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SC2Epistasis

This repository contains the code for reproducing the results of the manuscript: Epistasis and the changing fitness landscapes of SARS-CoV-2.

Overview

The manuscript builds on the clade specific fitness effects of amino acid mutations obtained from SARS2-mut-fitness-v2, based on the mutation counts from the UShER tree. A minimal epistatic model is inferred by minimization of an objective function defined from the discrepancies of fitness effects across clades.

Repository structure

  • data/: contains input files such as mutational effects and clade founder mutations.
  • results/: contains numerical output files and in the results/figures/ subdirectory, plots appearing in the manuscript.
  • script/: scripts to perform the analysis and generate the figures.
  • src/: source code for major functions definition.
  • Project.toml and Manifest.toml: files containing dependencies for environment reproducibility.

Main output files

  • results/delta_fit.csv: dataframe reporting the fitness effects of mutations in pairs of clades whose founders differ at least for one mismatch.
  • results/clade_diff.csv: dataframe summarizing the mismatches between clade founders.
  • fit_zscore_epi.jld2: JLD file quantifying the raw epistatic signal.
  • results/jcoup_l1_1em3_3d.csv: dataframe storing the inferred epistatic couplings. Columns include:
    • $\sigma^{wt}_i$: wildtype amino acid at site i.
    • $i$: residue index of site i.
    • $\sigma_i$: mutant amino acid at site i.
    • $j$: residue index of site j.
    • $\sigma_j$: background amino acid at site j.
    • $J$: inferred coupling $J_{ij}(\sigma_i, \sigma_j; \sigma^{wt}_i)$.

Main scripts

  • script/delta_fit.jl: script to generate the dataframe with fitness effects between pairs of clades.
  • script/init_inf.jl: script to initialize the structs used for inference.
  • script/infer_couplings.jl: script to infer the epistatic couplings by minimizing the objective

Main source code

  • src/types.jl: definition of tailored structs used for inference.
  • src/numerical_optim.jl : definition of the optimization algorithm.

Code

The code for performing the analysis relies on the Julia programming language. To run the code, follow the steps below.

Clone the repository

git clone git@github.com:neherlab/SC2Epistasis.git

Set up Julia environment

Navigate to the repository directory and open the Julia REPL with the number of desired threads from the shell:

julia -t <number_of_threads>

Switch to the package manager by pressing ]. Then, you need to activate and instantiate the environment:

(@v1.11) pkg> activate .
(SC2Epistasis) pkg> instantiate

If you use Julia for the first time, you may also need to build the PyCall package in order to use the matplolib plotting library:

julia> ENV["PYTHON"]=""
(SC2Epistasis) pkg> build PyCall

You can now import the module SC2Epistasis in the Julia REPL:

julia> using SC2Epistasis

Which contains the functions defined in the src/ directory. After the first installation, you can run code from the REPL simply by:

shell> julia -t <number_of_threads>
(SC2Epistasis) pkg> activate .
julia> using SC2Epistasis

Running scripts

You can run the scripts in the script/ directory from the Julia REPL using the include function, i.e.:

julia> include("script/<script_name>.jl")

Every script imports the required packages and defines additional necessary functions.

Infer coupling parameters

In order to infer the coupling parameters, run the script:

julia> include("script/infer_couplings.jl")

This implicitly runs the script script/init_inf.jl, which initializes the tailored structs used for inference:

  • data::Vector{Data}: structs array containing the input data.
  • optx::Vector{Optx}: structs array containing the optimization parameters.
  • qform::Vector{QForm}: structs array containing the parameters of the quadratic form.

Then, it runs the inference function learn(optx, qform, l1_vec; kwargs...) which returns the optimal value of the objective and modify in place the coupling parameters stored in optx.

References