model2_demography_WITH_NEUTRAL.slim

// model2_demography.slim
//
// By Ben Haller, 3 June 2025
// Messer Lab, Cornell University

// This simulates humans with full genomes.  This version adds in the
// demographic model of Gravel (2011).  In addition, it simulates only
// non-neutral mutations, in preparation for using tree-seq recording.
//
// NOTE: This WITH_NEUTRAL version is a special version of model 2 that
// still includes neutral mutations, as in model 1.  This is to see how
// long model 2 takes to run if it includes neutral mutations as well.
// This is not the publication version of model 2!

// This model requires SLiM 5.0 or later to run.  For further information,
// see the publication associated with this repository.


// This user-defined function sets up paths for our data repository
// NOTE: the base repository path needs to be configured for your setup here!
function (void)defineRepositoryPaths(void)
{
	// Set the working directory to our data repository
	defineConstant("REPO_PATH", "/path/to/SimHumanity/");
	if (!fileExists(REPO_PATH))
		stop("incorrect repository path");
	setwd(REPO_PATH);
	
	// This is the subpath to the nuclear chromosome data files
	defineConstant("CHR_PATH", "stdpopsim extraction/extracted/");
	if (!fileExists(CHR_PATH))
		stop("malformed repository; missing extracted data");
	
	// This is the subpath to the mtDNA data files
	defineConstant("MT_PATH", "mtDNA info/");
	if (!fileExists(MT_PATH))
		stop("malformed repository; missing mitochondrial data");
}

// This loads genetic element data from `path` using readCSV() to configure
// the chromosome as a mosaic of coding (g1) and non-coding (g0) regions
// NOTE: in this version of the model, we don't define g0 regions at all.
function (void)initializeGenomicElementsFromFile(string$ gpath)
{
	ge_df = readCSV(gpath, colNames=c("id", "start", "end"));
	ge_ids = ge_df.getValue("id");
	ge_starts = ge_df.getValue("start");
	ge_ends = ge_df.getValue("end");
	coding = (ge_ids == 1);
	initializeGenomicElement(1, ge_starts[coding], ge_ends[coding]);
}

initialize() {
	// Find our data repository and subpaths within it
	defineRepositoryPaths();
	
	// Enable modeling of explicit nucleotides
	initializeSLiMOptions(nucleotideBased=T);
	
	// Enable separate sexes; we want to simulate sex chromosomes
	initializeSex();
	
	// Define constants for the DFE that stdpopsim calls "PosNeg_R24",
	// from Rodrigues et al., 2024 (https://doi.org/10.1093/genetics/iyae006)
	// MU_NEUTR is the neutral mutation rate within coding regions; in
	// non-coding regions all mutations are neutral so it uses MU_TOTAL
	defineConstant("MU_TOTAL", 2.0e-8);
	defineConstant("MU_BENEF", 1e-12);
	defineConstant("MU_DELET", 1.2e-8);
	defineConstant("MU_NEUTR", MU_TOTAL - (MU_BENEF + MU_DELET));
	
	// Mutation type m0: neutral mutations
	// Mutation type m1: deleterious mutations
	// Mutation type m2: beneficial mutations
	initializeMutationTypeNuc("m0", 0.5, "f", 0.0);
	initializeMutationTypeNuc("m1", 0.5, "g", -0.03, 0.16);
	initializeMutationTypeNuc("m2", 0.5, "e", 0.01);
	
	// We use the Jukes-Cantor mutational model with a constant mutation rate
	mutMatrix = mmJukesCantor(MU_TOTAL / 3.0);
	
	// Genomic element type g0: non-coding regions
	// Genomic element type g1: coding regions
	initializeGenomicElementType("g0", m0, 1.0, mutMatrix);
	initializeGenomicElementType("g1", c(m0, m1, m2),
		c(MU_NEUTR, MU_DELET, MU_BENEF), mutMatrix);
	
	// Define the ids, symbols, types, and lengths of all nuclear chromosomes
	ids = 1:24;
	symbols = c(1:22, "X", "Y");
	types = c(rep("A", 22), "X", "Y");
	lengths = c(248956422, 242193529, 198295559, 190214555, 181538259,
		170805979, 159345973, 145138636, 138394717, 133797422, 135086622,
		133275309, 114364328, 107043718, 101991189, 90338345, 83257441,
		80373285, 58617616, 64444167, 46709983, 50818468, 156040895,
		57227415);
	
	for (id in ids, symbol in symbols, type in types, length in lengths)
	{
		initializeChromosome(id, length, type, symbol);
		
		// Use a random initial nucleotide sequence; this could be read from FASTA
		initializeAncestralNucleotides(randomNucleotides(length));
		
		// Read the recombination rate map from a file
		rpath = CHR_PATH + "chr" + symbol + "_recombination.txt";
		initializeRecombinationRateFromFile(rpath, length-1, scale=1.0, sep=",");
		
		// Read the genomic element structure of coding vs. non-coding regions
		// from another file, which gives genomic element types and positions
		gpath = CHR_PATH + "chr" + symbol + "_genomic_elements.txt";
		initializeGenomicElementsFromFile(gpath);
	}
	
	// Handle the mtDNA separately since its data is in a different place
	// It also loads a FASTA file for its sequence, as a proof of concept
	initializeChromosome(25, 16569, "HF", "MT");
	initializeAncestralNucleotides(MT_PATH + "mtDNA_MOD.FASTA");
	initializeRecombinationRate(0.0);
	initializeHotspotMap(20.0);
	initializeGenomicElementsFromFile(MT_PATH + "chrMT_genomic_elements.txt");
}

// INITIALIZE the ancestral African population
1 early() {
	sim.addSubpop("p1", asInteger(round(7310.370867595234)));
}

// END BURN-IN; EXPAND the African population
73105 early() {
	p1.setSubpopulationSize(asInteger(round(14474.54608753566)));
}

// SPLIT Eurasians (p2) from Africans (p1) and SET UP MIGRATION between them
76968 early() {
	sim.addSubpopSplit("p2", asInteger(round(1861.288190027689)), p1);
	p1.setMigrationRates(c(p2), c(15.24422112e-5));
	p2.setMigrationRates(c(p1), c(15.24422112e-5));
}

// SPLIT p2 into European (p2) and East Asian (p3) subpopulations;
// RESIZE p2 to reflect the split; SET UP MIGRATION between them
78084 early() {
	sim.addSubpopSplit("p3", asInteger(round(553.8181989)), p2);
	p2.setSubpopulationSize(asInteger(round(1032.1046957333444)));
	
	p1.setMigrationRates(c(p2, p3), c(2.54332678e-5, 0.7770583877e-5));
	p2.setMigrationRates(c(p1, p3), c(2.54332678e-5, 3.115817913e-5));
	p3.setMigrationRates(c(p1, p2), c(0.7770583877e-5, 3.115817913e-5));
}

// EXPONENTIAL GROWTH in Europe (p2) and East Asia (p3)
78084:79024 early() {
	t = community.tick - 78084;
	p2_size = round(1032.1046957333444 * (1 + 0.003784324268)^t);
	p3_size = round(553.8181989 * (1 + 0.004780219543)^t);
	
	p2.setSubpopulationSize(asInteger(p2_size));
	p3.setSubpopulationSize(asInteger(p3_size));
}

// OUTPUT AND TERMINATE
79024 late() {
}