strain_phylogenetics

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strain_phylogenetics

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Tools for analyzing and comparing SARS-CoV-2 phylogenies

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## Tools for analyzing and comparing SARS-CoV-2 phylogenies

[license-badge]: https://img.shields.io/badge/License-MIT-yellow.svg 
[license-link]: https://github.com/yatisht/strain_phylogenetics/blob/master/LICENSE

[![License][license-badge]][license-link]
[![Build Status](https://github.com/yatisht/strain_phylogenetics/workflows/build/badge.svg)](https://github.com/yatisht/strain_phylogenetics/actions)

**Note: UShER (Ultrafast Sample Placement on Existing Trees) has been moved to https://github.com/yatisht/usher.**

This repository provides tools primarily designed for analyzing Nextstrain (http://nextstrain.org/ncov/) and other phylogenies generated for the SARS-CoV-2 genome but is also applicable for other phylogenetic applications. Detailed discussion of the tools can be found in the reference at the bottom of this page. Instructions below demonstrate the usage of these tools through examples.

### Clone the repository
```
    $ git clone https://github.com/yatisht/strain_phylogenetics.git
    $ cd strain_phylogenetics
```

### Install prerequisites and build programs
* Perhaps the simplest build process for this repo on any platform (Windows, Linux or MacOS) is using [Docker](https://www.docker.com/) (see installation instructions [here](https://docs.docker.com/get-docker/)). Once Docker is installed (which takes a few minutes typically), the following two commands would build the programs and start a new bash in an Ubuntu 18.04 container following which the remaining commands on this page should work smoothly.
```
    $ docker build -t strain_phylogenetics .
    $ docker run -t -i strain_phylogenetics /bin/bash
```
* Alternatively, we also provide installation scripts for **MacOS (10.14 and above)**, **Ubuntu (18.04 and above)** and **CentOS (7 and above)** if you don't have Docker or prefer not to use it for some reason.

* For MacOS 10.14 and above: 
```
    $ ./installMacOS.sh  
```
* For Ubuntu 18.04 and above (requires sudo privileges):
```
    $ ./installUbuntu.sh  
```
* For CentOS 7 and above (requires sudo privileges): 
```
    $ ./installCentOS.sh  
```

### Newick and Variant Call Format (VCF) input files

Example files are provided in the subdirectories tree/ and vcf/ .  Phylogenetic trees must be valid [Newick](https://en.wikipedia.org/wiki/Newick_format)-formatted files and variants must be [Variant Call Format (VCF)](https://en.wikipedia.org/wiki/Variant_Call_Format) files that include sample genotypes.  The leaf labels in the Newick files must exactly match the sample names in the VCF header line starting with "#CHROM".  Files in these formats generated from [Nextstrain](https://nextstrain.org/ncov) data are available from the [UCSC Genome Browser](https://genome.ucsc.edu/cgi-bin/hgTrackUi?db=wuhCor1&g=nextstrainSamples).

### Compute most-parsimonious state assignments in a tree for a variant list 
```
    $ ./build/find_parsimonious_assignments --tree tree/pruned-sumtree-for-cog.nh --vcf vcf/pruned-sumtree-for-cog.vcf > pruned-sumtree-for-cog_PARSIMONY.txt
```
* The above command reads the tree topology of the input Newick file and assigns an internal numeric label for each internal node (ignoring the internal labels and branch lengths if already provided by the input Newick). The first two lines of the output file print the input tree with internal nodes labelled in Newick format. The output is too large to display, so we view the first 1000 characters using the command below.

```
    $ head -c 1000 pruned-sumtree-for-cog_PARSIMONY.txt
    > Tree (in newick format) with internal nodes labelled: 
    > ((Shanghai_SH0007_2020,Hangzhou_ZJU-07_2020,Wuhan_IPBCAMS-WH-03_2019,Wuhan_WH01_2019,Wuhan_WIV07_2019,Shanghai_SH0093_2020,Wuhan_HBCDC-HB-01_2019,Wuhan_IPBCAMS-WH-01_2019,Wuhan_IVDC-HB-04_2020,Wuhan_IVDC-HB-05_2019,Wuhan_WIV05_2019,Sweden_01_2020,Taiwan_2_2020,USA_CA2_2020,Shanghai_SH0040_2020,Singapore_7_2020,Australia_VIC02_2020,France_IDF0515_2020,Hangzhou_ZJU-01_2020,Shanghai_SH0037_2020,Nepal_61_2020,Wuhan_HBCDC-HB-03_2019,Wuhan_IVDC-HB-01_2019,Wuhan_WIV06_2019,Wuhan_WIV04_2019,China_WH-09_2020,Wuhan_IPBCAMS-WH-04_2019,Wuhan_IPBCAMS-WH-02_2019,Wuhan_WH03_2020,Jiangxi_IVDC-JX-002_2020,Zhejiang_WZ-01_2020,Japan_KY-V-029_2020,Hangzhou_ZJU-03_2020,Zhejiang_WZ-02_2020,Netherlands_Utrecht_12_2020,Nonthaburi_61_2020,Nonthaburi_74_2020,Hangzhou_ZJU-05_2020,Hangzhou_HZ-1_2020,Singapore_1_2020,Taiwan_NTU02_2020,England_SHEF-BFD36_2020,France_IDF0626_2020,Malaysia_MKAK-CL-2020-7554_2020,Cambodia_0012_2020,Finland_1_2020,England_200641094

```
* For each variant/site in the VCF file, the output file then displays the allele frequency for each alternate variant, its total parsimony score, the list of nodes (comma-separated, if its length is <=4) for which the branches leading to it have acquired a mutation (forward [F] or backward [B], the sizes of the clades affected by those mutations and a list of flagged leaves which are affected by a mutation affecting 3 or fewer leaves. An example line from the file is displayed below.
```
    > G11083T	T_alt_alleles=61	parsimony_score=13		G>T_mutation_nodes=France_IDF0515_2020[F],Hangzhou_ZJU-01_2020[F],Shanghai_SH0037_2020[F],21[F],37[F],48[F],54[F],160[F],81[F],Switzerland_SZ1417_2020[F],Brazil_SPBR-12_2020[F]	T>G_mutation_nodes=Anhui_SZ005_2020[B],Brazil_SPBR-10_2020[B]	G>T_mutation_clade_sizes=1,1,1,26,4,6,15,2,3,1,1	T>G_mutation_clade_sizes=1,1	flagged_leaves=Anhui_SZ005_2020,Brazil_SPBR-10_2020,Brazil_SPBR-12_2020,France_IDF0515_2020,Hangzhou_ZJU-01_2020,Netherlands_Utrecht_1363564_2020,Netherlands_Utrecht_1363628_2020,Netherlands_Utrecht_6_2020,Shanghai_SH0037_2020,Switzerland_SZ1417_2020,USA_AZ1_2020,Yunnan_IVDC-YN-003_2020
```

### Identify extremal sites   
```
    $ python3 scripts/identify_extremal_sites.py -in pruned-sumtree-for-cog_PARSIMONY.txt
```
* The above can be used for identifying and flagging extremal sites i.e. sites having exceptional parsimony scores relative to their allele frequencies and therefore also suspected to contain systematic errors. The above command identifies 6 extremal sites (C11074T, C27046T, T13402G, A3778G, G24390C, G26144T) with a phylogenetic instability value of 3.03. For the precise definition of extremal sites and phylogenetic instability, refer to our manuscript referenced at the bottom. The code also provides an ability to ignore high-frequency C\>T and G\>T mutations using optional flags.
```
    $ python3 scripts/identify_extremal_sites.py -in pruned-sumtree-for-cog_PARSIMONY.txt -ignoreCtoT=1 -ignoreGtoT=1
```
* The above command identifies three extremal sites (T13402G, A3778G, G24390C) with a phylogenetic instability value of 2.32.

### Plot Extremal Sites  
* Plotting extremal sites requires [installing R](https://docs.rstudio.com/resources/install-r/) and the [plyr](https://www.rdocumentation.org/packages/plyr) package. 
```
    $ python3 scripts/generate_plot_extremal_sites_data.py -in pruned-sumtree-for-cog_PARSIMONY.txt > plot_extremal_sites_data.txt
    $ Rscript --vanilla scripts/plot_parsimony.r plot_extremal_sites_data.txt extremal_sites_plot.pdf
```
* The above command first creates raw input data for the extremal sites plot. Next, the R command accepts the generated data and creates a log(allele count) by parsimony plot for all variant sites in a given vcf. It produces three plots, one of all data, one ignoring C>U mutations and one ignoring C>U and G>U mutations, as shown below. 
![Extremal](https://raw.githubusercontent.com/yatisht/strain_phylogenetics/master/images/extremal.png)

### Compute distances between tree pairs
```
    $ python3 scripts/compute_entropy_weighted_tree_distance.py -T1 tree/pruned-cog-for-sumtree.nh  -T2 tree/pruned-sumtree-for-cog.nh -CORES=2 > dist_pruned-cog-for-sumtree_pruned-sumtree-for-cog.txt
```
* The above command computes the entropy-weighted total distance (asymmetric and symmetric) between two trees pruned to contain a common set of 422 SARS-CoV-2 samples: the [COG-UK](https://www.cogconsortium.uk/data/) tree from April 24, 2020 and a consensus tree made using the [SumTrees](https://dendropy.org/programs/sumtrees.html) tool from 31 Nextstrain trees generated between March 23 and April 30, 2020. For detailed description of the distance metric, refer to our manuscript referenced at the bottom. The distance values are printed in the bottom 3 lines of the output file.
```
    $ tail -n 3 dist_pruned-cog-for-sumtree_pruned-sumtree-for-cog.txt
    > D(T1,T2) =  4.263117527652659
    > D(T2,T1) =  1.1491837172916255
    > S(T1,T2) =  2.7061506224721423
```
* The output file also provides the best-matching T2 branch(es), matching split distance and entropy-weighted matching split distance for each branch in T1. An example line in the output file displaying these values for T1 branch labelled 135 is as follows:
```
    > 135 119 6   0.09230354241562243
```

### Rotate trees for tanglegrams
* A common visualization strategy for comparing two tree topologies is to use tanglegrams i.e. plot them side-by-side with common leaves connected by straight lines. A visually appealing tanglegram is one in which corresponding clades in both trees are arranged in the same vertical order and there is a minimum crossing of connecting lines with each other. While node rotation algorithms in the context of tanglegram visualization have been implemented in the [cophylo](https://www.rdocumentation.org/packages/phytools/versions/0.7-20/topics/cophylo) and [Dendroscope3](http://dendroscope.org/) tools, these algorithms are either slow or inadequate for large SARS-CoV-2 phylogenies. We implemented a quick heuristic to produce vastly improved tanglegrams.
```
    $ ./build/rotate_trees --T1 tree/pruned-sumtree-for-cog.nh --T2 tree/pruned-cog-for-sumtree.nh --T1_out rot-pruned-sumtree-for-cog.nh --T2_out rot-pruned-cog-for-sumtree.nh
```
* The above command produces rotated trees (rot-pruned-cog-for-sumtree.nh and rot-pruned-sumtree-for-cog.nh) with a much improved tanglegram as seen below (images generated with the help of [cophylo](https://www.rdocumentation.org/packages/phytools/versions/0.7-20/topics/cophylo) tool, setting rotate to FALSE).

![Rot-tanglegrams](https://raw.githubusercontent.com/yatisht/strain_phylogenetics/master/images/tanglegrams_comparison.png)

* Below is a GIF of approximately 20 frames showing various operations of the tree rotation algorithm operating on a much larger pair of trees (~4k leaves) generated with help from [bpt26](https://github.com/bpt26).

![Rot-gif](https://raw.githubusercontent.com/yatisht/strain_phylogenetics/master/images/rotation.gif)

### Pairwise merging of trees 
```
    $ python3 scripts/tree_merge.py -T1 tree/pruned-sumtree-for-cog.nh -T2 tree/pruned-cog-for-sumtree.nh -symmetric 1 -T_out symm-merged-sumtree-cog.nh  
```
* The above command produces a merged tree (symm-merged-sumtree-cog.nh) from two input trees (pruned-sumtree-for-cog.nh and pruned-cog-for-sumtree.nh) that is maximally resolved and compatible with both input trees (refer to our manuscript referenced at the bottom for more details).  Below are the resulting tanglegrams of the resulting merged tree with the two input trees (after applying tree rotation). The above command can also be used without the symmetric flag for its asymmetric version (where the first input tree is given a priority to resolve the merged tree) or using the intersectOnly flag that produces a simple consensus of the two input trees.

![Merged-tanglegrams](https://raw.githubusercontent.com/yatisht/strain_phylogenetics/master/images/tanglegrams_merged.png)

### Reference
* Yatish Turakhia, Nicola De Maio, Bryan Thornlow, Landen Gozashti, Robert Lanfear, Conor R. Walker, Angie S. Hinrichs, Jason D. Fernandes, Rui Borges, Greg Slodkowicz, Lukas Weilguny, David Haussler, Nick Goldman and Russell Corbett-Detig, "Stability of SARS-CoV-2 Phylogenies", PLOS Genetics 2020 (https://doi.org/10.1371/journal.pgen.1009175).

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