Colate

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Software for inferring coalescence rates for unphased, low-coverage genomes

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# Colate

**Software for inferring coalescence rates for unphased, low-coverage genomes.**
- Required input: Two samples specified in bcf/bam format 
- Requires mutation ages obtained from a genealogy (e.g., using [Relate](https://myersgroup.github.io/relate/)). Precomputed mutation ages available below.
- That's it!

Please send any comments, questions and bug reports to leo.speidel@outlook.com. 
Paper describing the method: https://academic.oup.com/mbe/article/38/9/3497/6299394 
Preprint: https://www.biorxiv.org/content/10.1101/2021.02.17.431573v1

![alt text](https://github.com/leospeidel/Colate/blob/master/plot_LBK_Loschbour.png)

# Example scripts and data

A working example using chromosome 1 of two ancient human genomes (LBK and Loschbour; [Lazaridis et al., Nature 2014](https://www.nature.com/articles/nature13673)) can be downloaded from [here](https://www.dropbox.com/s/7koyq7mfow7fx0r/colate_example.tgz?dl=0) (512Mb). 
The same example for all chromosomes is available [here](https://www.dropbox.com/s/5yz8tdgg97dfe3e/colate_example_wg.tgz?dl=0) (7Gb).

# Installation

**Precompiled binaries for several platforms can be found under ./binaries.**

Requirements*:

- C++11
- cmake
- ZLIB
- OpenSSL
- lzma

*On my cluster, I have to load modules CMake, GCC, and BCFtools to compile. 
*On a Mac, I installed CMake and openssl@1.1 using homebrew and updated paths in lines 24-29 of CMakeLists.txt.

To compile from source use
```` bash
cd build
cmake ..
make
````

Colate uses a modifed version of [htslib](https://github.com/samtools/htslib), which has been copied to ./include/vcf/.

# Documentation

## Files required:
- Two sequences, in bcf or bam format, for which coalescence rates will be calculated
- A reference genome in fasta format (see below)
- Genome mask file (optional), to filter out unreliable regions.
- Mutation ages obtained from a genealogy (see below for precomputed mutation ages)

We provide a preprocessed file for the SGDP data (aligned to GRCh37) here: [SGDP_mutages.tar](https://www.dropbox.com/s/pysvzyx68553wxx/SGDP_mutages.tar?dl=0) (654Mb). 
A human reference genome (GRCh37) in the required format (i.e., separated by chromosome): [GRCh37.tgz](https://www.dropbox.com/s/mazsr64cndlblo3/GRCh37.tgz?dl=0) (512Mb)

## Step 1

**(not needed if using SGDP genealogy from above, you can simply download these files above)**

Get mutations ages from a genealogy; this step will add fixed mutations to a *.mut file (see [Relate documentation](https://myersgroup.github.io/relate/getting_started.html#Output) for file format), which is needed for Colate.

- ancestral genome in fasta format
- reference genome in fasta format
- anc/mut files of a Relate genealogy
- bcf of samples used to build Relate genealogy
Link to human ancestral genomes can be found [here](https://myersgroup.github.io/relate/input_data.html#Data).

```` bash
chr=1
${PATH_TO_BINARY}/Colate --mode preprocess_mut \
	--anc example_chr${chr}.anc.gz \
	--mut example_chr${chr}.mut.gz \
	--reference_bcf example_chr${chr}.bcf \
	--ref_genome GRCh37_chr${chr}.fa.gz \
	--anc_genome human_ancestor_${chr}.fa.gz \
	--mask example_mask_chr${chr}.fa \
	-o example_fixed_chr${chr}
	
#output is example_fixed_chr${chr}.mut
````

## Step 2: Run Colate

You can either directly run Colate on bcfs or bams, or precompute an input file, which is beneficial when running Colate repeatedly on the same samples.

### Precompute Colate input files and then run Colate
#### 1. Precompute Colate input files for target and reference:

**bcfs**:
- bcfs contain samples of interest (Please use e.g., bcftools view -S or -s to subset bcf files).
- chr.txt: Chromosome names, one per line (can be any strings)
- If chromosome names are "1", "2", etc, then input files are *\_chr1.bcf, *\_chr2.bcf etc.
- target\_masks and ref\_genome should be separated by chromosome, i.e. GRCh37\_chr1.fa.gz, GRCh37\_chr2.fa.gz etc.
- Target masks are given as fasta files, with "P" for passing and "N" for non-passing bases (one file per chromosome). These should always be specified when input is calculated from a BCF. The mask should indicate where the sample was callable, such that we know where the sample is homozygous REF.
- If --chr is not specified, full file names are required (e.g., --target example.bcf), however these should only contain a single chromosome.

```` bash
mut="example_fixed" #name of .mut files obtained from step 1 (or downloaded)
${PATH_TO_BINARY}/Colate \
	--mode make_tmp \
	--mut ${mut} \
	--target_bcf example_target \ 
	--target_mask target_mask \
	--ref_genome GRCh37 \
        --chr chr.txt \
	-o example_out
	
#output is example_out.colate.in
````

**bam**:
- bam should be sorted by chromosome name (same order as in chr.txt), and by position.
- ref_genome should be separated by chromosome, i.e. GRCh37\_chr1.fa.gz, GRCh37\_chr2.fa.gz etc.
- chr.txt: Chromosome names, one per line (can be any strings but consistent with file names)

```` bash
mut="example_fixed" #name of .mut files obtained from step 1 (or downloaded)
${PATH_TO_BINARY}/Colate \
	--mode make_tmp \
	--mut ${mut} \
	--target_bam example_target.bam \ 
	--ref_genome GRCh37 \
        --chr chr.txt \
	-o example_out
	
#output is example_out.colate.in
````

#### 2. Compute coalescenece rates

- Mask files are not necessary if already specified earlier, unless you want to specifically mask out further regions of the genome.

```` bash
#Optional:
#--target_mask, --reference_mask, 
#--target_age, --reference_age (specified in years)
#--years_per_gen, --num_bootstrap
#--coal is used to specify arbitrary epoch boundaries and initial coalescence rates (file format .coal).

mut="example_fixed" #name of .mut files obtained from step 1 (or downloaded)
bins="3,7,0.2" #epochs in log10 years (format: start,end,stepsize)
${PATH_TO_BINARY}/Colate \
	--mode mut \
	--mut ${mut} \
	--target_tmp example_target.colate.in \
	--reference_tmp example_reference.colate.in \
        --bins ${bins} \
	--chr chr.txt \
	--num_bootstrap 20 \
	--target_age 1000 \
	--reference_age 0 \
	--years_per_gen 28 \
	-o example_out
	
#output is example_out.coal, see bottom of page for file format.
````

### Run directly on bcfs or bams

#### bcfs

- If chromosome names are "1", "2", etc, then input files are *\_chr1.bcf, *\_chr2.bcf etc.
- If --chr is not specified, full file names are required (e.g., --target example.bcf), however these should only contain a single chromosome.
- chr.txt: Chromosome names, one per line (can be any strings)
- Target and reference masks are given as fasta files, with "P" for passing and "N" for non-passing bases (one file per chromosome). These should always be specified when input is calculated from a BCF. The masks should indicate, where the sample was callable, such that we know where the sample is homozygous REF.

```` bash
#--target_mask, --reference_mask, 
#--target_age, --reference_age (specified in years)
#--years_per_gen, --num_bootstrap are optional
#--coal is used to specify arbitrary epoch boundaries and initial coalescence rates (file format .coal).

#age is specified in years.
#Assumption is any site not in the bcf is homozygous reference (unless masked out by a mask file).

mut="example_fixed" #name of .mut files obtained from step 1 (or downloaded)
bins="3,7,0.2" #epochs in log10 years (format: start,end,stepsize)
${PATH_TO_BINARY}/Colate \
	--mode mut \
	--mut ${mut} \
	--target_bcf example_target \
	--reference_bcf example_reference \
        --ref_genome GRCh37_chr${chr}.fa.gz \
	--target_mask target_mask \
	--reference_mask reference_mask \
	--bins ${bins} \
	--chr chr.txt \
	--num_bootstrap 20 \
	--target_age 1000 \
	--reference_age 0 \
	--years_per_gen 28 \
	-o example_out
	
#output is example_out.coal, see bottom of page for file format.
````

#### bam

- bams should be sorted by chromosome name (same order as in chr.txt), and by position.
- ref_genome should be separated by chromosome, i.e. GRCh37\_chr1.fa.gz, GRCh37\_chr2.fa.gz etc.
- chr.txt: Chromosome names, one per line (can be any strings)

```` bash
#--target_age, --reference_age (specified in years)
#--years_per_gen, --num_bootstrap are optional
#--coal is used to specify arbitrary epoch boundaries and initial coalescence rates (file format .coal).

mut="example_fixed" #name of .mut files obtained from step 1 (or downloaded)
bins="3,7,0.2" #epochs in log10 years (format: start,end,stepsize)
${PATH_TO_BINARY}/Colate \
	--mode mut \
	--mut ${mut} \
	--target_bam example_target.bam \
	--reference_bam example_reference.bam \
        --ref_genome GRCh37 \
	--bins ${bins} \
	--chr chr.txt \
	--num_bootstrap 20 \
	--target_age 1000 \
	--reference_age 0 \
	--years_per_gen 28 \
	-o example_out
	
#output is example_out.coal, see bottom of page for file format.
````

# Output format

*coal files (see [Relate documentation](https://myersgroup.github.io/relate/modules.html#PopulationSizeScript_FileFormats) for file format).
These can be loaded using the [relater R package](https://github.com/leospeidel/relater).

```` R
library(relater)
coal <- read.coal("example_out.coal") #group2 indexes bootstrap iterations
````
Summarize bootstrap iterations:
```` R
library(dplyr)
coal %>% group_by(epoch.start) %>% 
 summarize(mean = mean(haploid.coalescence.rate), 
	 lower = quantile(haploid.coalescence.rate, prob = 0.025), 
		 upper = quantile(haploid.coalescence.rate, prob = 0.975)) -> coal
````

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