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SHM.cpp
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SHM.cpp
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#include <iostream>
#include <fstream>
#include <map>
#include <algorithm> // for replace function
#include "SHM.h"
#include "cell.h"
#include<vector>
#include<string>
#include <random>
#include <regex>
#include <boost/math/distributions/inverse_gamma.hpp>
#include <boost/algorithm/string.hpp>
#include <time.h>
#include <experimental/filesystem>
#include <sstream>
#include <iterator>
#include <experimental/filesystem>
using namespace std;
///R-SHM
#include "random.h"
#include "SHM.h"
///R-SHM
std::map<std::string, std::vector<float>> Seq_affinity;
std::map<std::string, std::map<std::string, std::map<int, std::map<std::string, std::string>>>> Restricted_db;
std::map<std::vector<std::string>, std::vector<float>> CDRs_affinity;
std::map<std::vector<std::string>, std::string> FWRs_db;
std::map<std::string, std::vector<float>> Seq_affinity_original;
std::map<std::string, std::map<std::string, std::map<int, std::map<std::string, std::string>>>> Restricted_db_original;
std::map<std::vector<std::string>, std::vector<float>> CDRs_affinity_original;
std::map<std::vector<std::string>, std::string> FWRs_db_original;
static std::mt19937 generator(global_seed+3);
static std::mt19937 generator2(global_seed +1532);
std::default_random_engine generator_fasta(global_seed +1);
static std::mt19937 gen(global_seed +2);
void confirmBCR(vector<float> &BCReceptor, std::string sequence, std::map<std::string, std::string> AA_REGIONS, int mother_ID, int cell_ID) {
string const Sequence_path= base_Path + "/" + "bcinflow09/Sequence_db.csv";
fstream database;
std::ifstream database2 (Sequence_path);
string const Sequence_path_restricted= base_Path + "/" + "bcinflow09/Restricted_db.csv";
fstream database_restricted;
std::ifstream database2_restricted (Sequence_path_restricted);
string const Sequence_path_CDR= base_Path + "/" + "bcinflow09/CDRs_db.csv";
fstream database_CDRs;
std::ifstream database2_CDRs (Sequence_path_CDR);
string const Sequence_path_FWRs= base_Path + "/" + "bcinflow09/FWRs_db.csv";
fstream database_FWRs;
std::ifstream database2_FWRs (Sequence_path_FWRs);
if (Seq_affinity.size() == 0) {
database.open(Sequence_path,fstream::app);
// If file does not exist, Create new file
if (!database )
{
cout << "Cannot open file, file does not exist. Creating new file.." << endl;
database.close();
database.open(Sequence_path, fstream::out);
//database.close();
}
database.close();
database_restricted.open(Sequence_path_restricted,fstream::app);
// If file does not exist, Create new file
if (!database_restricted )
{
cout << "Cannot open file, file does not exist. Creating new file.." << endl;
database_restricted.close();
database_restricted.open(Sequence_path_restricted, fstream::out);
//database.close();
}
database_restricted.close();
database_CDRs.open(Sequence_path_CDR,fstream::app);
// If file does not exist, Create new file
if (!database_CDRs )
{
cout << "Cannot open file, file does not exist. Creating new file.." << endl;
database_CDRs.close();
database_CDRs.open(Sequence_path_CDR, fstream::out);
//database.close();
}
database_CDRs.close();
database_FWRs.open(Sequence_path_FWRs,fstream::app);
// If file does not exist, Create new file
if (!database_FWRs )
{
cout << "Cannot open file, file does not exist. Creating new file.." << endl;
database_FWRs.close();
database_FWRs.open(Sequence_path_FWRs, fstream::out);
//database.close();
}
database_FWRs.close();
int iy = 0;
vector<string> row;
string line, word, temp;
if (database2.is_open())
{
while (database2.good()) {
iy +=1;
row.clear();
if (getline(database2, line, '\n' )) //test the read for success
{
if (line.length() != 0) {
istringstream s(line);
while (std::getline(s, word, ',')) {
row.push_back(word);
}
Seq_affinity[row[0]] = {std::stof(row[1]), std::stof(row[2]), std::stof(row[3]),std::stof(row[4])};
}
else
{
cout << "failed to read file" << endl;
}
}
}
database2.close();
}
Seq_affinity_original=Seq_affinity;
int iy_restricted = 0;
vector<string> row_restricted;
string line_restricted, word_restricted, temp_restricted;
if (database2_restricted.is_open())
{
while (database2_restricted.good()) {
iy_restricted +=1;
row_restricted.clear();
if (getline(database2_restricted, line_restricted, '\n' )) //test the read for success
{
if (line_restricted.length() != 0) {
istringstream s_restricted(line_restricted);
while (std::getline(s_restricted, word_restricted, ',')) {
row_restricted.push_back(word_restricted);
}
Restricted_db[row_restricted[0]][row_restricted[1]][std::stof(row_restricted[2])][row_restricted[3]] = row_restricted[4];
}
else
{
cout << "failed to read file" << endl;
}
}
}
database2_restricted.close();
}
Restricted_db_original=Restricted_db;
vector<string> row_CDR;
string lineCDR, wordCDR;
if (database2_CDRs.is_open())
{
while (database2_CDRs.good()) {
row_CDR.clear();
if (getline(database2_CDRs, lineCDR, '\n' )) //test the read for success
{
if (lineCDR.length() != 0) {
istringstream sCDR(lineCDR);
while (std::getline(sCDR, wordCDR, ',')) {
row_CDR.push_back(wordCDR);
}
CDRs_affinity[{row_CDR[0], row_CDR[1],row_CDR[2]}] = {std::stof(row_CDR[3]), std::stof(row_CDR[4]), std::stof(row_CDR[5]),std::stof(row_CDR[6])};
}
else
{
cout << "failed to read file" << endl;
}
}
}
database2_CDRs.close();
}
CDRs_affinity_original=CDRs_affinity;
vector<string> row_FWR;
string lineFWR, wordFWR;
if (database2_FWRs.is_open())
{
while (database2_FWRs.good()) {
row_FWR.clear();
if (getline(database2_FWRs, lineFWR, '\n' )) //test the read for success
{
if (lineFWR.length() != 0) {
istringstream sFWR(lineFWR);
while (std::getline(sFWR, wordFWR, ',')) {
row_FWR.push_back(wordFWR);
}
if (row_FWR[1]!= "") {
FWRs_db[{row_FWR[0], row_FWR[1]}] = row_FWR[2];
} else {
//cout << lineFWR <<endl;
}
}
else
{
cout << "failed to read file" << endl;
}
}
}
database2_FWRs.close();
}
FWRs_db_original=FWRs_db;
}
vector<float> results;
if (Seq_affinity.find(sequence)!= Seq_affinity.end()) {
results=Seq_affinity.find(sequence)->second;
BCReceptor[0]=results[0];
BCReceptor[1]=results[1];
BCReceptor[2]=results[2];
BCReceptor[3]=results[3];
if(mother_ID==-1) {
if (FWRs_db.find({"FWR1", AA_REGIONS["FWR1"]})== FWRs_db.end() ) {
FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]="N";
}
if (FWRs_db.find({"FWR2", AA_REGIONS["FWR2"]})== FWRs_db.end() ) {
FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]="N";
}
if (FWRs_db.find({"FWR3", AA_REGIONS["FWR3"]})== FWRs_db.end() ) {
FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]="N";
}
if (FWRs_db.find({"FWR4", AA_REGIONS["FWR4"]})== FWRs_db.end() ) {
FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]="N";
}
if (CDRs_affinity.find({AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}) == CDRs_affinity.end() && FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]=="N" && FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]=="N" && FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]=="N" && FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]=="N") {
CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}] = {BCReceptor[0],BCReceptor[1],BCReceptor[2],BCReceptor[3]};
}
if (CDRs_affinity.find({AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}) != CDRs_affinity.end() && FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]=="N" && FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]=="N" && FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]=="N" && FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]=="N") {
if(BCReceptor[0]!=CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}][0] ||
BCReceptor[1]!=CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}][1] ||
BCReceptor[2]!=CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}][2] ||
BCReceptor[3]!=CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}][3]){
cout<<"Same CDRs, different affinity! Check CDRs "<<AA_REGIONS["CDR1"]<<" "<<AA_REGIONS["CDR2"]<<" "<<AA_REGIONS["CDR3"]<<endl;
}
}
}
} else if (CDRs_affinity.find({AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}) != CDRs_affinity.end() && FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]=="N" && FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]=="N" && FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]=="N" && FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]=="N"){
//cout<<"CDR_aff"<<endl;
results=CDRs_affinity.find({AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]})->second;
BCReceptor[0]=results[0];
BCReceptor[1]=results[1];
BCReceptor[2]=results[2];
BCReceptor[3]=results[3];
Seq_affinity[sequence] = {BCReceptor[0],BCReceptor[1],BCReceptor[2],BCReceptor[3]};
if(mother_ID==-1) {
cout<<"Founder cell " << cell_ID << "not found in Seq db" <<endl;
}
} else {
//cout<<"Strangely last"<<endl;
if(FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]=="L" || FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]=="L" || FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]=="L" || FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]=="L" ){
//cout<<"Lethal"<<endl;
Seq_affinity[sequence] = {9,9,9,9};
} else {
Seq_affinity[sequence] = {BCReceptor[0],BCReceptor[1],BCReceptor[2],BCReceptor[3]};
}
if(mother_ID==-1) {
cout<<"Founder cell " << cell_ID << "not found in Seq db" <<endl;
}
}
if (CDRs_affinity.find({AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}) == CDRs_affinity.end() && FWRs_db[{"FWR1", AA_REGIONS["FWR1"]}]=="N" && FWRs_db[{"FWR2", AA_REGIONS["FWR2"]}]=="N" && FWRs_db[{"FWR3", AA_REGIONS["FWR3"]}]=="N" && FWRs_db[{"FWR4", AA_REGIONS["FWR4"]}]=="N") {
//cout<<"Added to CDRs_aff"<<endl;
CDRs_affinity[{AA_REGIONS["CDR1"],AA_REGIONS["CDR2"],AA_REGIONS["CDR3"]}] = {BCReceptor[0],BCReceptor[1],BCReceptor[2],BCReceptor[3]};
}
}
void setGermBCR(vector<float> &BCReceptor, vector<float> &Germ_BCR, int mother_ID) {
if (mother_ID == -1) {
Germ_BCR=BCReceptor;
}
}
///1. Load FASTA files
void add_seq_to_Restricted (std::map<std::string, std::string> & AA_REGIONS, std::string sequence_name) {
if (Restricted_db.find(sequence_name)== Restricted_db.end()) {
std::vector<string> regions= {"FWR1","FWR2","FWR3","FWR4"};
for(int reg =0; reg < regions.size(); reg++) {
for(int aas=0; aas < AA_REGIONS[regions[reg]].length() ; aas++) {
Restricted_db[sequence_name][regions[reg]][aas][string(1,AA_REGIONS[regions[reg]][aas])] = "Neutral";
if (string(1,AA_REGIONS[regions[reg]][aas]).compare("")==0 || Restricted_db[sequence_name][regions[reg]][aas][string(1,AA_REGIONS[regions[reg]][aas])].compare("")==0) {
cout << "add_seq_to_Restricted"<<endl;
}
}
}
}
}
////1.1. Check DNA from fasta is DNA
bool checkDNA(std::string DNA){
bool Unvalid = false;
for (int i = 0; i < DNA.length(); i++) {
if (DNA[i] != 'C' && DNA[i] != 'A' && DNA[i] != 'G' && DNA[i] != 'T'){
Unvalid = true;
break;
}
}
return Unvalid;
}
////1.2.DNA to RNA
void findAndReplaceAll(std::string & data, std::string toSearch, std::string replaceStr)
{
// Get the first occurrence
size_t pos = data.find(toSearch);
// Repeat till end is reached
while( pos != std::string::npos)
{
// Replace this occurrence of Sub String
data.replace(pos, toSearch.size(), replaceStr);
// Get the next occurrence from the current position
pos =data.find(toSearch, pos + toSearch.size());
}
}
///FUTURE:
///1.3. Find paths of fasta files
void findFastas(std::string path) { //Fastas have to end in .fasta
for (const auto & entry : std::experimental::filesystem::directory_iterator(path)) {
if (!entry.path().extension().compare(".fasta")) {
fastas.push_back(entry.path());
}
}
}
///1.4. mapToString
std::string mapToString(std::map<std::string, std::vector<int>> &m) {
std::stringstream result2;
int ida = 1;
for (auto it = m.cbegin(); it != m.cend(); it++) {
if (ida != 1) {
result2 << "/";
}
result2 << it->first << ":";
std::copy(it->second.begin(), it->second.end(), std::ostream_iterator<int>(result2, "-"));
ida +=1;
}
return result2.str();
}
std::string mapToString2(std::map<std::string, std::string> &m) {
std::stringstream result2;
int ida = 1;
for(auto& kv : m) {
if (ida != 1) {
result2 << "/";
}
result2 << kv.first << ':' << kv.second;
ida +=1;
}
std::string resultados = result2.str();
if (!resultados.empty() && resultados[resultados.length()-1] == '\n') {
resultados.erase(resultados.length()-1);
}
return result2.str();
}
///1.5 Load sequence, regions and mutations in B-cell
void getSequence(std::map<std::string, std::string> & REGIONS, std::map<std::string, std::vector<int>> & MUTATIONS, std::string &sequence, std::string &germline_name, int &ORF) {
int argc = 2;
bool All_not_OK= true;
do {
if (fastas.size () == 0) {
findFastas(fasta_path);
}
if (fastas_remaining.size() == 0) {
fastas_remaining=fastas;
std::random_device rd;
static auto rng = std::default_random_engine {};
std::shuffle(std::begin(fastas_remaining), std::end(fastas_remaining), generator_fasta);
}
std::string input = fastas_remaining.back();
fastas_remaining.pop_back();
germline_name=std::experimental::filesystem::path(input).filename();
//const char *argv[] = {"/home/rgarcia/Escritorio/NGly_scripts/Fastas/seq.fasta"}; ///R cambiar en algun momento a parametro
if( argc <= 1 ){
std::cerr << "Usage: "<<input<<" [infile]" << std::endl;
}
std::ifstream input3(input, std::ios::binary);
if(!input3.good()){
std::cerr << "Error opening '"<<input<<"'. Bailing out." << std::endl;
}
std::string line, name, content;
while( std::getline( input3, line )){
if( line[0] == '>' ){ // Identifier marker
if( !line.empty() ){
name = line.substr(1);
}
content.clear();
} else if( !name.empty() ){
boost::to_upper(line);
if( line.find(' ') != std::string::npos ){ // Invalid sequence--no spaces allowed
std::cerr << "Error, check FASTA file. Bailing out." << std::endl;
} else {
if ( checkDNA(line)) {
std::cerr << "Error, check strange characters in FASTA line :" << line << ". Bailing out." << std::endl;
};
findAndReplaceAll(line, "T", "U");
content += line;
REGIONS[name]=content;
}
} else if ( line.empty()) {
std::cerr << "Error, check FASTA file. Bailing out." << std::endl;
}
}
if (REGIONS.size() != 7) {
std::cerr << "Error, check FASTA file FWR and CDR nomenclature. Bailing out." << std::endl;
}
sequence= REGIONS["FWR1"] +REGIONS["CDR1"] +REGIONS["FWR2"] +REGIONS["CDR2"] +REGIONS["FWR3"] +REGIONS["CDR3"] +REGIONS["FWR4"] ;
All_not_OK= false;
ORF=1;
if(isThereAnStop(DNAtoprotein(sequence))) {
cout << "A seq "<< input << " has no good 1st ORF" << endl;
std::map<std::string, std::string> tmporal =REGIONS;
REGIONS["FWR1"].erase(0,1);
ORF=2;
sequence= REGIONS["FWR1"] +REGIONS["CDR1"] +REGIONS["FWR2"] +REGIONS["CDR2"] +REGIONS["FWR3"] +REGIONS["CDR3"] +REGIONS["FWR4"] ;
if(isThereAnStop(DNAtoprotein(sequence))) {
ORF=3;
REGIONS["FWR1"].erase(0,1);
sequence= REGIONS["FWR1"] +REGIONS["CDR1"] +REGIONS["FWR2"] +REGIONS["CDR2"] +REGIONS["FWR3"] +REGIONS["CDR3"] +REGIONS["FWR4"] ;
} if(isThereAnStop(DNAtoprotein(sequence))) {
cout << "A seq "<< input << " has no valid ORF" << endl;
ORF=454;
All_not_OK= true;
}
}
} while (All_not_OK);
MUTATIONS = {
{ "FWR1", vector<int>(REGIONS["FWR1"].length()) },
{ "FWR2", vector<int>(REGIONS["FWR2"].length()) },
{ "FWR3", vector<int>(REGIONS["FWR3"].length()) },
{ "FWR4", vector<int>(REGIONS["FWR4"].length()) },
{ "CDR1", vector<int>(REGIONS["CDR1"].length()) },
{ "CDR2", vector<int>(REGIONS["CDR2"].length()) },
{ "CDR3", vector<int>(REGIONS["CDR3"].length()) },
};
}
///2. Conversion to AA, NGly detection, STOP detection
////2.1. Conversion to AA
std::string DNAtoprotein (std::string newSequence) {
int firstBase, secondBase, thirdBase;
std::string protein ="";
char aminoAcid[4][4][4]; ////CONFIRMAR QUE ESTA BIEN! :D
//A = 0, C = 1, G = 2, U = 3
//phenylalanine - F
aminoAcid[3][3][3] = 'F';
aminoAcid[3][3][1] = 'F';
//Leucine - L
aminoAcid[3][3][0] = 'L';
aminoAcid[3][3][2] = 'L';
//Serine - S
aminoAcid[3][1][3] = 'S';
aminoAcid[3][1][1] = 'S';
aminoAcid[3][1][0] = 'S';
aminoAcid[3][1][2] = 'S';
//tyrosine - Y
aminoAcid[3][0][3] = 'Y';
aminoAcid[3][0][1] = 'Y';
//stop codon
aminoAcid[3][0][0] = '.';
aminoAcid[3][0][2] = '.';
//cysteine - C
aminoAcid[3][2][3] = 'C';
aminoAcid[3][2][1] = 'C';
//stop codon
aminoAcid[3][2][0] = '.';
//tryptophan - W
aminoAcid[3][2][2] = 'W';
//leucine - L
aminoAcid[1][3][3] = 'L';
aminoAcid[1][3][1] = 'L';
aminoAcid[1][3][0] = 'L';
aminoAcid[1][3][2] = 'L';
//proline - P
aminoAcid[1][1][3] = 'P';
aminoAcid[1][1][1] = 'P';
aminoAcid[1][1][0] = 'P';
aminoAcid[1][1][2] = 'P';
//histidine - H
aminoAcid[1][0][3] = 'H';
aminoAcid[1][0][1] = 'H';
//glutamine - Q
aminoAcid[1][0][0] = 'Q';
aminoAcid[1][0][2] = 'Q';
//arginine - R
aminoAcid[1][2][3] = 'R';
aminoAcid[1][2][1] = 'R';
aminoAcid[1][2][0] = 'R';
aminoAcid[1][2][2] = 'R';
//isoleucine - I
aminoAcid[0][3][3] = 'I';
aminoAcid[0][3][1] = 'I';
aminoAcid[0][3][0] = 'I';
//methionine(start codon) - M
aminoAcid[0][3][2] = 'M';
//threonine -T
aminoAcid[0][1][3] = 'T';
aminoAcid[0][1][1] = 'T';
aminoAcid[0][1][0] = 'T';
aminoAcid[0][1][2] = 'T';
//asparagine - N
aminoAcid[0][0][3] = 'N';
aminoAcid[0][0][1] = 'N';
//lysine - K
aminoAcid[0][0][0] = 'K';
aminoAcid[0][0][2] = 'K';
//serine - S
aminoAcid[0][2][3] = 'S';
aminoAcid[0][2][1] = 'S';
//arginine - R
aminoAcid[0][2][0] = 'R';
aminoAcid[0][2][2] = 'R';
//valine - V
aminoAcid[2][3][3] = 'V';
aminoAcid[2][3][1] = 'V';
aminoAcid[2][3][0] = 'V';
aminoAcid[2][3][2] = 'V';
//alanine - A
aminoAcid[2][1][3] = 'A';
aminoAcid[2][1][1] = 'A';
aminoAcid[2][1][0] = 'A';
aminoAcid[2][1][2] = 'A';
//aspartic acid - D
aminoAcid[2][0][3] = 'D';
aminoAcid[2][0][1] = 'D';
//glutamic acid - E
aminoAcid[2][0][0] = 'E';
aminoAcid[2][0][2] = 'E';
//glycine - G
aminoAcid[2][2][3] = 'G';
aminoAcid[2][2][1] = 'G';
aminoAcid[2][2][0] = 'G';
aminoAcid[2][2][2] = 'G';
bool isthereadot = false;
for(int i = 0; i < newSequence.length() - 2; i += 3)
{
if(newSequence[i] == 'A')
{
firstBase = 0;
}
else if(newSequence[i] == 'C')
{
firstBase = 1;
}
else if(newSequence[i] == 'G')
{
firstBase = 2;
}
else if(newSequence[i] == 'U')
{
firstBase = 3;
} else {
isthereadot = true;
}
if(newSequence[i+1] == 'A')
{
secondBase = 0;
}
else if(newSequence[i+1] == 'C')
{
secondBase = 1;
}
else if(newSequence[i+1] == 'G')
{
secondBase = 2;
}
else if(newSequence[i+1] == 'U')
{
secondBase = 3;
} else {
isthereadot = true;
}
if(newSequence[i+2] == 'A')
{
thirdBase = 0;
}
else if(newSequence[i+2] == 'C')
{
thirdBase = 1;
}
else if(newSequence[i+2] == 'G')
{
thirdBase = 2;
}
else if(newSequence[i+2] == 'U')
{
thirdBase = 3;
} else {
isthereadot = true;
}
bool readSequence = true;
if (aminoAcid[firstBase][secondBase][thirdBase] == aminoAcid[0][3][2])
{
readSequence = true; //hace falta hacer AUG translation?
}
if (isthereadot) {
protein= protein + ".";
///break;
} else {
if(readSequence)
{
protein = protein + aminoAcid[firstBase][secondBase][thirdBase];
}
else
{
continue;
}
}
}
return protein;
}
////2.2. NGly detection
std::map<std::string, std::string> Separating(std::map<std::string, vector<int>> MUTATIONS, std::string protein_sequence) {
std::map<std::string, std::string> AA_REGIONS;
int FWR1=((MUTATIONS["FWR1"].size()+1)/3) ;
int FWR2=((MUTATIONS["FWR2"].size()+1)/3) ;
int FWR3=((MUTATIONS["FWR3"].size()+1)/3) ;
int FWR4=((MUTATIONS["FWR4"].size()+1)/3) ;
int CDR1=((MUTATIONS["CDR1"].size()+1)/3) ;
int CDR2=((MUTATIONS["CDR2"].size()+1)/3) ;
int CDR3=((MUTATIONS["CDR3"].size()+1)/3) ;
AA_REGIONS["FWR1"]=protein_sequence.substr(0,FWR1);
AA_REGIONS["CDR1"]=protein_sequence.substr(FWR1,CDR1);
AA_REGIONS["FWR2"]=protein_sequence.substr(FWR1+CDR1,FWR2);
AA_REGIONS["CDR2"]=protein_sequence.substr(FWR1+CDR1+FWR2,CDR2);
AA_REGIONS["FWR3"]=protein_sequence.substr(FWR1+CDR1+FWR2+CDR2,FWR3);
AA_REGIONS["CDR3"]=protein_sequence.substr(FWR1+CDR1+FWR2+CDR2+FWR3,CDR3);
AA_REGIONS["FWR4"]=protein_sequence.substr(FWR1+CDR1+FWR2+CDR2+FWR3+CDR3,FWR4);
if((AA_REGIONS["FWR1"] + AA_REGIONS["CDR1"]+ AA_REGIONS["FWR2"] +AA_REGIONS["CDR2"] +AA_REGIONS["FWR3"] + AA_REGIONS["CDR3"] + AA_REGIONS["FWR4"]) != protein_sequence) {
std::cout<<"Strangely " << AA_REGIONS["FWR1"] + AA_REGIONS["CDR1"]+ AA_REGIONS["FWR2"] +AA_REGIONS["CDR2"] +AA_REGIONS["FWR3"] + AA_REGIONS["CDR3"] + AA_REGIONS["FWR4"] << "not the same as "<< protein_sequence << std::endl;
}
return AA_REGIONS;
}
std::vector <int> Blacklisting(std::map<std::string, vector<int>> MUTATIONS) {
vector <int> blacklist;
int FWR1=((MUTATIONS["FWR1"].size()+1)/3) ;
int FWR2=((MUTATIONS["FWR2"].size()+1)/3) ;
int FWR3=((MUTATIONS["FWR3"].size()+1)/3) ;
int FWR4=((MUTATIONS["FWR4"].size()+1)/3) ;
int CDR1=((MUTATIONS["CDR1"].size()+1)/3) ;
int CDR2=((MUTATIONS["CDR2"].size()+1)/3) ;
int CDR3=((MUTATIONS["CDR3"].size()+1)/3) ;
blacklist.resize(FWR1);
std::iota(blacklist.begin(), blacklist.end(), 0);
blacklist.resize(blacklist.size()+FWR2);
std::iota(blacklist.begin()+FWR1, blacklist.end(), CDR1+FWR1);
blacklist.resize(blacklist.size()+FWR3);
std::iota(blacklist.begin()+FWR1+FWR2, blacklist.end(), FWR1+CDR1+FWR2+CDR2);
blacklist.resize(blacklist.size()+FWR4);
std::iota(blacklist.begin()+FWR1+FWR2+FWR3, blacklist.end(), FWR1+CDR1+FWR2+CDR2+FWR3+CDR3);
return blacklist;
}
std::vector<int> NGly_positions (std::string sequence, std::vector<int> blacklist, std::vector<int> &FULL_NGly_sites) {
std::string pattern("N[^P](S|T)"); // Regex expression
std::regex rx(pattern); // Getting the regex object
/////Get number matches (no needed, can get length indexes)
//std::ptrdiff_t number_of_matches = std::distance(std::sregex_iterator(sequence.begin(), sequence.end(), rx),std::sregex_iterator());
//std::cout << number_of_matches << std::endl; // Displaying results
////Get position indexes EMPIEZA EN 0
vector<int> index_matches; // results saved here
// (should be {2, 8}, but always get only {2})
for(auto it = std::sregex_iterator(sequence.begin(), sequence.end(), rx);
it != std::sregex_iterator(); ++it)
{
index_matches.push_back(it->position());
}
//std::cout << "Numero de N-Gly sites: "<< index_matches.size()<< std::endl;
FULL_NGly_sites = index_matches;
std::vector<int> filtered;
//not need to sort since it already sorted
std::set_difference(index_matches.begin(), index_matches.end(), blacklist.begin(), blacklist.end(), std::inserter(filtered, filtered.begin()));
//for (int x = 0; x != index_matches.size(); ++x)
//{
// std::cout << index_matches[x] << std::endl;
// //std::cout << dar.at(x) << "- calling at member" << std::endl;
//}
return filtered;
}
////2.3. STOP detection
bool isThereAnStop (std::string sequence) {
bool thereIsAStop = false;
if (sequence.find('.') != std::string::npos)
{
thereIsAStop = true;
}
return thereIsAStop;
}
///3. Mutation and affinities
////3.1. Choose which cells will mutate using poisson distribution
std::vector<int> whichCellsToMutate(int new_n_cells, double lambda) {
std::vector<int> p;
static std::random_device rd;
if(std::fabs(lambda - 0.) > std::numeric_limits<double>::epsilon() ) {
std::poisson_distribution<int> pd(lambda);
p.push_back(pd(gen));
} else {
p.push_back(0);
}
// for (int i = 0; i < new_n_cells; ++i){
// p.push_back(pd(gen));
// }
return p;
}
////3.2 SHM tree
void randomMutWhere(int num_of_mutations, std::map<std::string, std::string> & REGIONS, std::map<std::string, std::vector<int>> & MUTATIONS, std::map<std::string, std::vector<int>> & SILENT_MUTATIONS, std::string & sequence, std::string & protein_sequence, std::map<std::string, double> RATES_OF_MUTATIONS,std::string & sequence_name) {
//std::cout<<sequence<<std::endl;
std::vector<string> regions= {"FWR1","CDR1","FWR2","CDR2","FWR3","CDR3","FWR4"};
std::random_device gen;
std::uniform_real_distribution<double> distribution(0.0,std::nextafter(1.0, std::numeric_limits<double>::max()));
float probRegion;
bool Replacement;
bool Lethal;
int reg;
struct timespec ts;
std::string originalSeq;
std::string originalSeqAA;
std::string mutatedSeq;
int mutationPlace;
std::random_device gen2;
std::uniform_int_distribution<int> point(0,1);
std::map<std::string, std::string> REGIONS_TMP= REGIONS;
int prueba = 0;
Lethal = false;
bool Keep_searching=true;
bool Restricted_is_OK=false;
vector<string> regiones_F={"FWR1","FWR2", "FWR3","FWR4"};
std::map<std::string, std::string> AA_REGIONS_TMP;
std::map<std::string, std::string> AA_REGIONS;
int MutationPlace;
string AA;
//cout << "Num of mutations: " << num_of_mutations;
for (int i = 0; i < num_of_mutations; ++i){
Replacement = false;
Lethal=false;
probRegion= distribution(generator);
if (probRegion <= RATES_OF_MUTATIONS["alpha_FWR"] && !Lethal) {
if (probRegion <= RATES_OF_MUTATIONS["alpha_FWR1"]) {
reg=0;
if (distribution(generator) <= RATES_OF_MUTATIONS["beta_FWR1"]) {
Replacement=true;
}
} else if (probRegion <= (RATES_OF_MUTATIONS["alpha_FWR1"]+RATES_OF_MUTATIONS["alpha_FWR2"])) {
reg=2;
if (distribution(generator) <= RATES_OF_MUTATIONS["beta_FWR2"]) {
Replacement=true;
}
} else if (probRegion <= (RATES_OF_MUTATIONS["alpha_FWR1"]+RATES_OF_MUTATIONS["alpha_FWR2"]+RATES_OF_MUTATIONS["alpha_FWR3"])) {
reg=4;
if (distribution(generator) <= RATES_OF_MUTATIONS["beta_FWR3"]) {
Replacement=true;
}
} else {
reg=6;
if (distribution(generator) <= RATES_OF_MUTATIONS["beta_FWR4"]) {
Replacement=true;
}
}
} else {
if (probRegion <= (RATES_OF_MUTATIONS["alpha_FWR"] + RATES_OF_MUTATIONS["alpha_CDR1"])) {
reg=1;
if (distribution(generator) <= RATES_OF_MUTATIONS["gamma_CDR1"]) {
Replacement=true;
}
} else if (probRegion <= (RATES_OF_MUTATIONS["alpha_FWR"] + RATES_OF_MUTATIONS["alpha_CDR1"]+RATES_OF_MUTATIONS["alpha_CDR2"])) {
reg=3;
if (distribution(generator) <= RATES_OF_MUTATIONS["gamma_CDR2"]) {
Replacement=true;
}
} else {
reg=5;
if (distribution(generator) <= RATES_OF_MUTATIONS["gamma_CDR3"]) {
Replacement=true;
}
}
}
if (Replacement==true && (reg == 0 || reg == 2 || reg == 4|| reg == 6) && distribution(generator) <= RATES_OF_MUTATIONS["delta"]){
Lethal = true;
}
//std::cout<<"igual es a proteina"<<std::endl;
//cout<<reg<<" "<<Replacement<<" "<< Lethal<< endl;
REGIONS_TMP= REGIONS;
Keep_searching=true;
if (Replacement && !Lethal) { ////////|| (reg == 1 || reg == 3 || reg == 5), tener en cuenta que puede haber stops en los CDR... y ver que se esta adicionando a restricted db neutral
//cout << "R no L " << regions[reg] << endl;
point=std::uniform_int_distribution<int>(0,REGIONS[regions[reg]].length()-1);
mutationPlace = point(generator2);
originalSeq=REGIONS["FWR1"] +REGIONS["CDR1"] +REGIONS["FWR2"] +REGIONS["CDR2"] +REGIONS["FWR3"] +REGIONS["CDR3"] +REGIONS["FWR4"];
originalSeqAA=DNAtoprotein(originalSeq);
mutatedSeq=originalSeq;
prueba=0;
//std::cout<<"Replacement"<<std::endl;
while (Keep_searching) {
Restricted_is_OK=false;
if (prueba > 25) { //hay aminoacidos que no se mutan pase lo que pase en una posicion
//std::cout << "mutacion previa en" << mutationPlace << std::endl;
mutationPlace = point(generator2);
prueba=0;
//std::cout << "cambio mutacion a " << mutationPlace << std::endl;
}
REGIONS_TMP= REGIONS;
prueba++;
//clock_gettime(CLOCK_MONOTONIC, &ts);
/* using nano-seconds instead of seconds */
//srand((time_t)ts.tv_nsec); ////RRRR-remove
//srand ( time(NULL) ); ///RRR Se puede optimizar mas
const char arrayNucleotides[4] = {'A', 'U', 'G', 'C'};
//int RandIndex = rand() % 4;
int RandIndex = random::randomInteger(4);
REGIONS_TMP[regions[reg]][mutationPlace] = arrayNucleotides[RandIndex];
mutatedSeq=REGIONS_TMP["FWR1"] +REGIONS_TMP["CDR1"] +REGIONS_TMP["FWR2"] +REGIONS_TMP["CDR2"] +REGIONS_TMP["FWR3"] +REGIONS_TMP["CDR3"] +REGIONS_TMP["FWR4"];
AA_REGIONS_TMP= Separating(MUTATIONS, DNAtoprotein(mutatedSeq));
AA_REGIONS= Separating(MUTATIONS, originalSeqAA);
if(AA_REGIONS_TMP[regions[reg]].compare(AA_REGIONS[regions[reg]])!= 0) {
if (std::find(regiones_F.begin(), regiones_F.end(), regions[reg]) != regiones_F.end()) {
int confirmar=0;