Mercurial > repos > davidvanzessen > mutation_analysis
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| author | davidvanzessen |
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| date | Mon, 29 Aug 2016 05:36:10 -0400 |
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######################################################################################### # License Agreement # # THIS WORK IS PROVIDED UNDER THE TERMS OF THIS CREATIVE COMMONS PUBLIC LICENSE # ("CCPL" OR "LICENSE"). THE WORK IS PROTECTED BY COPYRIGHT AND/OR OTHER # APPLICABLE LAW. ANY USE OF THE WORK OTHER THAN AS AUTHORIZED UNDER THIS LICENSE # OR COPYRIGHT LAW IS PROHIBITED. # # BY EXERCISING ANY RIGHTS TO THE WORK PROVIDED HERE, YOU ACCEPT AND AGREE TO BE # BOUND BY THE TERMS OF THIS LICENSE. TO THE EXTENT THIS LICENSE MAY BE CONSIDERED # TO BE A CONTRACT, THE LICENSOR GRANTS YOU THE RIGHTS CONTAINED HERE IN # CONSIDERATION OF YOUR ACCEPTANCE OF SUCH TERMS AND CONDITIONS. # # BASELIne: Bayesian Estimation of Antigen-Driven Selection in Immunoglobulin Sequences # Coded by: Mohamed Uduman & Gur Yaari # Copyright 2012 Kleinstein Lab # Version: 1.3 (01/23/2014) ######################################################################################### # Global variables FILTER_BY_MUTATIONS = 1000 # Nucleotides NUCLEOTIDES = c("A","C","G","T") # Amino Acids AMINO_ACIDS <- c("F", "F", "L", "L", "S", "S", "S", "S", "Y", "Y", "*", "*", "C", "C", "*", "W", "L", "L", "L", "L", "P", "P", "P", "P", "H", "H", "Q", "Q", "R", "R", "R", "R", "I", "I", "I", "M", "T", "T", "T", "T", "N", "N", "K", "K", "S", "S", "R", "R", "V", "V", "V", "V", "A", "A", "A", "A", "D", "D", "E", "E", "G", "G", "G", "G") names(AMINO_ACIDS) <- c("TTT", "TTC", "TTA", "TTG", "TCT", "TCC", "TCA", "TCG", "TAT", "TAC", "TAA", "TAG", "TGT", "TGC", "TGA", "TGG", "CTT", "CTC", "CTA", "CTG", "CCT", "CCC", "CCA", "CCG", "CAT", "CAC", "CAA", "CAG", "CGT", "CGC", "CGA", "CGG", "ATT", "ATC", "ATA", "ATG", "ACT", "ACC", "ACA", "ACG", "AAT", "AAC", "AAA", "AAG", "AGT", "AGC", "AGA", "AGG", "GTT", "GTC", "GTA", "GTG", "GCT", "GCC", "GCA", "GCG", "GAT", "GAC", "GAA", "GAG", "GGT", "GGC", "GGA", "GGG") names(AMINO_ACIDS) <- names(AMINO_ACIDS) #Amino Acid Traits #"*" "A" "C" "D" "E" "F" "G" "H" "I" "K" "L" "M" "N" "P" "Q" "R" "S" "T" "V" "W" "Y" #B = "Hydrophobic/Burried" N = "Intermediate/Neutral" S="Hydrophilic/Surface") TRAITS_AMINO_ACIDS_CHOTHIA98 <- c("*","N","B","S","S","B","N","N","B","S","B","B","S","N","S","S","N","N","B","B","N") names(TRAITS_AMINO_ACIDS_CHOTHIA98) <- sort(unique(AMINO_ACIDS)) TRAITS_AMINO_ACIDS <- array(NA,21) # Codon Table CODON_TABLE <- as.data.frame(matrix(NA,ncol=64,nrow=12)) # Substitution Model: Smith DS et al. 1996 substitution_Literature_Mouse <- matrix(c(0, 0.156222928, 0.601501588, 0.242275484, 0.172506739, 0, 0.241239892, 0.586253369, 0.54636291, 0.255795364, 0, 0.197841727, 0.290240811, 0.467680608, 0.24207858, 0),nrow=4,byrow=T,dimnames=list(NUCLEOTIDES,NUCLEOTIDES)) substitution_Flu_Human <- matrix(c(0,0.2795596,0.5026927,0.2177477,0.1693210,0,0.3264723,0.5042067,0.4983549,0.3328321,0,0.1688130,0.2021079,0.4696077,0.3282844,0),4,4,byrow=T,dimnames=list(NUCLEOTIDES,NUCLEOTIDES)) substitution_Flu25_Human <- matrix(c(0,0.2580641,0.5163685,0.2255674,0.1541125,0,0.3210224,0.5248651,0.5239281,0.3101292,0,0.1659427,0.1997207,0.4579444,0.3423350,0),4,4,byrow=T,dimnames=list(NUCLEOTIDES,NUCLEOTIDES)) load("FiveS_Substitution.RData") # Mutability Models: Shapiro GS et al. 2002 triMutability_Literature_Human <- matrix(c(0.24, 1.2, 0.96, 0.43, 2.14, 2, 1.11, 1.9, 0.85, 1.83, 2.36, 1.31, 0.82, 0.52, 0.89, 1.33, 1.4, 0.82, 1.83, 0.73, 1.83, 1.62, 1.53, 0.57, 0.92, 0.42, 0.42, 1.47, 3.44, 2.58, 1.18, 0.47, 0.39, 1.12, 1.8, 0.68, 0.47, 2.19, 2.35, 2.19, 1.05, 1.84, 1.26, 0.28, 0.98, 2.37, 0.66, 1.58, 0.67, 0.92, 1.76, 0.83, 0.97, 0.56, 0.75, 0.62, 2.26, 0.62, 0.74, 1.11, 1.16, 0.61, 0.88, 0.67, 0.37, 0.07, 1.08, 0.46, 0.31, 0.94, 0.62, 0.57, 0.29, NA, 1.44, 0.46, 0.69, 0.57, 0.24, 0.37, 1.1, 0.99, 1.39, 0.6, 2.26, 1.24, 1.36, 0.52, 0.33, 0.26, 1.25, 0.37, 0.58, 1.03, 1.2, 0.34, 0.49, 0.33, 2.62, 0.16, 0.4, 0.16, 0.35, 0.75, 1.85, 0.94, 1.61, 0.85, 2.09, 1.39, 0.3, 0.52, 1.33, 0.29, 0.51, 0.26, 0.51, 3.83, 2.01, 0.71, 0.58, 0.62, 1.07, 0.28, 1.2, 0.74, 0.25, 0.59, 1.09, 0.91, 1.36, 0.45, 2.89, 1.27, 3.7, 0.69, 0.28, 0.41, 1.17, 0.56, 0.93, 3.41, 1, 1, NA, 5.9, 0.74, 2.51, 2.24, 2.24, 1.95, 3.32, 2.34, 1.3, 2.3, 1, 0.66, 0.73, 0.93, 0.41, 0.65, 0.89, 0.65, 0.32, NA, 0.43, 0.85, 0.43, 0.31, 0.31, 0.23, 0.29, 0.57, 0.71, 0.48, 0.44, 0.76, 0.51, 1.7, 0.85, 0.74, 2.23, 2.08, 1.16, 0.51, 0.51, 1, 0.5, NA, NA, 0.71, 2.14), nrow=64,byrow=T) triMutability_Literature_Mouse <- matrix(c(1.31, 1.35, 1.42, 1.18, 2.02, 2.02, 1.02, 1.61, 1.99, 1.42, 2.01, 1.03, 2.02, 0.97, 0.53, 0.71, 1.19, 0.83, 0.96, 0.96, 0, 1.7, 2.22, 0.59, 1.24, 1.07, 0.51, 1.68, 3.36, 3.36, 1.14, 0.29, 0.33, 0.9, 1.11, 0.63, 1.08, 2.07, 2.27, 1.74, 0.22, 1.19, 2.37, 1.15, 1.15, 1.56, 0.81, 0.34, 0.87, 0.79, 2.13, 0.49, 0.85, 0.97, 0.36, 0.82, 0.66, 0.63, 1.15, 0.94, 0.85, 0.25, 0.93, 1.19, 0.4, 0.2, 0.44, 0.44, 0.88, 1.06, 0.77, 0.39, 0, 0, 0, 0, 0, 0, 0.43, 0.43, 0.86, 0.59, 0.59, 0, 1.18, 0.86, 2.9, 1.66, 0.4, 0.2, 1.54, 0.43, 0.69, 1.71, 0.68, 0.55, 0.91, 0.7, 1.71, 0.09, 0.27, 0.63, 0.2, 0.45, 1.01, 1.63, 0.96, 1.48, 2.18, 1.2, 1.31, 0.66, 2.13, 0.49, 0, 0, 0, 2.97, 2.8, 0.79, 0.4, 0.5, 0.4, 0.11, 1.68, 0.42, 0.13, 0.44, 0.93, 0.71, 1.11, 1.19, 2.71, 1.08, 3.43, 0.4, 0.67, 0.47, 1.02, 0.14, 1.56, 1.98, 0.53, 0.33, 0.63, 2.06, 1.77, 1.46, 3.74, 2.93, 2.1, 2.18, 0.78, 0.73, 2.93, 0.63, 0.57, 0.17, 0.85, 0.52, 0.31, 0.31, 0, 0, 0.51, 0.29, 0.83, 0.54, 0.28, 0.47, 0.9, 0.99, 1.24, 2.47, 0.73, 0.23, 1.13, 0.24, 2.12, 0.24, 0.33, 0.83, 1.41, 0.62, 0.28, 0.35, 0.77, 0.17, 0.72, 0.58, 0.45, 0.41), nrow=64,byrow=T) triMutability_Names <- c("AAA", "AAC", "AAG", "AAT", "ACA", "ACC", "ACG", "ACT", "AGA", "AGC", "AGG", "AGT", "ATA", "ATC", "ATG", "ATT", "CAA", "CAC", "CAG", "CAT", "CCA", "CCC", "CCG", "CCT", "CGA", "CGC", "CGG", "CGT", "CTA", "CTC", "CTG", "CTT", "GAA", "GAC", "GAG", "GAT", "GCA", "GCC", "GCG", "GCT", "GGA", "GGC", "GGG", "GGT", "GTA", "GTC", "GTG", "GTT", "TAA", "TAC", "TAG", "TAT", "TCA", "TCC", "TCG", "TCT", "TGA", "TGC", "TGG", "TGT", "TTA", "TTC", "TTG", "TTT") load("FiveS_Mutability.RData") # Functions # Translate codon to amino acid translateCodonToAminoAcid<-function(Codon){ return(AMINO_ACIDS[Codon]) } # Translate amino acid to trait change translateAminoAcidToTraitChange<-function(AminoAcid){ return(TRAITS_AMINO_ACIDS[AminoAcid]) } # Initialize Amino Acid Trait Changes initializeTraitChange <- function(traitChangeModel=1,species=1,traitChangeFileName=NULL){ if(!is.null(traitChangeFileName)){ tryCatch( traitChange <- read.delim(traitChangeFileName,sep="\t",header=T) , error = function(ex){ cat("Error|Error reading trait changes. Please check file name/path and format.\n") q() } ) }else{ traitChange <- TRAITS_AMINO_ACIDS_CHOTHIA98 } TRAITS_AMINO_ACIDS <<- traitChange } # Read in formatted nucleotide substitution matrix initializeSubstitutionMatrix <- function(substitutionModel,species,subsMatFileName=NULL){ if(!is.null(subsMatFileName)){ tryCatch( subsMat <- read.delim(subsMatFileName,sep="\t",header=T) , error = function(ex){ cat("Error|Error reading substitution matrix. Please check file name/path and format.\n") q() } ) if(sum(apply(subsMat,1,sum)==1)!=4) subsMat = t(apply(subsMat,1,function(x)x/sum(x))) }else{ if(substitutionModel==1)subsMat <- substitution_Literature_Mouse if(substitutionModel==2)subsMat <- substitution_Flu_Human if(substitutionModel==3)subsMat <- substitution_Flu25_Human } if(substitutionModel==0){ subsMat <- matrix(1,4,4) subsMat[,] = 1/3 subsMat[1,1] = 0 subsMat[2,2] = 0 subsMat[3,3] = 0 subsMat[4,4] = 0 } NUCLEOTIDESN = c(NUCLEOTIDES,"N", "-") if(substitutionModel==5){ subsMat <- FiveS_Substitution return(subsMat) }else{ subsMat <- rbind(subsMat,rep(NA,4),rep(NA,4)) return( matrix(data.matrix(subsMat),6,4,dimnames=list(NUCLEOTIDESN,NUCLEOTIDES) ) ) } } # Read in formatted Mutability file initializeMutabilityMatrix <- function(mutabilityModel=1, species=1,mutabilityMatFileName=NULL){ if(!is.null(mutabilityMatFileName)){ tryCatch( mutabilityMat <- read.delim(mutabilityMatFileName,sep="\t",header=T) , error = function(ex){ cat("Error|Error reading mutability matrix. Please check file name/path and format.\n") q() } ) }else{ mutabilityMat <- triMutability_Literature_Human if(species==2) mutabilityMat <- triMutability_Literature_Mouse } if(mutabilityModel==0){ mutabilityMat <- matrix(1,64,3)} if(mutabilityModel==5){ mutabilityMat <- FiveS_Mutability return(mutabilityMat) }else{ return( matrix( data.matrix(mutabilityMat), 64, 3, dimnames=list(triMutability_Names,1:3)) ) } } # Read FASTA file formats # Modified from read.fasta from the seqinR package baseline.read.fasta <- function (file = system.file("sequences/sample.fasta", package = "seqinr"), seqtype = c("DNA", "AA"), as.string = FALSE, forceDNAtolower = TRUE, set.attributes = TRUE, legacy.mode = TRUE, seqonly = FALSE, strip.desc = FALSE, sizeof.longlong = .Machine$sizeof.longlong, endian = .Platform$endian, apply.mask = TRUE) { seqtype <- match.arg(seqtype) lines <- readLines(file) if (legacy.mode) { comments <- grep("^;", lines) if (length(comments) > 0) lines <- lines[-comments] } ind_groups<-which(substr(lines, 1L, 3L) == ">>>") lines_mod<-lines if(!length(ind_groups)){ lines_mod<-c(">>>All sequences combined",lines) } ind_groups<-which(substr(lines_mod, 1L, 3L) == ">>>") lines <- array("BLA",dim=(length(ind_groups)+length(lines_mod))) id<-sapply(1:length(ind_groups),function(i)ind_groups[i]+i-1)+1 lines[id] <- "THIS IS A FAKE SEQUENCE" lines[-id] <- lines_mod rm(lines_mod) ind <- which(substr(lines, 1L, 1L) == ">") nseq <- length(ind) if (nseq == 0) { stop("no line starting with a > character found") } start <- ind + 1 end <- ind - 1 while( any(which(ind%in%end)) ){ ind=ind[-which(ind%in%end)] nseq <- length(ind) if (nseq == 0) { stop("no line starting with a > character found") } start <- ind + 1 end <- ind - 1 } end <- c(end[-1], length(lines)) sequences <- lapply(seq_len(nseq), function(i) paste(lines[start[i]:end[i]], collapse = "")) if (seqonly) return(sequences) nomseq <- lapply(seq_len(nseq), function(i) { #firstword <- strsplit(lines[ind[i]], " ")[[1]][1] substr(lines[ind[i]], 2, nchar(lines[ind[i]])) }) if (seqtype == "DNA") { if (forceDNAtolower) { sequences <- as.list(tolower(chartr(".","-",sequences))) }else{ sequences <- as.list(toupper(chartr(".","-",sequences))) } } if (as.string == FALSE) sequences <- lapply(sequences, s2c) if (set.attributes) { for (i in seq_len(nseq)) { Annot <- lines[ind[i]] if (strip.desc) Annot <- substr(Annot, 2L, nchar(Annot)) attributes(sequences[[i]]) <- list(name = nomseq[[i]], Annot = Annot, class = switch(seqtype, AA = "SeqFastaAA", DNA = "SeqFastadna")) } } names(sequences) <- nomseq return(sequences) } # Replaces non FASTA characters in input files with N replaceNonFASTAChars <-function(inSeq="ACGTN-AApA"){ gsub('[^ACGTNacgt[:punct:]-[:punct:].]','N',inSeq,perl=TRUE) } # Find the germlines in the FASTA list germlinesInFile <- function(seqIDs){ firstChar = sapply(seqIDs,function(x){substr(x,1,1)}) secondChar = sapply(seqIDs,function(x){substr(x,2,2)}) return(firstChar==">" & secondChar!=">") } # Find the groups in the FASTA list groupsInFile <- function(seqIDs){ sapply(seqIDs,function(x){substr(x,1,2)})==">>" } # In the process of finding germlines/groups, expand from the start to end of the group expandTillNext <- function(vecPosToID){ IDs = names(vecPosToID) posOfInterests = which(vecPosToID) expandedID = rep(NA,length(IDs)) expandedIDNames = gsub(">","",IDs[posOfInterests]) startIndexes = c(1,posOfInterests[-1]) stopIndexes = c(posOfInterests[-1]-1,length(IDs)) expandedID = unlist(sapply(1:length(startIndexes),function(i){ rep(i,stopIndexes[i]-startIndexes[i]+1) })) names(expandedID) = unlist(sapply(1:length(startIndexes),function(i){ rep(expandedIDNames[i],stopIndexes[i]-startIndexes[i]+1) })) return(expandedID) } # Process FASTA (list) to return a matrix[input, germline) processInputAdvanced <- function(inputFASTA){ seqIDs = names(inputFASTA) numbSeqs = length(seqIDs) posGermlines1 = germlinesInFile(seqIDs) numbGermlines = sum(posGermlines1) posGroups1 = groupsInFile(seqIDs) numbGroups = sum(posGroups1) consDef = NA if(numbGermlines==0){ posGermlines = 2 numbGermlines = 1 } glPositionsSum = cumsum(posGermlines1) glPositions = table(glPositionsSum) #Find the position of the conservation row consDefPos = as.numeric(names(glPositions[names(glPositions)!=0 & glPositions==1]))+1 if( length(consDefPos)> 0 ){ consDefID = match(consDefPos, glPositionsSum) #The coservation rows need to be pulled out and stores seperately consDef = inputFASTA[consDefID] inputFASTA = inputFASTA[-consDefID] seqIDs = names(inputFASTA) numbSeqs = length(seqIDs) posGermlines1 = germlinesInFile(seqIDs) numbGermlines = sum(posGermlines1) posGroups1 = groupsInFile(seqIDs) numbGroups = sum(posGroups1) if(numbGermlines==0){ posGermlines = 2 numbGermlines = 1 } } posGroups <- expandTillNext(posGroups1) posGermlines <- expandTillNext(posGermlines1) posGermlines[posGroups1] = 0 names(posGermlines)[posGroups1] = names(posGroups)[posGroups1] posInput = rep(TRUE,numbSeqs) posInput[posGroups1 | posGermlines1] = FALSE matInput = matrix(NA, nrow=sum(posInput), ncol=2) rownames(matInput) = seqIDs[posInput] colnames(matInput) = c("Input","Germline") vecInputFASTA = unlist(inputFASTA) matInput[,1] = vecInputFASTA[posInput] matInput[,2] = vecInputFASTA[ which( names(inputFASTA)%in%paste(">",names(posGermlines)[posInput],sep="") )[ posGermlines[posInput]] ] germlines = posGermlines[posInput] groups = posGroups[posInput] return( list("matInput"=matInput, "germlines"=germlines, "groups"=groups, "conservationDefinition"=consDef )) } # Replace leading and trailing dashes in the sequence replaceLeadingTrailingDashes <- function(x,readEnd){ iiGap = unlist(gregexpr("-",x[1])) ggGap = unlist(gregexpr("-",x[2])) #posToChange = intersect(iiGap,ggGap) seqIn = replaceLeadingTrailingDashesHelper(x[1]) seqGL = replaceLeadingTrailingDashesHelper(x[2]) seqTemplate = rep('N',readEnd) seqIn <- c(seqIn,seqTemplate[(length(seqIn)+1):readEnd]) seqGL <- c(seqGL,seqTemplate[(length(seqGL)+1):readEnd]) # if(posToChange!=-1){ # seqIn[posToChange] = "-" # seqGL[posToChange] = "-" # } seqIn = c2s(seqIn[1:readEnd]) seqGL = c2s(seqGL[1:readEnd]) lenGL = nchar(seqGL) if(lenGL<readEnd){ seqGL = paste(seqGL,c2s(rep("N",readEnd-lenGL)),sep="") } lenInput = nchar(seqIn) if(lenInput<readEnd){ seqIn = paste(seqIn,c2s(rep("N",readEnd-lenInput)),sep="") } return( c(seqIn,seqGL) ) } replaceLeadingTrailingDashesHelper <- function(x){ grepResults = gregexpr("-*",x) grepResultsPos = unlist(grepResults) grepResultsLen = attr(grepResults[[1]],"match.length") #print(paste("x = '", x, "'", sep="")) x = s2c(x) if(x[1]=="-"){ x[1:grepResultsLen[1]] = "N" } if(x[length(x)]=="-"){ x[(length(x)-grepResultsLen[length(grepResultsLen)]+1):length(x)] = "N" } return(x) } # Check sequences for indels checkForInDels <- function(matInputP){ insPos <- checkInsertion(matInputP) delPos <- checkDeletions(matInputP) return(list("Insertions"=insPos, "Deletions"=delPos)) } # Check sequences for insertions checkInsertion <- function(matInputP){ insertionCheck = apply( matInputP,1, function(x){ inputGaps <- as.vector( gregexpr("-",x[1])[[1]] ) glGaps <- as.vector( gregexpr("-",x[2])[[1]] ) return( is.finite( match(FALSE, glGaps%in%inputGaps ) ) ) }) return(as.vector(insertionCheck)) } # Fix inserstions fixInsertions <- function(matInputP){ insPos <- checkInsertion(matInputP) sapply((1:nrow(matInputP))[insPos],function(rowIndex){ x <- matInputP[rowIndex,] inputGaps <- gregexpr("-",x[1])[[1]] glGaps <- gregexpr("-",x[2])[[1]] posInsertions <- glGaps[!(glGaps%in%inputGaps)] inputInsertionToN <- s2c(x[2]) inputInsertionToN[posInsertions]!="-" inputInsertionToN[posInsertions] <- "N" inputInsertionToN <- c2s(inputInsertionToN) matInput[rowIndex,2] <<- inputInsertionToN }) return(insPos) } # Check sequences for deletions checkDeletions <-function(matInputP){ deletionCheck = apply( matInputP,1, function(x){ inputGaps <- as.vector( gregexpr("-",x[1])[[1]] ) glGaps <- as.vector( gregexpr("-",x[2])[[1]] ) return( is.finite( match(FALSE, inputGaps%in%glGaps ) ) ) }) return(as.vector(deletionCheck)) } # Fix sequences with deletions fixDeletions <- function(matInputP){ delPos <- checkDeletions(matInputP) sapply((1:nrow(matInputP))[delPos],function(rowIndex){ x <- matInputP[rowIndex,] inputGaps <- gregexpr("-",x[1])[[1]] glGaps <- gregexpr("-",x[2])[[1]] posDeletions <- inputGaps[!(inputGaps%in%glGaps)] inputDeletionToN <- s2c(x[1]) inputDeletionToN[posDeletions] <- "N" inputDeletionToN <- c2s(inputDeletionToN) matInput[rowIndex,1] <<- inputDeletionToN }) return(delPos) } # Trim DNA sequence to the last codon trimToLastCodon <- function(seqToTrim){ seqLen = nchar(seqToTrim) trimmedSeq = s2c(seqToTrim) poi = seqLen tailLen = 0 while(trimmedSeq[poi]=="-" || trimmedSeq[poi]=="."){ tailLen = tailLen + 1 poi = poi - 1 } trimmedSeq = c2s(trimmedSeq[1:(seqLen-tailLen)]) seqLen = nchar(trimmedSeq) # Trim sequence to last codon if( getCodonPos(seqLen)[3] > seqLen ) trimmedSeq = substr(seqToTrim,1, ( (getCodonPos(seqLen)[1])-1 ) ) return(trimmedSeq) } # Given a nuclotide position, returns the pos of the 3 nucs that made the codon # e.g. nuc 86 is part of nucs 85,86,87 getCodonPos <- function(nucPos){ codonNum = (ceiling(nucPos/3))*3 return( (codonNum-2):codonNum) } # Given a nuclotide position, returns the codon number # e.g. nuc 86 = codon 29 getCodonNumb <- function(nucPos){ return( ceiling(nucPos/3) ) } # Given a codon, returns all the nuc positions that make the codon getCodonNucs <- function(codonNumb){ getCodonPos(codonNumb*3) } computeCodonTable <- function(testID=1){ if(testID<=4){ # Pre-compute every codons intCounter = 1 for(pOne in NUCLEOTIDES){ for(pTwo in NUCLEOTIDES){ for(pThree in NUCLEOTIDES){ codon = paste(pOne,pTwo,pThree,sep="") colnames(CODON_TABLE)[intCounter] = codon intCounter = intCounter + 1 CODON_TABLE[,codon] = mutationTypeOptimized(cbind(permutateAllCodon(codon),rep(codon,12))) } } } chars = c("N","A","C","G","T", "-") for(a in chars){ for(b in chars){ for(c in chars){ if(a=="N" | b=="N" | c=="N"){ #cat(paste(a,b,c),sep="","\n") CODON_TABLE[,paste(a,b,c,sep="")] = rep(NA,12) } } } } chars = c("-","A","C","G","T") for(a in chars){ for(b in chars){ for(c in chars){ if(a=="-" | b=="-" | c=="-"){ #cat(paste(a,b,c),sep="","\n") CODON_TABLE[,paste(a,b,c,sep="")] = rep(NA,12) } } } } CODON_TABLE <<- as.matrix(CODON_TABLE) } } collapseClone <- function(vecInputSeqs,glSeq,readEnd,nonTerminalOnly=0){ #print(length(vecInputSeqs)) vecInputSeqs = unique(vecInputSeqs) if(length(vecInputSeqs)==1){ return( list( c(vecInputSeqs,glSeq), F) ) }else{ charInputSeqs <- sapply(vecInputSeqs, function(x){ s2c(x)[1:readEnd] }) charGLSeq <- s2c(glSeq) matClone <- sapply(1:readEnd, function(i){ posNucs = unique(charInputSeqs[i,]) posGL = charGLSeq[i] error = FALSE if(posGL=="-" & sum(!(posNucs%in%c("-","N")))==0 ){ return(c("-",error)) } if(length(posNucs)==1) return(c(posNucs[1],error)) else{ if("N"%in%posNucs){ error=TRUE } if(sum(!posNucs[posNucs!="N"]%in%posGL)==0){ return( c(posGL,error) ) }else{ #return( c(sample(posNucs[posNucs!="N"],1),error) ) if(nonTerminalOnly==0){ return( c(sample(charInputSeqs[i,charInputSeqs[i,]!="N" & charInputSeqs[i,]!=posGL],1),error) ) }else{ posNucs = charInputSeqs[i,charInputSeqs[i,]!="N" & charInputSeqs[i,]!=posGL] posNucsTable = table(posNucs) if(sum(posNucsTable>1)==0){ return( c(posGL,error) ) }else{ return( c(sample( posNucs[posNucs%in%names(posNucsTable)[posNucsTable>1]],1),error) ) } } } } }) #print(length(vecInputSeqs)) return(list(c(c2s(matClone[1,]),glSeq),"TRUE"%in%matClone[2,])) } } # Compute the expected for each sequence-germline pair getExpectedIndividual <- function(matInput){ if( any(grep("multicore",search())) ){ facGL <- factor(matInput[,2]) facLevels = levels(facGL) LisGLs_MutabilityU = mclapply(1:length(facLevels), function(x){ computeMutabilities(facLevels[x]) }) facIndex = match(facGL,facLevels) LisGLs_Mutability = mclapply(1:nrow(matInput), function(x){ cInput = rep(NA,nchar(matInput[x,1])) cInput[s2c(matInput[x,1])!="N"] = 1 LisGLs_MutabilityU[[facIndex[x]]] * cInput }) LisGLs_Targeting = mclapply(1:dim(matInput)[1], function(x){ computeTargeting(matInput[x,2],LisGLs_Mutability[[x]]) }) LisGLs_MutationTypes = mclapply(1:length(matInput[,2]),function(x){ #print(x) computeMutationTypes(matInput[x,2]) }) LisGLs_Exp = mclapply(1:dim(matInput)[1], function(x){ computeExpected(LisGLs_Targeting[[x]],LisGLs_MutationTypes[[x]]) }) ul_LisGLs_Exp = unlist(LisGLs_Exp) return(matrix(ul_LisGLs_Exp,ncol=4,nrow=(length(ul_LisGLs_Exp)/4),byrow=T)) }else{ facGL <- factor(matInput[,2]) facLevels = levels(facGL) LisGLs_MutabilityU = lapply(1:length(facLevels), function(x){ computeMutabilities(facLevels[x]) }) facIndex = match(facGL,facLevels) LisGLs_Mutability = lapply(1:nrow(matInput), function(x){ cInput = rep(NA,nchar(matInput[x,1])) cInput[s2c(matInput[x,1])!="N"] = 1 LisGLs_MutabilityU[[facIndex[x]]] * cInput }) LisGLs_Targeting = lapply(1:dim(matInput)[1], function(x){ computeTargeting(matInput[x,2],LisGLs_Mutability[[x]]) }) LisGLs_MutationTypes = lapply(1:length(matInput[,2]),function(x){ #print(x) computeMutationTypes(matInput[x,2]) }) LisGLs_Exp = lapply(1:dim(matInput)[1], function(x){ computeExpected(LisGLs_Targeting[[x]],LisGLs_MutationTypes[[x]]) }) ul_LisGLs_Exp = unlist(LisGLs_Exp) return(matrix(ul_LisGLs_Exp,ncol=4,nrow=(length(ul_LisGLs_Exp)/4),byrow=T)) } } # Compute mutabilities of sequence based on the tri-nucleotide model computeMutabilities <- function(paramSeq){ seqLen = nchar(paramSeq) seqMutabilites = rep(NA,seqLen) gaplessSeq = gsub("-", "", paramSeq) gaplessSeqLen = nchar(gaplessSeq) gaplessSeqMutabilites = rep(NA,gaplessSeqLen) if(mutabilityModel!=5){ pos<- 3:(gaplessSeqLen) subSeq = substr(rep(gaplessSeq,gaplessSeqLen-2),(pos-2),(pos+2)) gaplessSeqMutabilites[pos] = tapply( c( getMutability( substr(subSeq,1,3), 3) , getMutability( substr(subSeq,2,4), 2), getMutability( substr(subSeq,3,5), 1) ),rep(1:(gaplessSeqLen-2),3),mean,na.rm=TRUE ) #Pos 1 subSeq = substr(gaplessSeq,1,3) gaplessSeqMutabilites[1] = getMutability(subSeq , 1) #Pos 2 subSeq = substr(gaplessSeq,1,4) gaplessSeqMutabilites[2] = mean( c( getMutability( substr(subSeq,1,3), 2) , getMutability( substr(subSeq,2,4), 1) ),na.rm=T ) seqMutabilites[which(s2c(paramSeq)!="-")]<- gaplessSeqMutabilites return(seqMutabilites) }else{ pos<- 3:(gaplessSeqLen) subSeq = substr(rep(gaplessSeq,gaplessSeqLen-2),(pos-2),(pos+2)) gaplessSeqMutabilites[pos] = sapply(subSeq,function(x){ getMutability5(x) }, simplify=T) seqMutabilites[which(s2c(paramSeq)!="-")]<- gaplessSeqMutabilites return(seqMutabilites) } } # Returns the mutability of a triplet at a given position getMutability <- function(codon, pos=1:3){ triplets <- rownames(mutability) mutability[ match(codon,triplets) ,pos] } getMutability5 <- function(fivemer){ return(mutability[fivemer]) } # Returns the substitution probabilty getTransistionProb <- function(nuc){ substitution[nuc,] } getTransistionProb5 <- function(fivemer){ if(any(which(fivemer==colnames(substitution)))){ return(substitution[,fivemer]) }else{ return(array(NA,4)) } } # Given a nuc, returns the other 3 nucs it can mutate to canMutateTo <- function(nuc){ NUCLEOTIDES[- which(NUCLEOTIDES==nuc)] } # Given a nucleotide, returns the probabilty of other nucleotide it can mutate to canMutateToProb <- function(nuc){ substitution[nuc,canMutateTo(nuc)] } # Compute targeting, based on precomputed mutatbility & substitution computeTargeting <- function(param_strSeq,param_vecMutabilities){ if(substitutionModel!=5){ vecSeq = s2c(param_strSeq) matTargeting = sapply( 1:length(vecSeq), function(x) { param_vecMutabilities[x] * getTransistionProb(vecSeq[x]) } ) #matTargeting = apply( rbind(vecSeq,param_vecMutabilities),2, function(x) { as.vector(as.numeric(x[2]) * getTransistionProb(x[1])) } ) dimnames( matTargeting ) = list(NUCLEOTIDES,1:(length(vecSeq))) return (matTargeting) }else{ seqLen = nchar(param_strSeq) seqsubstitution = matrix(NA,ncol=seqLen,nrow=4) paramSeq <- param_strSeq gaplessSeq = gsub("-", "", paramSeq) gaplessSeqLen = nchar(gaplessSeq) gaplessSeqSubstitution = matrix(NA,ncol=gaplessSeqLen,nrow=4) pos<- 3:(gaplessSeqLen) subSeq = substr(rep(gaplessSeq,gaplessSeqLen-2),(pos-2),(pos+2)) gaplessSeqSubstitution[,pos] = sapply(subSeq,function(x){ getTransistionProb5(x) }, simplify=T) seqsubstitution[,which(s2c(paramSeq)!="-")]<- gaplessSeqSubstitution #matTargeting <- param_vecMutabilities %*% seqsubstitution matTargeting <- sweep(seqsubstitution,2,param_vecMutabilities,`*`) dimnames( matTargeting ) = list(NUCLEOTIDES,1:(seqLen)) return (matTargeting) } } # Compute the mutations types computeMutationTypes <- function(param_strSeq){ #cat(param_strSeq,"\n") #vecSeq = trimToLastCodon(param_strSeq) lenSeq = nchar(param_strSeq) vecCodons = sapply({1:(lenSeq/3)}*3-2,function(x){substr(param_strSeq,x,x+2)}) matMutationTypes = matrix( unlist(CODON_TABLE[,vecCodons]) ,ncol=lenSeq,nrow=4, byrow=F) dimnames( matMutationTypes ) = list(NUCLEOTIDES,1:(ncol(matMutationTypes))) return(matMutationTypes) } computeMutationTypesFast <- function(param_strSeq){ matMutationTypes = matrix( CODON_TABLE[,param_strSeq] ,ncol=3,nrow=4, byrow=F) #dimnames( matMutationTypes ) = list(NUCLEOTIDES,1:(length(vecSeq))) return(matMutationTypes) } mutationTypeOptimized <- function( matOfCodons ){ apply( matOfCodons,1,function(x){ mutationType(x[2],x[1]) } ) } # Returns a vector of codons 1 mutation away from the given codon permutateAllCodon <- function(codon){ cCodon = s2c(codon) matCodons = t(array(cCodon,dim=c(3,12))) matCodons[1:4,1] = NUCLEOTIDES matCodons[5:8,2] = NUCLEOTIDES matCodons[9:12,3] = NUCLEOTIDES apply(matCodons,1,c2s) } # Given two codons, tells you if the mutation is R or S (based on your definition) mutationType <- function(codonFrom,codonTo){ if(testID==4){ if( is.na(codonFrom) | is.na(codonTo) | is.na(translateCodonToAminoAcid(codonFrom)) | is.na(translateCodonToAminoAcid(codonTo)) ){ return(NA) }else{ mutationType = "S" if( translateAminoAcidToTraitChange(translateCodonToAminoAcid(codonFrom)) != translateAminoAcidToTraitChange(translateCodonToAminoAcid(codonTo)) ){ mutationType = "R" } if(translateCodonToAminoAcid(codonTo)=="*" | translateCodonToAminoAcid(codonFrom)=="*"){ mutationType = "Stop" } return(mutationType) } }else if(testID==5){ if( is.na(codonFrom) | is.na(codonTo) | is.na(translateCodonToAminoAcid(codonFrom)) | is.na(translateCodonToAminoAcid(codonTo)) ){ return(NA) }else{ if(codonFrom==codonTo){ mutationType = "S" }else{ codonFrom = s2c(codonFrom) codonTo = s2c(codonTo) mutationType = "Stop" nucOfI = codonFrom[which(codonTo!=codonFrom)] if(nucOfI=="C"){ mutationType = "R" }else if(nucOfI=="G"){ mutationType = "S" } } return(mutationType) } }else{ if( is.na(codonFrom) | is.na(codonTo) | is.na(translateCodonToAminoAcid(codonFrom)) | is.na(translateCodonToAminoAcid(codonTo)) ){ return(NA) }else{ mutationType = "S" if( translateCodonToAminoAcid(codonFrom) != translateCodonToAminoAcid(codonTo) ){ mutationType = "R" } if(translateCodonToAminoAcid(codonTo)=="*" | translateCodonToAminoAcid(codonFrom)=="*"){ mutationType = "Stop" } return(mutationType) } } } #given a mat of targeting & it's corresponding mutationtypes returns #a vector of Exp_RCDR,Exp_SCDR,Exp_RFWR,Exp_RFWR computeExpected <- function(paramTargeting,paramMutationTypes){ # Replacements RPos = which(paramMutationTypes=="R") #FWR Exp_R_FWR = sum(paramTargeting[ RPos[which(FWR_Nuc_Mat[RPos]==T)] ],na.rm=T) #CDR Exp_R_CDR = sum(paramTargeting[ RPos[which(CDR_Nuc_Mat[RPos]==T)] ],na.rm=T) # Silents SPos = which(paramMutationTypes=="S") #FWR Exp_S_FWR = sum(paramTargeting[ SPos[which(FWR_Nuc_Mat[SPos]==T)] ],na.rm=T) #CDR Exp_S_CDR = sum(paramTargeting[ SPos[which(CDR_Nuc_Mat[SPos]==T)] ],na.rm=T) return(c(Exp_R_CDR,Exp_S_CDR,Exp_R_FWR,Exp_S_FWR)) } # Count the mutations in a sequence # each mutation is treated independently analyzeMutations2NucUri_website <- function( rev_in_matrix ){ paramGL = rev_in_matrix[2,] paramSeq = rev_in_matrix[1,] #Fill seq with GL seq if gapped #if( any(paramSeq=="-") ){ # gapPos_Seq = which(paramSeq=="-") # gapPos_Seq_ToReplace = gapPos_Seq[paramGL[gapPos_Seq] != "-"] # paramSeq[gapPos_Seq_ToReplace] = paramGL[gapPos_Seq_ToReplace] #} #if( any(paramSeq=="N") ){ # gapPos_Seq = which(paramSeq=="N") # gapPos_Seq_ToReplace = gapPos_Seq[paramGL[gapPos_Seq] != "N"] # paramSeq[gapPos_Seq_ToReplace] = paramGL[gapPos_Seq_ToReplace] #} analyzeMutations2NucUri( matrix(c( paramGL, paramSeq ),2,length(paramGL),byrow=T) ) } #1 = GL #2 = Seq analyzeMutations2NucUri <- function( in_matrix=matrix(c(c("A","A","A","C","C","C"),c("A","G","G","C","C","A")),2,6,byrow=T) ){ paramGL = in_matrix[2,] paramSeq = in_matrix[1,] paramSeqUri = paramGL #mutations = apply(rbind(paramGL,paramSeq), 2, function(x){!x[1]==x[2]}) mutations_val = paramGL != paramSeq if(any(mutations_val)){ mutationPos = {1:length(mutations_val)}[mutations_val] mutationPos = mutationPos[sapply(mutationPos, function(x){!any(paramSeq[getCodonPos(x)]=="N")})] length_mutations =length(mutationPos) mutationInfo = rep(NA,length_mutations) if(any(mutationPos)){ pos<- mutationPos pos_array<-array(sapply(pos,getCodonPos)) codonGL = paramGL[pos_array] codonSeq = sapply(pos,function(x){ seqP = paramGL[getCodonPos(x)] muCodonPos = {x-1}%%3+1 seqP[muCodonPos] = paramSeq[x] return(seqP) }) GLcodons = apply(matrix(codonGL,length_mutations,3,byrow=TRUE),1,c2s) Seqcodons = apply(codonSeq,2,c2s) mutationInfo = apply(rbind(GLcodons , Seqcodons),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) names(mutationInfo) = mutationPos } if(any(!is.na(mutationInfo))){ return(mutationInfo[!is.na(mutationInfo)]) }else{ return(NA) } }else{ return (NA) } } processNucMutations2 <- function(mu){ if(!is.na(mu)){ #R if(any(mu=="R")){ Rs = mu[mu=="R"] nucNumbs = as.numeric(names(Rs)) R_CDR = sum(as.integer(CDR_Nuc[nucNumbs]),na.rm=T) R_FWR = sum(as.integer(FWR_Nuc[nucNumbs]),na.rm=T) }else{ R_CDR = 0 R_FWR = 0 } #S if(any(mu=="S")){ Ss = mu[mu=="S"] nucNumbs = as.numeric(names(Ss)) S_CDR = sum(as.integer(CDR_Nuc[nucNumbs]),na.rm=T) S_FWR = sum(as.integer(FWR_Nuc[nucNumbs]),na.rm=T) }else{ S_CDR = 0 S_FWR = 0 } retVec = c(R_CDR,S_CDR,R_FWR,S_FWR) retVec[is.na(retVec)]=0 return(retVec) }else{ return(rep(0,4)) } } ## Z-score Test computeZScore <- function(mat, test="Focused"){ matRes <- matrix(NA,ncol=2,nrow=(nrow(mat))) if(test=="Focused"){ #Z_Focused_CDR #P_Denom = sum( mat[1,c(5,6,8)], na.rm=T ) P = apply(mat[,c(5,6,8)],1,function(x){(x[1]/sum(x))}) R_mean = apply(cbind(mat[,c(1,2,4)],P),1,function(x){x[4]*(sum(x[1:3]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,1] = (mat[,1]-R_mean)/R_sd #Z_Focused_FWR #P_Denom = sum( mat[1,c(7,6,8)], na.rm=T ) P = apply(mat[,c(7,6,8)],1,function(x){(x[1]/sum(x))}) R_mean = apply(cbind(mat[,c(3,2,4)],P),1,function(x){x[4]*(sum(x[1:3]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,2] = (mat[,3]-R_mean)/R_sd } if(test=="Local"){ #Z_Focused_CDR #P_Denom = sum( mat[1,c(5,6,8)], na.rm=T ) P = apply(mat[,c(5,6)],1,function(x){(x[1]/sum(x))}) R_mean = apply(cbind(mat[,c(1,2)],P),1,function(x){x[3]*(sum(x[1:2]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,1] = (mat[,1]-R_mean)/R_sd #Z_Focused_FWR #P_Denom = sum( mat[1,c(7,6,8)], na.rm=T ) P = apply(mat[,c(7,8)],1,function(x){(x[1]/sum(x))}) R_mean = apply(cbind(mat[,c(3,4)],P),1,function(x){x[3]*(sum(x[1:2]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,2] = (mat[,3]-R_mean)/R_sd } if(test=="Imbalanced"){ #Z_Focused_CDR #P_Denom = sum( mat[1,c(5,6,8)], na.rm=T ) P = apply(mat[,5:8],1,function(x){((x[1]+x[2])/sum(x))}) R_mean = apply(cbind(mat[,1:4],P),1,function(x){x[5]*(sum(x[1:4]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,1] = (mat[,1]-R_mean)/R_sd #Z_Focused_FWR #P_Denom = sum( mat[1,c(7,6,8)], na.rm=T ) P = apply(mat[,5:8],1,function(x){((x[3]+x[4])/sum(x))}) R_mean = apply(cbind(mat[,1:4],P),1,function(x){x[5]*(sum(x[1:4]))}) R_sd=sqrt(R_mean*(1-P)) matRes[,2] = (mat[,3]-R_mean)/R_sd } matRes[is.nan(matRes)] = NA return(matRes) } # Return a p-value for a z-score z2p <- function(z){ p=NA if( !is.nan(z) && !is.na(z)){ if(z>0){ p = (1 - pnorm(z,0,1)) } else if(z<0){ p = (-1 * pnorm(z,0,1)) } else{ p = 0.5 } }else{ p = NA } return(p) } ## Bayesian Test # Fitted parameter for the bayesian framework BAYESIAN_FITTED<-c(0.407277142798302, 0.554007336744485, 0.63777155771234, 0.693989162719009, 0.735450014674917, 0.767972534429806, 0.794557287143399, 0.816906816601605, 0.83606796225341, 0.852729446430296, 0.867370424541641, 0.880339760590323, 0.891900995024999, 0.902259181289864, 0.911577919359,0.919990301665853, 0.927606458124537, 0.934518806350661, 0.940805863754375, 0.946534836475715, 0.951763691199255, 0.95654428191308, 0.960920179487397, 0.964930893680829, 0.968611312149038, 0.971992459313836, 0.975102110004818, 0.977964943023096, 0.980603428208439, 0.983037660179428, 0.985285800977406, 0.987364285326685, 0.989288037855441, 0.991070478823525, 0.992723699729969, 0.994259575477392, 0.995687688867975, 0.997017365051493, 0.998257085153047, 0.999414558305388, 1.00049681357804, 1.00151036237481, 1.00246080204981, 1.00335370751909, 1.0041939329768, 1.0049859393417, 1.00573382091263, 1.00644127217376, 1.00711179729107, 1.00774845526417, 1.00835412715854, 1.00893143010366, 1.00948275846309, 1.01001030293661, 1.01051606798079, 1.01100188771288, 1.01146944044216, 1.01192026195449, 1.01235575766094, 1.01277721370986) CONST_i <- sort(c(((2^(seq(-39,0,length.out=201)))/2)[1:200],(c(0:11,13:99)+0.5)/100,1-(2^(seq(-39,0,length.out=201)))/2)) # Given x, M & p, returns a pdf calculate_bayes <- function ( x=3, N=10, p=0.33, i=CONST_i, max_sigma=20,length_sigma=4001 ){ if(!0%in%N){ G <- max(length(x),length(N),length(p)) x=array(x,dim=G) N=array(N,dim=G) p=array(p,dim=G) sigma_s<-seq(-max_sigma,max_sigma,length.out=length_sigma) sigma_1<-log({i/{1-i}}/{p/{1-p}}) index<-min(N,60) y<-dbeta(i,x+BAYESIAN_FITTED[index],N+BAYESIAN_FITTED[index]-x)*(1-p)*p*exp(sigma_1)/({1-p}^2+2*p*{1-p}*exp(sigma_1)+{p^2}*exp(2*sigma_1)) if(!sum(is.na(y))){ tmp<-approx(sigma_1,y,sigma_s)$y tmp/sum(tmp)/{2*max_sigma/{length_sigma-1}} }else{ return(NA) } }else{ return(NA) } } # Given a mat of observed & expected, return a list of CDR & FWR pdf for selection computeBayesianScore <- function(mat, test="Focused", max_sigma=20,length_sigma=4001){ flagOneSeq = F if(nrow(mat)==1){ mat=rbind(mat,mat) flagOneSeq = T } if(test=="Focused"){ #CDR P = c(apply(mat[,c(5,6,8)],1,function(x){(x[1]/sum(x))}),0.5) N = c(apply(mat[,c(1,2,4)],1,function(x){(sum(x))}),0) X = c(mat[,1],0) bayesCDR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesCDR = bayesCDR[-length(bayesCDR)] #FWR P = c(apply(mat[,c(7,6,8)],1,function(x){(x[1]/sum(x))}),0.5) N = c(apply(mat[,c(3,2,4)],1,function(x){(sum(x))}),0) X = c(mat[,3],0) bayesFWR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesFWR = bayesFWR[-length(bayesFWR)] } if(test=="Local"){ #CDR P = c(apply(mat[,c(5,6)],1,function(x){(x[1]/sum(x))}),0.5) N = c(apply(mat[,c(1,2)],1,function(x){(sum(x))}),0) X = c(mat[,1],0) bayesCDR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesCDR = bayesCDR[-length(bayesCDR)] #FWR P = c(apply(mat[,c(7,8)],1,function(x){(x[1]/sum(x))}),0.5) N = c(apply(mat[,c(3,4)],1,function(x){(sum(x))}),0) X = c(mat[,3],0) bayesFWR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesFWR = bayesFWR[-length(bayesFWR)] } if(test=="Imbalanced"){ #CDR P = c(apply(mat[,c(5:8)],1,function(x){((x[1]+x[2])/sum(x))}),0.5) N = c(apply(mat[,c(1:4)],1,function(x){(sum(x))}),0) X = c(apply(mat[,c(1:2)],1,function(x){(sum(x))}),0) bayesCDR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesCDR = bayesCDR[-length(bayesCDR)] #FWR P = c(apply(mat[,c(5:8)],1,function(x){((x[3]+x[4])/sum(x))}),0.5) N = c(apply(mat[,c(1:4)],1,function(x){(sum(x))}),0) X = c(apply(mat[,c(3:4)],1,function(x){(sum(x))}),0) bayesFWR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesFWR = bayesFWR[-length(bayesFWR)] } if(test=="ImbalancedSilent"){ #CDR P = c(apply(mat[,c(6,8)],1,function(x){((x[1])/sum(x))}),0.5) N = c(apply(mat[,c(2,4)],1,function(x){(sum(x))}),0) X = c(apply(mat[,c(2,4)],1,function(x){(x[1])}),0) bayesCDR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesCDR = bayesCDR[-length(bayesCDR)] #FWR P = c(apply(mat[,c(6,8)],1,function(x){((x[2])/sum(x))}),0.5) N = c(apply(mat[,c(2,4)],1,function(x){(sum(x))}),0) X = c(apply(mat[,c(2,4)],1,function(x){(x[2])}),0) bayesFWR = apply(cbind(X,N,P),1,function(x){calculate_bayes(x=x[1],N=x[2],p=x[3],max_sigma=max_sigma,length_sigma=length_sigma)}) bayesFWR = bayesFWR[-length(bayesFWR)] } if(flagOneSeq==T){ bayesCDR = bayesCDR[1] bayesFWR = bayesFWR[1] } return( list("CDR"=bayesCDR, "FWR"=bayesFWR) ) } ##Covolution break2chunks<-function(G=1000){ base<-2^round(log(sqrt(G),2),0) return(c(rep(base,floor(G/base)-1),base+G-(floor(G/base)*base))) } PowersOfTwo <- function(G=100){ exponents <- array() i = 0 while(G > 0){ i=i+1 exponents[i] <- floor( log2(G) ) G <- G-2^exponents[i] } return(exponents) } convolutionPowersOfTwo <- function( cons, length_sigma=4001 ){ G = ncol(cons) if(G>1){ for(gen in log(G,2):1){ ll<-seq(from=2,to=2^gen,by=2) sapply(ll,function(l){cons[,l/2]<<-weighted_conv(cons[,l],cons[,l-1],length_sigma=length_sigma)}) } } return( cons[,1] ) } convolutionPowersOfTwoByTwos <- function( cons, length_sigma=4001,G=1 ){ if(length(ncol(cons))) G<-ncol(cons) groups <- PowersOfTwo(G) matG <- matrix(NA, ncol=length(groups), nrow=length(cons)/G ) startIndex = 1 for( i in 1:length(groups) ){ stopIndex <- 2^groups[i] + startIndex - 1 if(stopIndex!=startIndex){ matG[,i] <- convolutionPowersOfTwo( cons[,startIndex:stopIndex], length_sigma=length_sigma ) startIndex = stopIndex + 1 } else { if(G>1) matG[,i] <- cons[,startIndex:stopIndex] else matG[,i] <- cons #startIndex = stopIndex + 1 } } return( list( matG, groups ) ) } weighted_conv<-function(x,y,w=1,m=100,length_sigma=4001){ lx<-length(x) ly<-length(y) if({lx<m}| {{lx*w}<m}| {{ly}<m}| {{ly*w}<m}){ if(w<1){ y1<-approx(1:ly,y,seq(1,ly,length.out=m))$y x1<-approx(1:lx,x,seq(1,lx,length.out=m/w))$y lx<-length(x1) ly<-length(y1) } else { y1<-approx(1:ly,y,seq(1,ly,length.out=m*w))$y x1<-approx(1:lx,x,seq(1,lx,length.out=m))$y lx<-length(x1) ly<-length(y1) } } else{ x1<-x y1<-approx(1:ly,y,seq(1,ly,length.out=floor(lx*w)))$y ly<-length(y1) } tmp<-approx(x=1:(lx+ly-1),y=convolve(x1,rev(y1),type="open"),xout=seq(1,lx+ly-1,length.out=length_sigma))$y tmp[tmp<=0] = 0 return(tmp/sum(tmp)) } calculate_bayesGHelper <- function( listMatG,length_sigma=4001 ){ matG <- listMatG[[1]] groups <- listMatG[[2]] i = 1 resConv <- matG[,i] denom <- 2^groups[i] if(length(groups)>1){ while( i<length(groups) ){ i = i + 1 resConv <- weighted_conv(resConv, matG[,i], w= {{2^groups[i]}/denom} ,length_sigma=length_sigma) #cat({{2^groups[i]}/denom},"\n") denom <- denom + 2^groups[i] } } return(resConv) } # Given a list of PDFs, returns a convoluted PDF groupPosteriors <- function( listPosteriors, max_sigma=20, length_sigma=4001 ,Threshold=2 ){ listPosteriors = listPosteriors[ !is.na(listPosteriors) ] Length_Postrior<-length(listPosteriors) if(Length_Postrior>1 & Length_Postrior<=Threshold){ cons = matrix(unlist(listPosteriors),length(listPosteriors[[1]]),length(listPosteriors)) listMatG <- convolutionPowersOfTwoByTwos(cons,length_sigma=length_sigma) y<-calculate_bayesGHelper(listMatG,length_sigma=length_sigma) return( y/sum(y)/(2*max_sigma/(length_sigma-1)) ) }else if(Length_Postrior==1) return(listPosteriors[[1]]) else if(Length_Postrior==0) return(NA) else { cons = matrix(unlist(listPosteriors),length(listPosteriors[[1]]),length(listPosteriors)) y = fastConv(cons,max_sigma=max_sigma, length_sigma=length_sigma ) return( y/sum(y)/(2*max_sigma/(length_sigma-1)) ) } } fastConv<-function(cons, max_sigma=20, length_sigma=4001){ chunks<-break2chunks(G=ncol(cons)) if(ncol(cons)==3) chunks<-2:1 index_chunks_end <- cumsum(chunks) index_chunks_start <- c(1,index_chunks_end[-length(index_chunks_end)]+1) index_chunks <- cbind(index_chunks_start,index_chunks_end) case <- sum(chunks!=chunks[1]) if(case==1) End <- max(1,((length(index_chunks)/2)-1)) else End <- max(1,((length(index_chunks)/2))) firsts <- sapply(1:End,function(i){ indexes<-index_chunks[i,1]:index_chunks[i,2] convolutionPowersOfTwoByTwos(cons[ ,indexes])[[1]] }) if(case==0){ result<-calculate_bayesGHelper( convolutionPowersOfTwoByTwos(firsts) ) }else if(case==1){ last<-list(calculate_bayesGHelper( convolutionPowersOfTwoByTwos( cons[ ,index_chunks[length(index_chunks)/2,1]:index_chunks[length(index_chunks)/2,2]] ) ),0) result_first<-calculate_bayesGHelper(convolutionPowersOfTwoByTwos(firsts)) result<-calculate_bayesGHelper( list( cbind( result_first,last[[1]]), c(log(index_chunks_end[length(index_chunks)/2-1],2),log(index_chunks[length(index_chunks)/2,2]-index_chunks[length(index_chunks)/2,1]+1,2)) ) ) } return(as.vector(result)) } # Computes the 95% CI for a pdf calcBayesCI <- function(Pdf,low=0.025,up=0.975,max_sigma=20, length_sigma=4001){ if(length(Pdf)!=length_sigma) return(NA) sigma_s=seq(-max_sigma,max_sigma,length.out=length_sigma) cdf = cumsum(Pdf) cdf = cdf/cdf[length(cdf)] return( c(sigma_s[findInterval(low,cdf)-1] , sigma_s[findInterval(up,cdf)]) ) } # Computes a mean for a pdf calcBayesMean <- function(Pdf,max_sigma=20,length_sigma=4001){ if(length(Pdf)!=length_sigma) return(NA) sigma_s=seq(-max_sigma,max_sigma,length.out=length_sigma) norm = {length_sigma-1}/2/max_sigma return( (Pdf%*%sigma_s/norm) ) } # Returns the mean, and the 95% CI for a pdf calcBayesOutputInfo <- function(Pdf,low=0.025,up=0.975,max_sigma=20, length_sigma=4001){ if(is.na(Pdf)) return(rep(NA,3)) bCI = calcBayesCI(Pdf=Pdf,low=low,up=up,max_sigma=max_sigma,length_sigma=length_sigma) bMean = calcBayesMean(Pdf=Pdf,max_sigma=max_sigma,length_sigma=length_sigma) return(c(bMean, bCI)) } # Computes the p-value of a pdf computeSigmaP <- function(Pdf, length_sigma=4001, max_sigma=20){ if(length(Pdf)>1){ norm = {length_sigma-1}/2/max_sigma pVal = {sum(Pdf[1:{{length_sigma-1}/2}]) + Pdf[{{length_sigma+1}/2}]/2}/norm if(pVal>0.5){ pVal = pVal-1 } return(pVal) }else{ return(NA) } } # Compute p-value of two distributions compareTwoDistsFaster <-function(sigma_S=seq(-20,20,length.out=4001), N=10000, dens1=runif(4001,0,1), dens2=runif(4001,0,1)){ #print(c(length(dens1),length(dens2))) if(length(dens1)>1 & length(dens2)>1 ){ dens1<-dens1/sum(dens1) dens2<-dens2/sum(dens2) cum2 <- cumsum(dens2)-dens2/2 tmp<- sum(sapply(1:length(dens1),function(i)return(dens1[i]*cum2[i]))) #print(tmp) if(tmp>0.5)tmp<-tmp-1 return( tmp ) } else { return(NA) } #return (sum(sapply(1:N,function(i)(sample(sigma_S,1,prob=dens1)>sample(sigma_S,1,prob=dens2))))/N) } # get number of seqeunces contributing to the sigma (i.e. seqeunces with mutations) numberOfSeqsWithMutations <- function(matMutations,test=1){ if(test==4)test=2 cdrSeqs <- 0 fwrSeqs <- 0 if(test==1){#focused cdrMutations <- apply(matMutations, 1, function(x){ sum(x[c(1,2,4)]) }) fwrMutations <- apply(matMutations, 1, function(x){ sum(x[c(3,4,2)]) }) if( any(which(cdrMutations>0)) ) cdrSeqs <- sum(cdrMutations>0) if( any(which(fwrMutations>0)) ) fwrSeqs <- sum(fwrMutations>0) } if(test==2){#local cdrMutations <- apply(matMutations, 1, function(x){ sum(x[c(1,2)]) }) fwrMutations <- apply(matMutations, 1, function(x){ sum(x[c(3,4)]) }) if( any(which(cdrMutations>0)) ) cdrSeqs <- sum(cdrMutations>0) if( any(which(fwrMutations>0)) ) fwrSeqs <- sum(fwrMutations>0) } return(c("CDR"=cdrSeqs, "FWR"=fwrSeqs)) } shadeColor <- function(sigmaVal=NA,pVal=NA){ if(is.na(sigmaVal) & is.na(pVal)) return(NA) if(is.na(sigmaVal) & !is.na(pVal)) sigmaVal=sign(pVal) if(is.na(pVal) || pVal==1 || pVal==0){ returnColor = "#FFFFFF"; }else{ colVal=abs(pVal); if(sigmaVal<0){ if(colVal>0.1) returnColor = "#CCFFCC"; if(colVal<=0.1) returnColor = "#99FF99"; if(colVal<=0.050) returnColor = "#66FF66"; if(colVal<=0.010) returnColor = "#33FF33"; if(colVal<=0.005) returnColor = "#00FF00"; }else{ if(colVal>0.1) returnColor = "#FFCCCC"; if(colVal<=0.1) returnColor = "#FF9999"; if(colVal<=0.05) returnColor = "#FF6666"; if(colVal<=0.01) returnColor = "#FF3333"; if(colVal<0.005) returnColor = "#FF0000"; } } return(returnColor) } plotHelp <- function(xfrac=0.05,yfrac=0.05,log=FALSE){ if(!log){ x = par()$usr[1]-(par()$usr[2]-par()$usr[1])*xfrac y = par()$usr[4]+(par()$usr[4]-par()$usr[3])*yfrac }else { if(log==2){ x = par()$usr[1]-(par()$usr[2]-par()$usr[1])*xfrac y = 10^((par()$usr[4])+((par()$usr[4])-(par()$usr[3]))*yfrac) } if(log==1){ x = 10^((par()$usr[1])-((par()$usr[2])-(par()$usr[1]))*xfrac) y = par()$usr[4]+(par()$usr[4]-par()$usr[3])*yfrac } if(log==3){ x = 10^((par()$usr[1])-((par()$usr[2])-(par()$usr[1]))*xfrac) y = 10^((par()$usr[4])+((par()$usr[4])-(par()$usr[3]))*yfrac) } } return(c("x"=x,"y"=y)) } # SHMulation # Based on targeting, introduce a single mutation & then update the targeting oneMutation <- function(){ # Pick a postion + mutation posMutation = sample(1:(seqGermlineLen*4),1,replace=F,prob=as.vector(seqTargeting)) posNucNumb = ceiling(posMutation/4) # Nucleotide number posNucKind = 4 - ( (posNucNumb*4) - posMutation ) # Nuc the position mutates to #mutate the simulation sequence seqSimVec <- s2c(seqSim) seqSimVec[posNucNumb] <- NUCLEOTIDES[posNucKind] seqSim <<- c2s(seqSimVec) #update Mutability, Targeting & MutationsTypes updateMutabilityNTargeting(posNucNumb) #return(c(posNucNumb,NUCLEOTIDES[posNucKind])) return(posNucNumb) } updateMutabilityNTargeting <- function(position){ min_i<-max((position-2),1) max_i<-min((position+2),nchar(seqSim)) min_ii<-min(min_i,3) #mutability - update locally seqMutability[(min_i):(max_i)] <<- computeMutabilities(substr(seqSim,position-4,position+4))[(min_ii):(max_i-min_i+min_ii)] #targeting - compute locally seqTargeting[,min_i:max_i] <<- computeTargeting(substr(seqSim,min_i,max_i),seqMutability[min_i:max_i]) seqTargeting[is.na(seqTargeting)] <<- 0 #mutCodonPos = getCodonPos(position) mutCodonPos = seq(getCodonPos(min_i)[1],getCodonPos(max_i)[3]) #cat(mutCodonPos,"\n") mutTypeCodon = getCodonPos(position) seqMutationTypes[,mutTypeCodon] <<- computeMutationTypesFast( substr(seqSim,mutTypeCodon[1],mutTypeCodon[3]) ) # Stop = 0 if(any(seqMutationTypes[,mutCodonPos]=="Stop",na.rm=T )){ seqTargeting[,mutCodonPos][seqMutationTypes[,mutCodonPos]=="Stop"] <<- 0 } #Selection selectedPos = (min_i*4-4)+(which(seqMutationTypes[,min_i:max_i]=="R")) # CDR selectedCDR = selectedPos[which(matCDR[selectedPos]==T)] seqTargeting[selectedCDR] <<- seqTargeting[selectedCDR] * exp(selCDR) seqTargeting[selectedCDR] <<- seqTargeting[selectedCDR]/baseLineCDR_K # FWR selectedFWR = selectedPos[which(matFWR[selectedPos]==T)] seqTargeting[selectedFWR] <<- seqTargeting[selectedFWR] * exp(selFWR) seqTargeting[selectedFWR] <<- seqTargeting[selectedFWR]/baseLineFWR_K } # Validate the mutation: if the mutation has not been sampled before validate it, else discard it. validateMutation <- function(){ if( !(mutatedPos%in%mutatedPositions) ){ # if it's a new mutation uniqueMutationsIntroduced <<- uniqueMutationsIntroduced + 1 mutatedPositions[uniqueMutationsIntroduced] <<- mutatedPos }else{ if(substr(seqSim,mutatedPos,mutatedPos)==substr(seqGermline,mutatedPos,mutatedPos)){ # back to germline mutation mutatedPositions <<- mutatedPositions[-which(mutatedPositions==mutatedPos)] uniqueMutationsIntroduced <<- uniqueMutationsIntroduced - 1 } } } # Places text (labels) at normalized coordinates myaxis <- function(xfrac=0.05,yfrac=0.05,log=FALSE,w="text",cex=1,adj=1,thecol="black"){ par(xpd=TRUE) if(!log) text(par()$usr[1]-(par()$usr[2]-par()$usr[1])*xfrac,par()$usr[4]+(par()$usr[4]-par()$usr[3])*yfrac,w,cex=cex,adj=adj,col=thecol) else { if(log==2) text( par()$usr[1]-(par()$usr[2]-par()$usr[1])*xfrac, 10^((par()$usr[4])+((par()$usr[4])-(par()$usr[3]))*yfrac), w,cex=cex,adj=adj,col=thecol) if(log==1) text( 10^((par()$usr[1])-((par()$usr[2])-(par()$usr[1]))*xfrac), par()$usr[4]+(par()$usr[4]-par()$usr[3])*yfrac, w,cex=cex,adj=adj,col=thecol) if(log==3) text( 10^((par()$usr[1])-((par()$usr[2])-(par()$usr[1]))*xfrac), 10^((par()$usr[4])+((par()$usr[4])-(par()$usr[3]))*yfrac), w,cex=cex,adj=adj,col=thecol) } par(xpd=FALSE) } # Count the mutations in a sequence analyzeMutations <- function( inputMatrixIndex, model = 0 , multipleMutation=0, seqWithStops=0){ paramGL = s2c(matInput[inputMatrixIndex,2]) paramSeq = s2c(matInput[inputMatrixIndex,1]) #if( any(paramSeq=="N") ){ # gapPos_Seq = which(paramSeq=="N") # gapPos_Seq_ToReplace = gapPos_Seq[paramGL[gapPos_Seq] != "N"] # paramSeq[gapPos_Seq_ToReplace] = paramGL[gapPos_Seq_ToReplace] #} mutations_val = paramGL != paramSeq if(any(mutations_val)){ mutationPos = which(mutations_val)#{1:length(mutations_val)}[mutations_val] length_mutations =length(mutationPos) mutationInfo = rep(NA,length_mutations) pos<- mutationPos pos_array<-array(sapply(pos,getCodonPos)) codonGL = paramGL[pos_array] codonSeqWhole = paramSeq[pos_array] codonSeq = sapply(pos,function(x){ seqP = paramGL[getCodonPos(x)] muCodonPos = {x-1}%%3+1 seqP[muCodonPos] = paramSeq[x] return(seqP) }) GLcodons = apply(matrix(codonGL,length_mutations,3,byrow=TRUE),1,c2s) SeqcodonsWhole = apply(matrix(codonSeqWhole,length_mutations,3,byrow=TRUE),1,c2s) Seqcodons = apply(codonSeq,2,c2s) mutationInfo = apply(rbind(GLcodons , Seqcodons),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) names(mutationInfo) = mutationPos mutationInfoWhole = apply(rbind(GLcodons , SeqcodonsWhole),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) names(mutationInfoWhole) = mutationPos mutationInfo <- mutationInfo[!is.na(mutationInfo)] mutationInfoWhole <- mutationInfoWhole[!is.na(mutationInfoWhole)] if(any(!is.na(mutationInfo))){ #Filter based on Stop (at the codon level) if(seqWithStops==1){ nucleotidesAtStopCodons = names(mutationInfoWhole[mutationInfoWhole!="Stop"]) mutationInfo = mutationInfo[nucleotidesAtStopCodons] mutationInfoWhole = mutationInfo[nucleotidesAtStopCodons] }else{ countStops = sum(mutationInfoWhole=="Stop") if(seqWithStops==2 & countStops==0) mutationInfo = NA if(seqWithStops==3 & countStops>0) mutationInfo = NA } if(any(!is.na(mutationInfo))){ #Filter mutations based on multipleMutation if(multipleMutation==1 & !is.na(mutationInfo)){ mutationCodons = getCodonNumb(as.numeric(names(mutationInfoWhole))) tableMutationCodons <- table(mutationCodons) codonsWithMultipleMutations <- as.numeric(names(tableMutationCodons[tableMutationCodons>1])) if(any(codonsWithMultipleMutations)){ #remove the nucleotide mutations in the codons with multiple mutations mutationInfo <- mutationInfo[!(mutationCodons %in% codonsWithMultipleMutations)] #replace those codons with Ns in the input sequence paramSeq[unlist(lapply(codonsWithMultipleMutations, getCodonNucs))] = "N" matInput[inputMatrixIndex,1] <<- c2s(paramSeq) } } #Filter mutations based on the model if(any(mutationInfo)==T | is.na(any(mutationInfo))){ if(model==1 & !is.na(mutationInfo)){ mutationInfo <- mutationInfo[mutationInfo=="S"] } if(any(mutationInfo)==T | is.na(any(mutationInfo))) return(mutationInfo) else return(NA) }else{ return(NA) } }else{ return(NA) } }else{ return(NA) } }else{ return (NA) } } analyzeMutationsFixed <- function( inputArray, model = 0 , multipleMutation=0, seqWithStops=0){ paramGL = s2c(inputArray[2]) paramSeq = s2c(inputArray[1]) inputSeq <- inputArray[1] #if( any(paramSeq=="N") ){ # gapPos_Seq = which(paramSeq=="N") # gapPos_Seq_ToReplace = gapPos_Seq[paramGL[gapPos_Seq] != "N"] # paramSeq[gapPos_Seq_ToReplace] = paramGL[gapPos_Seq_ToReplace] #} mutations_val = paramGL != paramSeq if(any(mutations_val)){ mutationPos = which(mutations_val)#{1:length(mutations_val)}[mutations_val] length_mutations =length(mutationPos) mutationInfo = rep(NA,length_mutations) pos<- mutationPos pos_array<-array(sapply(pos,getCodonPos)) codonGL = paramGL[pos_array] codonSeqWhole = paramSeq[pos_array] codonSeq = sapply(pos,function(x){ seqP = paramGL[getCodonPos(x)] muCodonPos = {x-1}%%3+1 seqP[muCodonPos] = paramSeq[x] return(seqP) }) GLcodons = apply(matrix(codonGL,length_mutations,3,byrow=TRUE),1,c2s) SeqcodonsWhole = apply(matrix(codonSeqWhole,length_mutations,3,byrow=TRUE),1,c2s) Seqcodons = apply(codonSeq,2,c2s) mutationInfo = apply(rbind(GLcodons , Seqcodons),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) names(mutationInfo) = mutationPos mutationInfoWhole = apply(rbind(GLcodons , SeqcodonsWhole),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) names(mutationInfoWhole) = mutationPos mutationInfo <- mutationInfo[!is.na(mutationInfo)] mutationInfoWhole <- mutationInfoWhole[!is.na(mutationInfoWhole)] if(any(!is.na(mutationInfo))){ #Filter based on Stop (at the codon level) if(seqWithStops==1){ nucleotidesAtStopCodons = names(mutationInfoWhole[mutationInfoWhole!="Stop"]) mutationInfo = mutationInfo[nucleotidesAtStopCodons] mutationInfoWhole = mutationInfo[nucleotidesAtStopCodons] }else{ countStops = sum(mutationInfoWhole=="Stop") if(seqWithStops==2 & countStops==0) mutationInfo = NA if(seqWithStops==3 & countStops>0) mutationInfo = NA } if(any(!is.na(mutationInfo))){ #Filter mutations based on multipleMutation if(multipleMutation==1 & !is.na(mutationInfo)){ mutationCodons = getCodonNumb(as.numeric(names(mutationInfoWhole))) tableMutationCodons <- table(mutationCodons) codonsWithMultipleMutations <- as.numeric(names(tableMutationCodons[tableMutationCodons>1])) if(any(codonsWithMultipleMutations)){ #remove the nucleotide mutations in the codons with multiple mutations mutationInfo <- mutationInfo[!(mutationCodons %in% codonsWithMultipleMutations)] #replace those codons with Ns in the input sequence paramSeq[unlist(lapply(codonsWithMultipleMutations, getCodonNucs))] = "N" #matInput[inputMatrixIndex,1] <<- c2s(paramSeq) inputSeq <- c2s(paramSeq) } } #Filter mutations based on the model if(any(mutationInfo)==T | is.na(any(mutationInfo))){ if(model==1 & !is.na(mutationInfo)){ mutationInfo <- mutationInfo[mutationInfo=="S"] } if(any(mutationInfo)==T | is.na(any(mutationInfo))) return(list(mutationInfo,inputSeq)) else return(list(NA,inputSeq)) }else{ return(list(NA,inputSeq)) } }else{ return(list(NA,inputSeq)) } }else{ return(list(NA,inputSeq)) } }else{ return (list(NA,inputSeq)) } } # triMutability Background Count buildMutabilityModel <- function( inputMatrixIndex, model=0 , multipleMutation=0, seqWithStops=0, stopMutations=0){ #rowOrigMatInput = matInput[inputMatrixIndex,] seqGL = gsub("-", "", matInput[inputMatrixIndex,2]) seqInput = gsub("-", "", matInput[inputMatrixIndex,1]) #matInput[inputMatrixIndex,] <<- cbind(seqInput,seqGL) tempInput <- cbind(seqInput,seqGL) seqLength = nchar(seqGL) list_analyzeMutationsFixed<- analyzeMutationsFixed(tempInput, model, multipleMutation, seqWithStops) mutationCount <- list_analyzeMutationsFixed[[1]] seqInput <- list_analyzeMutationsFixed[[2]] BackgroundMatrix = mutabilityMatrix MutationMatrix = mutabilityMatrix MutationCountMatrix = mutabilityMatrix if(!is.na(mutationCount)){ if((stopMutations==0 & model==0) | (stopMutations==1 & (sum(mutationCount=="Stop")<length(mutationCount))) | (model==1 & (sum(mutationCount=="S")>0)) ){ fivermerStartPos = 1:(seqLength-4) fivemerLength <- length(fivermerStartPos) fivemerGL <- substr(rep(seqGL,length(fivermerStartPos)),(fivermerStartPos),(fivermerStartPos+4)) fivemerSeq <- substr(rep(seqInput,length(fivermerStartPos)),(fivermerStartPos),(fivermerStartPos+4)) #Background for(fivemerIndex in 1:fivemerLength){ fivemer = fivemerGL[fivemerIndex] if(!any(grep("N",fivemer))){ fivemerCodonPos = fivemerCodon(fivemerIndex) fivemerReadingFrameCodon = substr(fivemer,fivemerCodonPos[1],fivemerCodonPos[3]) fivemerReadingFrameCodonInputSeq = substr(fivemerSeq[fivemerIndex],fivemerCodonPos[1],fivemerCodonPos[3]) # All mutations model #if(!any(grep("N",fivemerReadingFrameCodon))){ if(model==0){ if(stopMutations==0){ if(!any(grep("N",fivemerReadingFrameCodonInputSeq))) BackgroundMatrix[fivemer] <- (BackgroundMatrix[fivemer] + 1) }else{ if( !any(grep("N",fivemerReadingFrameCodonInputSeq)) & translateCodonToAminoAcid(fivemerReadingFrameCodon)!="*" ){ positionWithinCodon = which(fivemerCodonPos==3)#positionsWithinCodon[(fivemerCodonPos[1]%%3)+1] BackgroundMatrix[fivemer] <- (BackgroundMatrix[fivemer] + probNonStopMutations[fivemerReadingFrameCodon,positionWithinCodon]) } } }else{ # Only silent mutations if( !any(grep("N",fivemerReadingFrameCodonInputSeq)) & translateCodonToAminoAcid(fivemerReadingFrameCodon)!="*" & translateCodonToAminoAcid(fivemerReadingFrameCodonInputSeq)==translateCodonToAminoAcid(fivemerReadingFrameCodon)){ positionWithinCodon = which(fivemerCodonPos==3) BackgroundMatrix[fivemer] <- (BackgroundMatrix[fivemer] + probSMutations[fivemerReadingFrameCodon,positionWithinCodon]) } } #} } } #Mutations if(stopMutations==1) mutationCount = mutationCount[mutationCount!="Stop"] if(model==1) mutationCount = mutationCount[mutationCount=="S"] mutationPositions = as.numeric(names(mutationCount)) mutationCount = mutationCount[mutationPositions>2 & mutationPositions<(seqLength-1)] mutationPositions = mutationPositions[mutationPositions>2 & mutationPositions<(seqLength-1)] countMutations = 0 for(mutationPosition in mutationPositions){ fivemerIndex = mutationPosition-2 fivemer = fivemerSeq[fivemerIndex] GLfivemer = fivemerGL[fivemerIndex] fivemerCodonPos = fivemerCodon(fivemerIndex) fivemerReadingFrameCodon = substr(fivemer,fivemerCodonPos[1],fivemerCodonPos[3]) fivemerReadingFrameCodonGL = substr(GLfivemer,fivemerCodonPos[1],fivemerCodonPos[3]) if(!any(grep("N",fivemer)) & !any(grep("N",GLfivemer))){ if(model==0){ countMutations = countMutations + 1 MutationMatrix[GLfivemer] <- (MutationMatrix[GLfivemer] + 1) MutationCountMatrix[GLfivemer] <- (MutationCountMatrix[GLfivemer] + 1) }else{ if( translateCodonToAminoAcid(fivemerReadingFrameCodonGL)!="*" ){ countMutations = countMutations + 1 positionWithinCodon = which(fivemerCodonPos==3) glNuc = substr(fivemerReadingFrameCodonGL,positionWithinCodon,positionWithinCodon) inputNuc = substr(fivemerReadingFrameCodon,positionWithinCodon,positionWithinCodon) MutationMatrix[GLfivemer] <- (MutationMatrix[GLfivemer] + substitution[glNuc,inputNuc]) MutationCountMatrix[GLfivemer] <- (MutationCountMatrix[GLfivemer] + 1) } } } } seqMutability = MutationMatrix/BackgroundMatrix seqMutability = seqMutability/sum(seqMutability,na.rm=TRUE) #cat(inputMatrixIndex,"\t",countMutations,"\n") return(list("seqMutability" = seqMutability,"numbMutations" = countMutations,"seqMutabilityCount" = MutationCountMatrix, "BackgroundMatrix"=BackgroundMatrix)) } } } #Returns the codon position containing the middle nucleotide fivemerCodon <- function(fivemerIndex){ codonPos = list(2:4,1:3,3:5) fivemerType = fivemerIndex%%3 return(codonPos[[fivemerType+1]]) } #returns probability values for one mutation in codons resulting in R, S or Stop probMutations <- function(typeOfMutation){ matMutationProb <- matrix(0,ncol=3,nrow=125,dimnames=list(words(alphabet = c(NUCLEOTIDES,"N"), length=3),c(1:3))) for(codon in rownames(matMutationProb)){ if( !any(grep("N",codon)) ){ for(muPos in 1:3){ matCodon = matrix(rep(s2c(codon),3),nrow=3,ncol=3,byrow=T) glNuc = matCodon[1,muPos] matCodon[,muPos] = canMutateTo(glNuc) substitutionRate = substitution[glNuc,matCodon[,muPos]] typeOfMutations = apply(rbind(rep(codon,3),apply(matCodon,1,c2s)),2,function(x){mutationType(c2s(x[1]),c2s(x[2]))}) matMutationProb[codon,muPos] <- sum(substitutionRate[typeOfMutations==typeOfMutation]) } } } return(matMutationProb) } #Mapping Trinucleotides to fivemers mapTriToFivemer <- function(triMutability=triMutability_Literature_Human){ rownames(triMutability) <- triMutability_Names Fivemer<-rep(NA,1024) names(Fivemer)<-words(alphabet=NUCLEOTIDES,length=5) Fivemer<-sapply(names(Fivemer),function(Word)return(sum( c(triMutability[substring(Word,3,5),1],triMutability[substring(Word,2,4),2],triMutability[substring(Word,1,3),3]),na.rm=TRUE))) Fivemer<-Fivemer/sum(Fivemer) return(Fivemer) } collapseFivemerToTri<-function(Fivemer,Weights=MutabilityWeights,position=1,NUC="A"){ Indices<-substring(names(Fivemer),3,3)==NUC Factors<-substring(names(Fivemer[Indices]),(4-position),(6-position)) tapply(which(Indices),Factors,function(i)weighted.mean(Fivemer[i],Weights[i],na.rm=TRUE)) } CountFivemerToTri<-function(Fivemer,Weights=MutabilityWeights,position=1,NUC="A"){ Indices<-substring(names(Fivemer),3,3)==NUC Factors<-substring(names(Fivemer[Indices]),(4-position),(6-position)) tapply(which(Indices),Factors,function(i)sum(Weights[i],na.rm=TRUE)) } #Uses the real counts of the mutated fivemers CountFivemerToTri2<-function(Fivemer,Counts=MutabilityCounts,position=1,NUC="A"){ Indices<-substring(names(Fivemer),3,3)==NUC Factors<-substring(names(Fivemer[Indices]),(4-position),(6-position)) tapply(which(Indices),Factors,function(i)sum(Counts[i],na.rm=TRUE)) } bootstrap<-function(x=c(33,12,21),M=10000,alpha=0.05){ N<-sum(x) if(N){ p<-x/N k<-length(x)-1 tmp<-rmultinom(M, size = N, prob=p) tmp_p<-apply(tmp,2,function(y)y/N) (apply(tmp_p,1,function(y)quantile(y,c(alpha/2/k,1-alpha/2/k)))) } else return(matrix(0,2,length(x))) } bootstrap2<-function(x=c(33,12,21),n=10,M=10000,alpha=0.05){ N<-sum(x) k<-length(x) y<-rep(1:k,x) tmp<-sapply(1:M,function(i)sample(y,n)) if(n>1)tmp_p<-sapply(1:M,function(j)sapply(1:k,function(i)sum(tmp[,j]==i)))/n if(n==1)tmp_p<-sapply(1:M,function(j)sapply(1:k,function(i)sum(tmp[j]==i)))/n (apply(tmp_p,1,function(z)quantile(z,c(alpha/2/(k-1),1-alpha/2/(k-1))))) } p_value<-function(x=c(33,12,21),M=100000,x_obs=c(2,5,3)){ n=sum(x_obs) N<-sum(x) k<-length(x) y<-rep(1:k,x) tmp<-sapply(1:M,function(i)sample(y,n)) if(n>1)tmp_p<-sapply(1:M,function(j)sapply(1:k,function(i)sum(tmp[,j]==i))) if(n==1)tmp_p<-sapply(1:M,function(j)sapply(1:k,function(i)sum(tmp[j]==i))) tmp<-rbind(sapply(1:3,function(i)sum(tmp_p[i,]>=x_obs[i])/M), sapply(1:3,function(i)sum(tmp_p[i,]<=x_obs[i])/M)) sapply(1:3,function(i){if(tmp[1,i]>=tmp[2,i])return(-tmp[2,i])else return(tmp[1,i])}) } #"D:\\Sequences\\IMGT Germlines\\Human_SNPless_IGHJ.FASTA" # Remove SNPs from IMGT germline segment alleles generateUnambiguousRepertoire <- function(repertoireInFile,repertoireOutFile){ repertoireIn <- read.fasta(repertoireInFile, seqtype="DNA",as.string=T,set.attributes=F,forceDNAtolower=F) alleleNames <- sapply(names(repertoireIn),function(x)strsplit(x,"|",fixed=TRUE)[[1]][2]) SNPs <- tapply(repertoireIn,sapply(alleleNames,function(x)strsplit(x,"*",fixed=TRUE)[[1]][1]),function(x){ Indices<-NULL for(i in 1:length(x)){ firstSeq = s2c(x[[1]]) iSeq = s2c(x[[i]]) Indices<-c(Indices,which(firstSeq[1:320]!=iSeq[1:320] & firstSeq[1:320]!="." & iSeq[1:320]!="." )) } return(sort(unique(Indices))) }) repertoireOut <- repertoireIn repertoireOut <- lapply(names(repertoireOut), function(repertoireName){ alleleName <- strsplit(repertoireName,"|",fixed=TRUE)[[1]][2] geneSegmentName <- strsplit(alleleName,"*",fixed=TRUE)[[1]][1] alleleSeq <- s2c(repertoireOut[[repertoireName]]) alleleSeq[as.numeric(unlist(SNPs[geneSegmentName]))] <- "N" alleleSeq <- c2s(alleleSeq) repertoireOut[[repertoireName]] <- alleleSeq }) names(repertoireOut) <- names(repertoireIn) write.fasta(repertoireOut,names(repertoireOut),file.out=repertoireOutFile) } ############ groupBayes2 = function(indexes, param_resultMat){ BayesGDist_Focused_CDR = calculate_bayesG( x=param_resultMat[indexes,1], N=apply(param_resultMat[indexes,c(1,2,4)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[1]/(x[1]+x[2]+x[4])})) BayesGDist_Focused_FWR = calculate_bayesG( x=param_resultMat[indexes,3], N=apply(param_resultMat[indexes,c(3,2,4)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[3]/(x[3]+x[2]+x[4])})) #BayesGDist_Local_CDR = calculate_bayesG( x=param_resultMat[indexes,1], N=apply(param_resultMat[indexes,c(1,2)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[1]/(x[1]+x[2])})) #BayesGDist_Local_FWR = calculate_bayesG( x=param_resultMat[indexes,3], N=apply(param_resultMat[indexes,c(3,4)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[3]/(x[3]+x[4])})) #BayesGDist_Global_CDR = calculate_bayesG( x=param_resultMat[indexes,1], N=apply(param_resultMat[indexes,c(1,2,3,4)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[1]/(x[1]+x[2]+x[3]+x[4])})) #BayesGDist_Global_FWR = calculate_bayesG( x=param_resultMat[indexes,3], N=apply(param_resultMat[indexes,c(1,2,3,4)],1,sum,na.rm=T), p=apply(param_resultMat[indexes,5:8],1,function(x){x[3]/(x[1]+x[2]+x[3]+x[4])})) return ( list("BayesGDist_Focused_CDR"=BayesGDist_Focused_CDR, "BayesGDist_Focused_FWR"=BayesGDist_Focused_FWR) ) #"BayesGDist_Local_CDR"=BayesGDist_Local_CDR, #"BayesGDist_Local_FWR" = BayesGDist_Local_FWR)) # "BayesGDist_Global_CDR" = BayesGDist_Global_CDR, # "BayesGDist_Global_FWR" = BayesGDist_Global_FWR) ) } calculate_bayesG <- function( x=array(), N=array(), p=array(), max_sigma=20, length_sigma=4001){ G <- max(length(x),length(N),length(p)) x=array(x,dim=G) N=array(N,dim=G) p=array(p,dim=G) indexOfZero = N>0 & p>0 N = N[indexOfZero] x = x[indexOfZero] p = p[indexOfZero] G <- length(x) if(G){ cons<-array( dim=c(length_sigma,G) ) if(G==1) { return(calculate_bayes(x=x[G],N=N[G],p=p[G],max_sigma=max_sigma,length_sigma=length_sigma)) } else { for(g in 1:G) cons[,g] <- calculate_bayes(x=x[g],N=N[g],p=p[g],max_sigma=max_sigma,length_sigma=length_sigma) listMatG <- convolutionPowersOfTwoByTwos(cons,length_sigma=length_sigma) y<-calculate_bayesGHelper(listMatG,length_sigma=length_sigma) return( y/sum(y)/(2*max_sigma/(length_sigma-1)) ) } }else{ return(NA) } } calculate_bayesGHelper <- function( listMatG,length_sigma=4001 ){ matG <- listMatG[[1]] groups <- listMatG[[2]] i = 1 resConv <- matG[,i] denom <- 2^groups[i] if(length(groups)>1){ while( i<length(groups) ){ i = i + 1 resConv <- weighted_conv(resConv, matG[,i], w= {{2^groups[i]}/denom} ,length_sigma=length_sigma) #cat({{2^groups[i]}/denom},"\n") denom <- denom + 2^groups[i] } } return(resConv) } weighted_conv<-function(x,y,w=1,m=100,length_sigma=4001){ lx<-length(x) ly<-length(y) if({lx<m}| {{lx*w}<m}| {{ly}<m}| {{ly*w}<m}){ if(w<1){ y1<-approx(1:ly,y,seq(1,ly,length.out=m))$y x1<-approx(1:lx,x,seq(1,lx,length.out=m/w))$y lx<-length(x1) ly<-length(y1) } else { y1<-approx(1:ly,y,seq(1,ly,length.out=m*w))$y x1<-approx(1:lx,x,seq(1,lx,length.out=m))$y lx<-length(x1) ly<-length(y1) } } else{ x1<-x y1<-approx(1:ly,y,seq(1,ly,length.out=floor(lx*w)))$y ly<-length(y1) } tmp<-approx(x=1:(lx+ly-1),y=convolve(x1,rev(y1),type="open"),xout=seq(1,lx+ly-1,length.out=length_sigma))$y tmp[tmp<=0] = 0 return(tmp/sum(tmp)) } ######################## mutabilityMatrixONE<-rep(0,4) names(mutabilityMatrixONE)<-NUCLEOTIDES # triMutability Background Count buildMutabilityModelONE <- function( inputMatrixIndex, model=0 , multipleMutation=0, seqWithStops=0, stopMutations=0){ #rowOrigMatInput = matInput[inputMatrixIndex,] seqGL = gsub("-", "", matInput[inputMatrixIndex,2]) seqInput = gsub("-", "", matInput[inputMatrixIndex,1]) matInput[inputMatrixIndex,] <<- c(seqInput,seqGL) seqLength = nchar(seqGL) mutationCount <- analyzeMutations(inputMatrixIndex, model, multipleMutation, seqWithStops) BackgroundMatrix = mutabilityMatrixONE MutationMatrix = mutabilityMatrixONE MutationCountMatrix = mutabilityMatrixONE if(!is.na(mutationCount)){ if((stopMutations==0 & model==0) | (stopMutations==1 & (sum(mutationCount=="Stop")<length(mutationCount))) | (model==1 & (sum(mutationCount=="S")>0)) ){ # ONEmerStartPos = 1:(seqLength) # ONEmerLength <- length(ONEmerStartPos) ONEmerGL <- s2c(seqGL) ONEmerSeq <- s2c(seqInput) #Background for(ONEmerIndex in 1:seqLength){ ONEmer = ONEmerGL[ONEmerIndex] if(ONEmer!="N"){ ONEmerCodonPos = getCodonPos(ONEmerIndex) ONEmerReadingFrameCodon = c2s(ONEmerGL[ONEmerCodonPos]) ONEmerReadingFrameCodonInputSeq = c2s(ONEmerSeq[ONEmerCodonPos] ) # All mutations model #if(!any(grep("N",ONEmerReadingFrameCodon))){ if(model==0){ if(stopMutations==0){ if(!any(grep("N",ONEmerReadingFrameCodonInputSeq))) BackgroundMatrix[ONEmer] <- (BackgroundMatrix[ONEmer] + 1) }else{ if( !any(grep("N",ONEmerReadingFrameCodonInputSeq)) & translateCodonToAminoAcid(ONEmerReadingFrameCodonInputSeq)!="*"){ positionWithinCodon = which(ONEmerCodonPos==ONEmerIndex)#positionsWithinCodon[(ONEmerCodonPos[1]%%3)+1] BackgroundMatrix[ONEmer] <- (BackgroundMatrix[ONEmer] + probNonStopMutations[ONEmerReadingFrameCodon,positionWithinCodon]) } } }else{ # Only silent mutations if( !any(grep("N",ONEmerReadingFrameCodonInputSeq)) & translateCodonToAminoAcid(ONEmerReadingFrameCodonInputSeq)!="*" & translateCodonToAminoAcid(ONEmerReadingFrameCodonInputSeq)==translateCodonToAminoAcid(ONEmerReadingFrameCodon) ){ positionWithinCodon = which(ONEmerCodonPos==ONEmerIndex) BackgroundMatrix[ONEmer] <- (BackgroundMatrix[ONEmer] + probSMutations[ONEmerReadingFrameCodon,positionWithinCodon]) } } } } } #Mutations if(stopMutations==1) mutationCount = mutationCount[mutationCount!="Stop"] if(model==1) mutationCount = mutationCount[mutationCount=="S"] mutationPositions = as.numeric(names(mutationCount)) mutationCount = mutationCount[mutationPositions>2 & mutationPositions<(seqLength-1)] mutationPositions = mutationPositions[mutationPositions>2 & mutationPositions<(seqLength-1)] countMutations = 0 for(mutationPosition in mutationPositions){ ONEmerIndex = mutationPosition ONEmer = ONEmerSeq[ONEmerIndex] GLONEmer = ONEmerGL[ONEmerIndex] ONEmerCodonPos = getCodonPos(ONEmerIndex) ONEmerReadingFrameCodon = c2s(ONEmerSeq[ONEmerCodonPos]) ONEmerReadingFrameCodonGL =c2s(ONEmerGL[ONEmerCodonPos]) if(!any(grep("N",ONEmer)) & !any(grep("N",GLONEmer))){ if(model==0){ countMutations = countMutations + 1 MutationMatrix[GLONEmer] <- (MutationMatrix[GLONEmer] + 1) MutationCountMatrix[GLONEmer] <- (MutationCountMatrix[GLONEmer] + 1) }else{ if( translateCodonToAminoAcid(ONEmerReadingFrameCodonGL)!="*" ){ countMutations = countMutations + 1 positionWithinCodon = which(ONEmerCodonPos==ONEmerIndex) glNuc = substr(ONEmerReadingFrameCodonGL,positionWithinCodon,positionWithinCodon) inputNuc = substr(ONEmerReadingFrameCodon,positionWithinCodon,positionWithinCodon) MutationMatrix[GLONEmer] <- (MutationMatrix[GLONEmer] + substitution[glNuc,inputNuc]) MutationCountMatrix[GLONEmer] <- (MutationCountMatrix[GLONEmer] + 1) } } } } seqMutability = MutationMatrix/BackgroundMatrix seqMutability = seqMutability/sum(seqMutability,na.rm=TRUE) #cat(inputMatrixIndex,"\t",countMutations,"\n") return(list("seqMutability" = seqMutability,"numbMutations" = countMutations,"seqMutabilityCount" = MutationCountMatrix, "BackgroundMatrix"=BackgroundMatrix)) # tmp<-list("seqMutability" = seqMutability,"numbMutations" = countMutations,"seqMutabilityCount" = MutationCountMatrix) } } ################ # $Id: trim.R 989 2006-10-29 15:28:26Z ggorjan $ trim <- function(s, recode.factor=TRUE, ...) UseMethod("trim", s) trim.default <- function(s, recode.factor=TRUE, ...) s trim.character <- function(s, recode.factor=TRUE, ...) { s <- sub(pattern="^ +", replacement="", x=s) s <- sub(pattern=" +$", replacement="", x=s) s } trim.factor <- function(s, recode.factor=TRUE, ...) { levels(s) <- trim(levels(s)) if(recode.factor) { dots <- list(x=s, ...) if(is.null(dots$sort)) dots$sort <- sort s <- do.call(what=reorder.factor, args=dots) } s } trim.list <- function(s, recode.factor=TRUE, ...) lapply(s, trim, recode.factor=recode.factor, ...) trim.data.frame <- function(s, recode.factor=TRUE, ...) { s[] <- trim.list(s, recode.factor=recode.factor, ...) s } ####################################### # Compute the expected for each sequence-germline pair by codon getExpectedIndividualByCodon <- function(matInput){ if( any(grep("multicore",search())) ){ facGL <- factor(matInput[,2]) facLevels = levels(facGL) LisGLs_MutabilityU = mclapply(1:length(facLevels), function(x){ computeMutabilities(facLevels[x]) }) facIndex = match(facGL,facLevels) LisGLs_Mutability = mclapply(1:nrow(matInput), function(x){ cInput = rep(NA,nchar(matInput[x,1])) cInput[s2c(matInput[x,1])!="N"] = 1 LisGLs_MutabilityU[[facIndex[x]]] * cInput }) LisGLs_Targeting = mclapply(1:dim(matInput)[1], function(x){ computeTargeting(matInput[x,2],LisGLs_Mutability[[x]]) }) LisGLs_MutationTypes = mclapply(1:length(matInput[,2]),function(x){ #print(x) computeMutationTypes(matInput[x,2]) }) LisGLs_R_Exp = mclapply(1:nrow(matInput), function(x){ Exp_R <- rollapply(as.zoo(1:readEnd),width=3,by=3, function(codonNucs){ RPos = which(LisGLs_MutationTypes[[x]][,codonNucs]=="R") sum( LisGLs_Targeting[[x]][,codonNucs][RPos], na.rm=T ) } ) }) LisGLs_S_Exp = mclapply(1:nrow(matInput), function(x){ Exp_S <- rollapply(as.zoo(1:readEnd),width=3,by=3, function(codonNucs){ SPos = which(LisGLs_MutationTypes[[x]][,codonNucs]=="S") sum( LisGLs_Targeting[[x]][,codonNucs][SPos], na.rm=T ) } ) }) Exp_R = matrix(unlist(LisGLs_R_Exp),nrow=nrow(matInput),ncol=readEnd/3,T) Exp_S = matrix(unlist(LisGLs_S_Exp),nrow=nrow(matInput),ncol=readEnd/3,T) return( list( "Expected_R"=Exp_R, "Expected_S"=Exp_S) ) }else{ facGL <- factor(matInput[,2]) facLevels = levels(facGL) LisGLs_MutabilityU = lapply(1:length(facLevels), function(x){ computeMutabilities(facLevels[x]) }) facIndex = match(facGL,facLevels) LisGLs_Mutability = lapply(1:nrow(matInput), function(x){ cInput = rep(NA,nchar(matInput[x,1])) cInput[s2c(matInput[x,1])!="N"] = 1 LisGLs_MutabilityU[[facIndex[x]]] * cInput }) LisGLs_Targeting = lapply(1:dim(matInput)[1], function(x){ computeTargeting(matInput[x,2],LisGLs_Mutability[[x]]) }) LisGLs_MutationTypes = lapply(1:length(matInput[,2]),function(x){ #print(x) computeMutationTypes(matInput[x,2]) }) LisGLs_R_Exp = lapply(1:nrow(matInput), function(x){ Exp_R <- rollapply(as.zoo(1:readEnd),width=3,by=3, function(codonNucs){ RPos = which(LisGLs_MutationTypes[[x]][,codonNucs]=="R") sum( LisGLs_Targeting[[x]][,codonNucs][RPos], na.rm=T ) } ) }) LisGLs_S_Exp = lapply(1:nrow(matInput), function(x){ Exp_S <- rollapply(as.zoo(1:readEnd),width=3,by=3, function(codonNucs){ SPos = which(LisGLs_MutationTypes[[x]][,codonNucs]=="S") sum( LisGLs_Targeting[[x]][,codonNucs][SPos], na.rm=T ) } ) }) Exp_R = matrix(unlist(LisGLs_R_Exp),nrow=nrow(matInput),ncol=readEnd/3,T) Exp_S = matrix(unlist(LisGLs_S_Exp),nrow=nrow(matInput),ncol=readEnd/3,T) return( list( "Expected_R"=Exp_R, "Expected_S"=Exp_S) ) } } # getObservedMutationsByCodon <- function(listMutations){ # numbSeqs <- length(listMutations) # obsMu_R <- matrix(0,nrow=numbSeqs,ncol=readEnd/3,dimnames=list(c(1:numbSeqs),c(1:(readEnd/3)))) # obsMu_S <- obsMu_R # temp <- mclapply(1:length(listMutations), function(i){ # arrMutations = listMutations[[i]] # RPos = as.numeric(names(arrMutations)[arrMutations=="R"]) # RPos <- sapply(RPos,getCodonNumb) # if(any(RPos)){ # tabR <- table(RPos) # obsMu_R[i,as.numeric(names(tabR))] <<- tabR # } # # SPos = as.numeric(names(arrMutations)[arrMutations=="S"]) # SPos <- sapply(SPos,getCodonNumb) # if(any(SPos)){ # tabS <- table(SPos) # obsMu_S[i,names(tabS)] <<- tabS # } # } # ) # return( list( "Observed_R"=obsMu_R, "Observed_S"=obsMu_S) ) # } getObservedMutationsByCodon <- function(listMutations){ numbSeqs <- length(listMutations) obsMu_R <- matrix(0,nrow=numbSeqs,ncol=readEnd/3,dimnames=list(c(1:numbSeqs),c(1:(readEnd/3)))) obsMu_S <- obsMu_R temp <- lapply(1:length(listMutations), function(i){ arrMutations = listMutations[[i]] RPos = as.numeric(names(arrMutations)[arrMutations=="R"]) RPos <- sapply(RPos,getCodonNumb) if(any(RPos)){ tabR <- table(RPos) obsMu_R[i,as.numeric(names(tabR))] <<- tabR } SPos = as.numeric(names(arrMutations)[arrMutations=="S"]) SPos <- sapply(SPos,getCodonNumb) if(any(SPos)){ tabS <- table(SPos) obsMu_S[i,names(tabS)] <<- tabS } } ) return( list( "Observed_R"=obsMu_R, "Observed_S"=obsMu_S) ) }