Exhaustive enumeration or derivative genome structures from simple rearrangement types. The simple rearrangement types are the following.
- Deletion
- Tandem duplication
- Unbalanced translocation (can happen intra-chromosomally and between sister chromatids)
- Balanced translocation (can happen intra-chromosomally and between sister chromatics)
- Telomeric break
- Telomeric break and fusion (i.e. one BFB cycle)
- Whole chromosome duplication
- Whole chromosome deletion
- Whole genome duplication
This program supports haploid or diploid wild type genomes with one or many distinct chromosomes.
SimSvGenomes is an unofficial placeholder name for this program.
This program requires glib.
I am not an expert in compiling C code, but here are commands that work for me on Ubuntu Linux.
# Compiling with maximum compiler optimisation (O3)
gcc -O3 rg_enumerator.multi_chr.main.c -lglib-2.0 -I/nfs/users/nfs_y/yl3/programs/glib-2.38.2/glib -I/nfs/users/nfs_y/yl3/programs/glib-2.38.2/ -o rg_enumerator.multi_chr.O3
# Compiling with debugging information - I use Valgrind
gcc -g rg_enumerator.multi_chr.main.c -lglib-2.0 -I/nfs/users/nfs_y/yl3/programs/glib-2.38.2/glib -I/nfs/users/nfs_y/yl3/programs/glib-2.38.2/ -o rg_enumerator.multi_chr
./rg_enumerator.multi_chr.O3 <n_chrs> <diploid> <max_dup_depth> <max_overall_depth>
Options:
n_chrs - integer, number of different chromosomes in the wild type genome.
diploid - 0 or 1, whether the wild type genome is haploid or diploid.
max_dup_depth - integer, maximum number of duplication-type rearrangements
to enumerate.
max_overall_depth - integer, maximum overall number of SVs to exhausively
enumerate.
Duplicating rearrangements are tandem duplication, BFB-induced fold-back inversion and whole-chromosome duplication.
Whole-genome duplication is hardcoded to occur at most once in the history of a simulated derivative genome.
As an example, feel free to try the following command.
./rg_enumerator.multi_chr.O3 2 1 2 2
The output of the program is a space-delimited file with the following columns.
- Detailed history of a simulated genome
- Simple history of a simulated genome
- Allelic copy number portion of the normalised rearrangement pattern string
- Rearrangement portion of the rearrangement pattern string
- Genome string describing the karyotype of the simulated genome
This is the simple history, but each individual rearrangement is appended by an index indicating the order in which it was generated. The two breakpoints of a rearrangement are enumerated in a given somatic genome in a defined order, so detailed history of a simulated genome enable the precise reconstruction of the breakpoint positions of each rearrangement to generate a given simulated genome.
Same as detailed history, but without the indices.
Chromosomes are semicolon-delimited. Segments within chromosomes are delimited by forward slashes ('/'). When run in diploid mode, maternal and paternal copy number of each segment are comma-separated.
Segments above are identified using a zero-based index in the order in which they appear. Rearrangements are forward slash-separated and the low and high end of each rearrangement is separated by a comma.
The normalised genome string of the current derivative chromosome. Every
individual haploid chromosome is described within a pair of curly brackets.
That is, there will be two chromosomes in a wild type genome containing a
single diploid chromosome. Each chromosome contains a semicolon-separated list
of segments, identified by three comma-separated integers. The meaning of the
integers are <segment ID>,<segment is paternal>,<segment is inverted>. Note
that segment IDs in the normalised genome string are distinct from segment IDs
in the rearrangement pattern string.
When this column contains a detailed history notation instead of a genome, string, it means that the detailed history specified in the first column produces a derivative genome with an identical structure to a previously encountered derivative genome that was generated using the detailed history in this column.
There are no chromosomal identities beyond rearrangements patterns present (or simulated) in each chromosome. For the purposes of this program "chr1" and "chr2" are the same thing and produce the same genome string as long as they have the same rearrangement patterns.
Balanced translocations, and direct inversions and fold-back rearrangements are generated with balanced breakpoints. For example, the rearrangement pattern string of '0+,1+/1-,2-'.
When annotating real rearrangement breakpoints in the PCAWG project, we had no way to distinguish balanced from unbalanced breakpoints (do breakpoints have to touch? or have a <10bp distance? or <100bp?). Therefore no breakpoints are annotated as balanced in PCAWG analysis, and therefore a direct inversion in actual PCAWG data would get the rearrangement pattern string '0+,2+/2-,4-', with deleted segments 1 and 3.
There are two ways to consolidate this difference. First way is to ignore it, because a direct inversion '0+,1+/1-,2-' will become '0+,2+/2-,4-' when a subsequent deletion overlaps with one of its breakpoints. So with a sufficient simulation depth, the "unbalanced versions" of balanced breakpoints will be guaranteed to be covered. Secondly, one could simply parse the rearrangement simulator output to convert all balanced breakpoint into their "unbalanced versions".
The maximum depth I have managed to reach with this program is on a single haploid chromosome down to five rearrangements, of which at most four are duplicating rearrangements.
Different depth thresholds are provided for duplicative and non-duplicative rearrangements because duplicative events duplicate existing segments and thus significantly increase the space in which subsequent breakpoints can occur. Whole-genome duplication events are limited to one per history because of the same reason.
The algorithms behind this program are described in some detail in the PCAWG-6 SV mechanisms manuscript. Feel free to contact me if you need more information.
If you would like to cite this work, please cite the PCAWG-6 SV mechanisms manuscript. Coming soon (hopefully...)
Copyright (c) 2014-2017 Genome Research Ltd.
Author: Yilong Li yl3@sanger.ac.uk, liyilong623@gmail.com
SimSvGenomes is free software: you can redistribute it and/or modify it under the terms of the GNU Affero General Public License as published by the Free Software Foundation; either version 3 of the License, or (at your option) any later version.
This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU Affero General Public License for more details.
You should have received a copy of the GNU Affero General Public License along with this program. If not, see http://www.gnu.org/licenses/.