in the halSummarizeMtuations section.

Example of HAL Genome Representation

The following is obtained by running h5ls -v -r (included with hdf5) on an ancestral genome, in this case a small simulated human-chimp ancestor named sHuman-sChimp. The genome itself is stored as a group. It contains four important 1-dimensional arrays:

  • BOTTOM_ARRAY: The bottom segments of the genome (containing alignment mapping to the descendants). The size of each entry is dependent on the number of descendants.
  • DNA_ARRAY: The DNA bases, stored as two bases / byte
  • SEQUENCE_ARRAY: The names and lengths of subsequences (ie chromosomes or scaffolds in the genome)
  • TOP_ARRAY: The top segments in the genome (containing alignment mapping to the parent). Paralogous top segments are presently stored in a circular linked list.

More information can be found in the manuscript:

Glenn Hickey, Benedict Paten, Dent Earl, Daniel Zerbino, and David Haussler. HAL: A Hierarchichal Format for Storing and Analyzing Multiple Genome Alignments. (submitted)

and API manual.

 /sHuman-sChimp           Group
    Location:  1:204059420
    Links:     1  
 /sHuman-sChimp/BOTTOM_ARRAY Dataset {1595768/1595768}
    Location:  1:365340961
    Links:     1
    Chunks:    {1000} 42000 bytes
    Storage:   67022256 logical bytes, 12879397 allocated bytes, 520.38% utilization
    Filter-0:  deflate-1 OPT {2}
    Filter-1:  deflate-1 OPT {2}
    Type:      struct {
            "genomeIdx"        +0    native long
            "length"           +8    native unsigned long
            "topIdx"           +16   native long
            "childIdx0"        +24   native long
            "reverseFlag0"     +32   native signed char
            "childIdx1"        +33   native long
            "reverseFlag1"     +41   native signed char
    } 42 bytes
 /sHuman-sChimp/DNA_ARRAY Dataset {92368315/92368315}
    Location:  1:253117606
    Links:     1
    Chunks:    {1000} 1000 bytes
    Storage:   92368315 logical bytes, 55478173 allocated bytes, 166.49% utilization
    Filter-0:  deflate-1 OPT {2}
    Filter-1:  deflate-1 OPT {2}
    Type:      native 8-bit field
 /sHuman-sChimp/Meta      Group
    Location:  1:204060452
    Links:     1
 /sHuman-sChimp/Rup       Group
    Attribute: Rup scalar
            Type:      variable-length null-terminated ASCII string
            Data:  "0"
    Location:  1:204061484
    Links:     1
 /sHuman-sChimp/SEQUENCE_ARRAY Dataset {1/1}
    Location:  1:253117878
    Links:     1
    Storage:   96 logical bytes, 96 allocated bytes, 100.00% utilization
    Type:      struct {
            "start"            +0    native unsigned long
            "length"           +8    native unsigned long
             "numSequences"     +16   native unsigned long
            "numBottomSegments" +24   native unsigned long
            "topSegmentArrayIndexOffset" +32   native unsigned long
            "bottomSegmentArrayIndexOffset" +40   native unsigned long
            "name"             +48   384-bit little-endian integer
            (8 bits of precision beginning at bit 0)
            (376 zero bits at bit 8)
    } 96 bytes
 /sHuman-sChimp/TOP_ARRAY Dataset {2273166/2273166}
    Location:  1:253118446
    Links:     1
    Chunks:    {1000} 33000 bytes
    Storage:   75014478 logical bytes, 13067609 allocated bytes, 574.05% utilization
    Filter-0:  deflate-1 OPT {2}
    Filter-1:  deflate-1 OPT {2}
    Type:      struct {
            "genomeIdx"        +0    native long
            "bottomIdx"        +8    native long
            "paralogyIdx"      +16   native long
            "parentIdx"        +24   native long
            "reverseFlag"      +32   native signed char
    } 33 bytes
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