Nothing
R/graphs.R
In SGSeq: Splice event prediction and quantification from RNA-seq data
Defines functions
extractIDs
reindex
makeVariantNames
expandSGVariantCounts
unmaskEvents
maskInnerEvents
getTerminalFeatureIDs
expandType
expandString
annotateSGVariants
findAllPaths
sortEvents
findEvents
findVariantsPerGene
getRepresentativeFeatureIDs
findSGVariantsFromSGFeatures
findSGVariants
findSGSegmentsPerGene
findSGSegments
subgraph
addSourceAndSinkNodes
neighborhood2
edges
nodes
spliceGraph
Documented in
annotateSGVariants
findSGVariants
makeVariantNames
spliceGraph <- function(features)
{
if (is(features, "SGFeatures")) {
features <- asGRanges(features)
} else if (is(features, "SGSegments")) {
features <- asGRangesList(features)
}
if (is(features, "GRanges")) {
edges <- features[mcols(features)$type %in% c("J", "E")]
i_J <- which(mcols(edges)$type == "J")
i_E <- which(mcols(edges)$type == "E")
d <- cbind(from = NA, to = NA, as.data.frame(mcols(edges)))
## splice junctions -> from nodes
D <- gr2pos(flank(edges[i_J], -1, start = TRUE))
d$from[i_J] <- paste0("D:", D)
## splice junctions -> to nodes
A <- gr2pos(flank(edges[i_J], -1, start = FALSE))
d$to[i_J] <- paste0("A:", A)
## exons -> from nodes
E_5p_int <- gr2pos(flank(edges[i_E], -1, start = TRUE))
E_5p_ext <- gr2pos(flank(edges[i_E], 1, start = TRUE))
i <- which(E_5p_int %in% A)
d$from[i_E][i] <- paste0("A:", E_5p_int[i])
i <- which(is.na(d$from[i_E]) & E_5p_ext %in% D)
d$from[i_E][i] <- paste0("D:", E_5p_ext[i])
i <- which(is.na(d$from[i_E]))
d$from[i_E][i] <- paste0("S:", E_5p_int[i])
## exons -> to nodes
E_3p_int <- gr2pos(flank(edges[i_E], -1, start = FALSE))
E_3p_ext <- gr2pos(flank(edges[i_E], 1, start = FALSE))
i <- which(E_3p_int %in% D)
d$to[i_E][i] <- paste0("D:", E_3p_int[i])
i <- which(is.na(d$to[i_E]) & E_3p_ext %in% A)
d$to[i_E][i] <- paste0("A:", E_3p_ext[i])
i <- which(is.na(d$to[i_E]))
d$to[i_E][i] <- paste0("E:", E_3p_int[i])
} else if (is(features, "GRangesList")) {
d <- as.data.frame(mcols(features))
}
g <- graph.data.frame(d = d, directed = TRUE)
gd <- edges(g)
gv <- nodes(g)
if (is(features, "GRanges")) {
splicesites <- features[mcols(features)$type %in% c("D" ,"A")]
gv$featureID <- mcols(splicesites)$featureID[match(gv$name,
feature2name(splicesites))]
}
gv_cluster <- as.integer(clusters(g)$membership)
gd_cluster <- gv_cluster[match(gd$from, gv$name)]
if (is.null(mcols(features)$geneID)) {
gv$geneID <- gv_cluster
gd$geneID <- gd_cluster
} else {
cluster2geneID <- tapply(gd$geneID, gd_cluster, unique,
simplify = FALSE)
if (any(elementNROWS(cluster2geneID) > 1)) {
stop("splice graph inconsistent with geneIDs")
} else {
cluster2geneID <- unlist(cluster2geneID)
}
gv$geneID <- cluster2geneID[match(gv_cluster, names(cluster2geneID))]
}
## For each gene, reorder nodes 5' to 3' and by type (S -> A -> D -> E)
tmp <- strsplit(gv$name, split = ":", fixed = TRUE)
type <- c(S = 0, A = 1, D = 2, E = 3)[vapply(tmp, "[", character(1), 1)]
pos <- as.integer(vapply(tmp, "[", character(1), 3))
strand <- vapply(tmp, "[", character(1), 4)
i_neg <- which(strand == "-")
pos[i_neg] <- -1 * pos[i_neg]
gv <- gv[order(gv$geneID, pos, type), ]
## For each gene, reorder edges in 5' to 3' direction
split_from <- strsplit(gd$from, split = ":", fixed = TRUE)
split_to <- strsplit(gd$to, split = ":", fixed = TRUE)
start <- as.integer(vapply(split_from, "[", character(1), 3))
end <- as.integer(vapply(split_to, "[", character(1), 3))
strand <- vapply(split_from, "[", character(1), 4)
i_neg <- which(strand == "-")
tmp_start_neg <- start[i_neg]
tmp_end_neg <- end[i_neg]
start[i_neg] <- -1 * tmp_end_neg
end[i_neg] <- -1 * tmp_start_neg
gd <- gd[order(gd$geneID, start, end), ]
## Create splice graph
g <- graph.data.frame(d = gd, directed = TRUE, vertices = gv)
return(g)
}
nodes <- function(g)
{
get.data.frame(g, "vertices")
}
edges <- function(g)
{
get.data.frame(g, "edges")
}
neighborhood2 <- function(graph, order, nodes, mode)
{
n <- neighborhood(graph, order, nodes, mode)
n <- mapply(setdiff, n, nodes, SIMPLIFY = FALSE)
return(n)
}
addSourceAndSinkNodes <- function(g)
{
gd <- edges(g)
gv <- nodes(g)
## Add unique source node and edges
i <- which(degree(g, mode = "in") == 0)
gd_R <- data.frame(matrix(NA, nrow = length(i), ncol = ncol(gd)))
names(gd_R) <- names(gd)
gd_R$from <- "R"
gd_R$to <- gv$name[i]
gv_R <- data.frame(matrix(NA, nrow = 1, ncol = ncol(gv)))
names(gv_R) <- names(gv)
gv_R$name <- "R"
## Add unique sink nodes and edges
i <- which(degree(g, mode = "out") == 0)
gd_K <- data.frame(matrix(NA, nrow = length(i), ncol = ncol(gd)))
names(gd_K) <- names(gd)
gd_K$from <- gv$name[i]
gd_K$to <- "K"
gv_K <- data.frame(matrix(NA, nrow = 1, ncol = ncol(gv)))
names(gv_K) <- names(gv)
gv_K$name <- "K"
## update graph
gd <- rbindDfsWithoutRowNames(gd_R, gd, gd_K)
gv <- rbindDfsWithoutRowNames(gv_R, gv, gv_K)
g <- graph.data.frame(d = gd, directed = TRUE, vertices = gv)
return(g)
}
subgraph <- function(g, geneIDs)
{
gv <- nodes(g)
i <- which(gv$geneID %in% geneIDs)
g <- induced.subgraph(g, i)
return(g)
}
findSGSegments <- function(features, cores = 1)
{
g <- spliceGraph(features)
gv <- nodes(g)
gd <- edges(g)
i_branch <- setNames(which(degree(g, mode = "out") != 1 |
degree(g, mode = "in") != 1), NULL)
geneID_n_branch <- table(gv$geneID[i_branch])
## Collapse graph for geneIDs with single isoform
## NOTE edges must be ordered in 5' to 3' direction
geneIDs_1 <- as.integer(names(which(geneID_n_branch == 2)))
i <- which(gd$geneID %in% geneIDs_1)
segments_1 <- IntegerList(split(gd$featureID[i], gd$geneID[i]))
## Collapse graph for geneID with multiple isoforms
## NOTE nodes must be ordered in 5' to 3' direction
geneIDs_2 <- as.integer(names(which(geneID_n_branch > 2)))
list_segments_2 <- mclapply(
geneIDs_2,
findSGSegmentsPerGene,
g = g,
mc.cores = cores)
## error checking only works for mc.preschedule = FALSE
## checkApplyResultsForErrors(
## list_segments_2,
## "findSGSegmentsPerGene",
## geneIDs_2,
## "try-error")
segments_2 <- IntegerList(do.call(c, list_segments_2))
segments <- c(segments_1, segments_2)
segmentID <- togroup0(segments)[match(featureID(features),
unlist(segments))]
return(segmentID)
}
findSGSegmentsPerGene <- function(g, geneID)
{
h <- subgraph(g, geneID)
## Extract nodes and edges
hv <- nodes(h)
hd <- edges(h)
## Find start and end nodes
starts <- setNames(which(degree(h, mode = "out") > 1 |
degree(h, mode = "in") != 1), NULL)
ends <- setNames(which(degree(h, mode = "in") > 1 |
degree(h, mode = "out") != 1), NULL)
list_neighbors <- neighborhood2(h, 1, starts, "out")
s <- starts[togroup0(list_neighbors)]
n <- unlist(list_neighbors)
r <- is.finite(shortest.paths(h, n, ends, "out"))
t <- ends[apply(r, 1, function(x) { min(which(x)) })]
fun <- function(from, to)
{
if (from == to) {
p <- integer()
} else if (edge.connectivity(h, from, to) == 1) {
p <- get.shortest.paths(h, from, to, output = "epath")$epath[[1]]
p <- as.integer(p)
} else {
p <- which(hd$from == hv$name[from] & hd$to == hv$name[to])
p <- as.list(p)
}
return(p)
}
segments_1 <- mapply(fun, s, n, SIMPLIFY = FALSE)
segments_2 <- mapply(fun, n, t, SIMPLIFY = FALSE)
i <- which(vapply(segments_1, is.list, logical(1)))
if (length(i) > 0) {
segments_2 <- c(segments_2[-i],
segments_2[rep(i, elementNROWS(segments_1[i]))])
segments_1 <- c(segments_1[-i],
unlist(segments_1[i], recursive = FALSE))
}
segments <- pc(IntegerList(segments_1), IntegerList(segments_2))
segments <- relist(hd$featureID[unlist(segments)], segments)
return(segments)
}
##' Identify splice variants from splice graph.
##'
##' @title Identify splice variants from splice graph
##' @param features \code{SGFeatures} object
##' @param maxnvariant If more than \code{maxnvariant} variants are
##' identified in an event, the event is skipped, resulting in a warning.
##' Set to \code{NA} to include all events.
##' @param annotate_events Logical indicating whether identified
##' splice variants should be annotated in terms of canonical events.
##' For details see help page for \code{\link{annotateSGVariants}}.
##' @param include Character string indicating whether identified splice
##' variants should be filtered. Possible options are \dQuote{default}
##' (only include variants for events with all variants closed),
##' \dQuote{closed} (only include closed variants) and \dQuote{all}
##' (include all variants).
##' @param cores Number of cores available for parallel processing
##' @return \code{SGVariants} object
##' @examples
##' sgv <- findSGVariants(sgf_pred)
##' @author Leonard Goldstein
findSGVariants <- function(features, maxnvariant = 20, annotate_events = TRUE,
include = c("default", "closed", "all"), cores = 1)
{
include <- match.arg(include)
if (!is(features, "SGFeatures")) {
stop("features must be an SGFeatures object")
}
variants <- findSGVariantsFromSGFeatures(features, maxnvariant, cores)
if (length(variants) == 0) {
return(variants)
}
if (annotate_events) {
message("Annotate variants...")
variants <- annotateSGVariants(variants)
}
variantName(variants) <- makeVariantNames(variants)
open <- !closed5p(variants) | !closed3p(variants)
if (include == "default") {
excl <- which(eventID(variants) %in% eventID(variants)[open])
} else if (include == "closed") {
excl <- which(open)
} else if (include == "all") {
excl <- vector()
}
if (length(excl) > 0) {
variants <- variants[-excl]
}
return(variants)
}
findSGVariantsFromSGFeatures <- function(features, maxnvariant, cores = 1)
{
message("Find segments...")
segments <- convertToSGSegments(features, cores)
message("Find variants...")
g <- spliceGraph(segments)
i <- setNames(which(degree(g, mode = "out") > 1 |
degree(g, mode = "in") > 1), NULL)
geneIDs <- unique(nodes(g)$geneID[i])
if (length(geneIDs) == 0) {
return(SGVariants())
}
list_variant_info <- mclapply(
geneIDs,
findVariantsPerGene,
g = g,
maxnvariant = maxnvariant,
mc.cores = cores)
## error checking only works for mc.preschedule = FALSE
## checkApplyResultsForErrors(
## list_variant_info,
## "findVariantsPerGene",
## geneIDs,
## "try-error")
variant_info <- rbindListOfDFs(list_variant_info, cores)
if (nrow(variant_info) == 0) {
return(SGVariants())
}
## obtain variants in terms of SGFeatures
variant_featureID <- extractIDs(variant_info$featureID)
variants <- split(features[match(unlist(variant_featureID),
featureID(features))], togroup0(variant_featureID))
names(variants) <- NULL
variant_gr <- unlist(range(variants))
## sort by genomic position
i <- order(variant_gr)
variant_info <- variant_info[i, ]
variants <- variants[i]
variant_gr <- variant_gr[i]
## obtain event IDs and variant IDs
ft <- paste(variant_info$from, variant_info$to)
variant_info$eventID <- as.integer(factor(ft, levels = unique(ft)))
variant_info$variantID <- seq_len(nrow(variant_info))
## replace source nodes with corresponding start nodes
x <- flank(variant_gr, -1, TRUE)
i <- which(variant_info$from == "R")
if (length(i) > 0) { variant_info$from[i] <- paste0("S:", gr2pos(x[i])) }
## replace sink nodes with corresponding end nodes
x <- flank(variant_gr, -1, FALSE)
i <- which(variant_info$to == "K")
if (length(i) > 0) { variant_info$to[i] <- paste0("E:", gr2pos(x[i])) }
## obtain representative feature IDs
f5p <- getRepresentativeFeatureIDs(variant_info, features, TRUE)
f3p <- getRepresentativeFeatureIDs(variant_info, features, FALSE)
## set 5' representative feature IDs for 3' closed variants
variant_info$featureID5p <- f5p
i <- which(!variant_info$closed3p)
variant_info$featureID5p[i] <- IntegerList(vector("list", length(i)))
## set 3' representative feature IDs for 5' closed variants
variant_info$featureID3p <- f3p
i <- which(!variant_info$closed5p)
variant_info$featureID3p[i] <- IntegerList(vector("list", length(i)))
## convert eventIDs to factor
eid <- factor(variant_info$eventID)
## set 5' representative feature IDs for 3' closed events
eid_f5p <- split(unlist(f5p), eid[togroup0(f5p)])
eid_f5p <- unique(IntegerList(eid_f5p))
variant_info$featureID5pEvent <- setNames(
eid_f5p[match(eid, names(eid_f5p))], NULL)
i <- which(!variant_info$closed3pEvent)
variant_info$featureID5pEvent[i] <- IntegerList(vector("list", length(i)))
## set 3' representative feature IDs for 5' closed events
eid_f3p <- split(unlist(f3p), eid[togroup0(f3p)])
eid_f3p <- unique(IntegerList(eid_f3p))
variant_info$featureID3pEvent <- setNames(
eid_f3p[match(eid, names(eid_f3p))], NULL)
i <- which(!variant_info$closed5pEvent)
variant_info$featureID3pEvent[i] <- IntegerList(vector("list", length(i)))
## create SGVariants object
mcols(variants) <- variant_info
variants <- SGVariants(variants)
variants <- annotatePaths(variants)
return(variants)
}
getRepresentativeFeatureIDs <- function(variant_info, features, start = TRUE)
{
variant_rep_id <- IntegerList(vector("list", nrow(variant_info)))
if (start) {
index <- grep("^D", variant_info$from)
tmp_info <- variant_info[index, ]
tmp_node <- tmp_info$from
} else {
index <- grep("^A", variant_info$to)
tmp_info <- variant_info[index, ]
tmp_node <- tmp_info$to
}
if (length(index) == 0) {
return(variant_rep_id)
}
tmp_rep_id <- getTerminalFeatureIDs(tmp_info$featureID, start)
## replace exons with splice sites
tmp_rep_id_unlisted <- unlist(tmp_rep_id)
tmp_rep_id_unlisted_i <- match(tmp_rep_id_unlisted, featureID(features))
i_E <- which(type(features)[tmp_rep_id_unlisted_i] == "E")
if (length(i_E) > 0) {
tmp_rep_id_unlisted_i[i_E] <- match(
tmp_node[togroup0(tmp_rep_id)][i_E], feature2name(features))
}
tmp_rep_id_unlisted <- featureID(features)[tmp_rep_id_unlisted_i]
tmp_rep_id <- relist(tmp_rep_id_unlisted, tmp_rep_id)
variant_rep_id[index] <- tmp_rep_id
return(variant_rep_id)
}
findVariantsPerGene <- function(g, geneID, maxnvariant)
{
## Extract subgraph corresponding to geneID
h <- subgraph(g, geneID)
## Add unique source and sink nodes
h <- addSourceAndSinkNodes(h)
## Extract data frames of nodes and edges
hv <- nodes(h)
hd <- edges(h)
## Find events
b <- findEvents(h)
## Sort events
b <- sortEvents(b, h)
## Initialize list of alternative paths
list_path_info <- vector("list", nrow(b))
## Initialize data frame of recursively defined paths
ref <- hd[, c("from", "to", "type", "featureID", "segmentID")]
ref$segmentID <- as.character(ref$segmentID)
n_skipped <- 0
for (k in seq_len(nrow(b))) {
from <- hv$name[b$start[k]]
to <- hv$name[b$end[k]]
paths_index_ref <- findAllPaths(from, to, NULL, ref, hv$name)
if (!is.na(maxnvariant) && (length(paths_index_ref) > maxnvariant ||
(length(paths_index_ref) == 1L && is.na(paths_index_ref)))) {
n_skipped <- n_skipped + 1
if (k < nrow(b)) {
## Include event in data frame of recursively defined events
ref <- rbindDfsWithoutRowNames(ref,
data.frame(
from = from,
to = to,
type = "",
featureID = "",
segmentID = "",
stringsAsFactors = FALSE))
}
next()
}
i <- unlist(paths_index_ref)
f <- togroup0(paths_index_ref)
paths_type <- unstrsplit(split(ref$type[i], f), "")
paths_featureID <- unstrsplit(split(ref$featureID[i], f), ",")
paths_segmentID <- unstrsplit(split(ref$segmentID[i], f), ",")
names(paths_type) <- NULL
names(paths_featureID) <- NULL
names(paths_segmentID) <- NULL
o <- order(nchar(paths_type), paths_type)
paths_type <- paths_type[o]
paths_featureID <- paths_featureID[o]
paths_segmentID <- paths_segmentID[o]
## determine whether variants are closed
paths_segmentIDs <- extractIDs(paths_segmentID)
i <- match(unlist(paths_segmentIDs), hd$segmentID)
paths_all_from <- relist(hd$from[i], paths_segmentIDs)
paths_all_to <- relist(hd$to[i], paths_segmentIDs)
paths_int_nodes <- lapply(pc(paths_all_from, paths_all_to),
setdiff, y = hv$name[c(b$start[k], b$end[k])])
paths_ext_nodes <- lapply(paths_int_nodes, setdiff, x = hv$name)
event_ext_nodes <- setdiff(hv$name, unlist(paths_int_nodes))
hme <- delete.vertices(h, b$end[k])
paths_nodes_out <- lapply(paths_int_nodes,
function(x) { unique(unlist(lapply(x,
function(y) { names(subcomponent(y,
graph = hme, mode = "out")) }))) })
paths_edges_out <- lapply(paths_int_nodes,
function(x) { setdiff(hd$segmentID[hd$from %in% x], NA) })
closed3pVariant <- elementNROWS(mapply(intersect,
paths_nodes_out, paths_ext_nodes, SIMPLIFY = FALSE)) == 0 &
elementNROWS(mapply(setdiff, paths_edges_out,
paths_segmentIDs, SIMPLIFY = FALSE)) == 0
closed3pEvent <- all(elementNROWS(lapply(paths_nodes_out,
intersect, event_ext_nodes)) == 0)
hms <- delete.vertices(h, b$start[k])
paths_nodes_in <- lapply(paths_int_nodes,
function(x) { unique(unlist(lapply(x,
function(y) { names(subcomponent(y,
graph = hms, mode = "in")) }))) })
paths_edges_in <- lapply(paths_int_nodes,
function(x) { setdiff(hd$segmentID[hd$to %in% x], NA) })
closed5pVariant <- elementNROWS(mapply(intersect,
paths_nodes_in, paths_ext_nodes, SIMPLIFY = FALSE)) == 0 &
elementNROWS(mapply(setdiff, paths_edges_in,
paths_segmentIDs, SIMPLIFY = FALSE)) == 0
closed5pEvent <- all(elementNROWS(lapply(paths_nodes_in,
intersect, event_ext_nodes)) == 0)
if (k < nrow(b) && closed3pEvent && closed5pEvent) {
## Include event in data frame of recursively defined paths
ref <- rbindDfsWithoutRowNames(ref,
data.frame(
from = from,
to = to,
type = paste0("(", paste(paths_type, collapse = "|"), ")"),
featureID = paste0("(", paste(paths_featureID,
collapse = "|"), ")"),
segmentID = paste0("(", paste(paths_segmentID,
collapse = "|"), ")"),
stringsAsFactors = FALSE))
ref <- ref[-unique(unlist(paths_index_ref)), ]
}
list_path_info[[k]] <- data.frame(
from = rep(from, length(o)),
to = rep(to, length(o)),
type = paths_type,
featureID = paths_featureID,
segmentID = paths_segmentID,
closed5p = closed5pVariant,
closed3p = closed3pVariant,
closed5pEvent = rep(closed5pEvent, length(o)),
closed3pEvent = rep(closed3pEvent, length(o)),
stringsAsFactors = FALSE)
}
if (n_skipped > 0) {
warning(paste(n_skipped, "events exceed maxnvariant in gene", geneID),
call. = FALSE, immediate. = TRUE)
}
if (all(elementNROWS(list_path_info) == 0)) {
return()
}
path_info <- do.call(rbindDfsWithoutRowNames, list_path_info)
## remove references to artifical source and sink nodes
path_info$type <- gsub("NA", "", path_info$type, fixed = TRUE)
path_info$featureID <- gsub("NA,", "", path_info$featureID, fixed = TRUE)
path_info$featureID <- gsub(",NA", "", path_info$featureID, fixed = TRUE)
path_info$segmentID <- gsub("NA,", "", path_info$segmentID, fixed = TRUE)
path_info$segmentID <- gsub(",NA", "", path_info$segmentID, fixed = TRUE)
## include geneID
path_info$geneID <- geneID
return(path_info)
}
findEvents <- function(g)
{
gv <- nodes(g)
i_start <- setNames(which(degree(g, mode = "out") > 1), NULL)
list_start <- vector()
list_end <- vector()
for (s in i_start) {
## Initialize vector of end nodes completing events from s
t <- vector()
## Consider alternative nodes immediately downstream (proximal) from s
alt_prox <- neighborhood2(g, 1, s, "out")[[1]]
## Proximal nodes with connectivity > 1 complete events
i <- which(vapply(alt_prox, edge.connectivity, numeric(1),
graph = g, source = s) > 1)
t <- c(t, alt_prox[i])
## Consider branchpoints reachable from s (excluding s)
branchpts <- which(is.finite(shortest.paths(g, s, mode = "out")))[-1]
## Keep track of alternative paths in terms of both proximal and
## downstream (distal) nodes when proceeding through branchpoints
alt_dist <- alt_prox
j <- 1
reachable <- is.finite(shortest.paths(g, alt_dist, branchpts[j],
"out"))
while (!all(reachable)) {
i <- which(reachable)
prox <- unique(alt_prox[i])
dist <- neighborhood2(g, 1, branchpts[j], "out")[[1]]
if (length(prox) > 1) {
t <- c(t, branchpts[j])
prox <- branchpts[j]
}
alt_prox <- alt_prox[-i]
alt_dist <- alt_dist[-i]
n_prox <- length(prox)
n_dist <- length(dist)
alt_prox <- c(alt_prox, rep(prox, rep(n_dist, n_prox)))
alt_dist <- c(alt_dist, rep(dist, n_prox))
j <- j + 1
reachable <- is.finite(shortest.paths(g, alt_dist,
branchpts[j], "out"))
}
t <- c(t, branchpts[j])
t <- unique(t)
list_start <- c(list_start, rep(s, length(t)))
list_end <- c(list_end, t)
}
## exclude special case when start and end node are
## source and sink node, respectively (cf. PLEKHA5)
exclude <- intersect(which(gv$name[list_start] == "R"),
which(gv$name[list_end] == "K"))
if (length(exclude) > 0) {
list_start <- list_start[-exclude]
list_end <- list_end[-exclude]
}
events <- data.frame(start = list_start, end = list_end)
return(events)
}
sortEvents <- function(events, g)
{
name_split <- strsplit(nodes(g)$name, ":", fixed = TRUE)
gv_type <- vapply(name_split, "[", character(1), 1)
gv_pos <- as.integer(vapply(name_split, "[", character(1), 3))
st <- setdiff(vapply(name_split, "[", character(1), 4), NA)
start_type <- gv_type[events$start]
start_pos <- gv_pos[events$start]
end_type <- gv_type[events$end]
end_pos <- gv_pos[events$end]
i_I <- which(start_type != "R" & end_type != "K")
i_I <- i_I[order(end_pos[i_I] - start_pos[i_I],
decreasing = (st == "-"))]
i_R <- which(start_type == "R")
i_R <- i_R[order(end_pos[i_R], decreasing = (st == "-"))]
i_K <- which(end_type == "K")
i_K <- i_K[order(start_pos[i_K], decreasing = (st == "+"))]
i <- c(i_I, i_R, i_K)
events <- events[i, ]
return(events)
}
findAllPaths <- function(from, to, path, ref, nodes)
{
if (from == to) {
return(path)
} else {
i <- which(ref$from == from)
i <- i[match(ref$to[i], nodes) <= match(to, nodes)]
if (length(i) > 0) {
if (any(!is.na(ref$type[i]) & ref$type[i] == "")) {
return(NA)
}
paths <- lapply(i, append, path, 0)
paths <- mapply(findAllPaths,
from = ref$to[i],
path = paths,
MoreArgs = list(to = to, ref = ref, nodes = nodes),
SIMPLIFY = FALSE,
USE.NAMES = FALSE)
i <- which(vapply(paths, is.list, logical(1)))
if (length(i) > 0) {
paths <- c(paths[-i], unlist(paths[i], recursive = FALSE))
}
i <- which(elementNROWS(paths) == 0)
if (length(i) > 0) {
paths <- paths[-i]
}
if (any(is.na(paths))) {
return(NA)
} else {
return(paths)
}
} else {
return()
}
}
}
##' Annotate splice variants in terms of canonical events.
##'
##' The following events are considered:
##'
##' \describe{
##' \item{\dQuote{SE}}{skipped exon}
##' \item{\dQuote{S2E}}{two consecutive exons skipped}
##' \item{\dQuote{RI}}{retained intron}
##' \item{\dQuote{MXE}}{mutually exclusive exons}
##' \item{\dQuote{A5SS}}{alternative 5' splice site}
##' \item{\dQuote{A3SS}}{alternative 3' splice site}
##' \item{\dQuote{AFE}}{alternative first exon}
##' \item{\dQuote{ALE}}{alternative last exon}
##' \item{\dQuote{AS}}{alternative start other than \dQuote{AFE}}
##' \item{\dQuote{AE}}{alternative end other than \dQuote{ALE}}
##' }
##'
##' For events \dQuote{SE} and \dQuote{S2E}, suffixes \dQuote{I} and
##' \dQuote{S} indicate inclusion and skipping, respectively.
##' For event \dQuote{RI} suffixes \dQuote{E} and \dQuote{R} indicate
##' exclusion and retention, respectively.
##' For events \dQuote{A5SS} and \dQuote{A3SS}, suffixes \dQuote{P} and
##' \dQuote{D} indicate use of the proximal (intron-shortening) and
##' distal (intron-lengthening) splice site, respectively.
##'
##' All considered events are binary events defined by two alternative
##' variants. A variant is annotated as a canonical event if it coincides
##' with one of the two variants in the canonical event, and there is at
##' least one variant in the same event that coincides with the second
##' variant of the canonical event.
##'
##' @title Annotate splice variants in terms of canonical events
##' @param variants \code{SGVariants} object
##' @return \code{variants} with added metadata column
##' \dQuote{variantType} indicating canonical event(s)
##' @keywords internal
##' @author Leonard Goldstein
annotateSGVariants <- function(variants)
{
## asymmetric events
list_ae_event_1 <- c("SE:I", "S2E:I", "RI:E", "A5SS:P", "A3SS:P")
list_ae_event_2 <- c("SE:S", "S2E:S", "RI:R", "A5SS:D", "A3SS:D")
list_ae_type_1 <- c("^JE+J$", "^JE+JE+J$", "^J$", "^E+J$", "^JE+$")
list_ae_type_2 <- c("^J$", "^J$", "^E+$", "^J$", "^J$")
## symmetric events
list_se_event <- c("AFE", "ALE", "MXE")
list_se_type <- c("^E+J$", "^JE+$", "^JE+J$")
## maximum number of Js in type patterns
t <- c(list_ae_type_1, list_ae_type_2, list_se_type)
max_n_J <- max(elementNROWS(gregexpr("J", t)))
## preliminaries
path_event_id <- eventID(variants)
path_event <- CharacterList(vector("list", length(variants)))
path_type <- expandType(type(variants), max_n_J)
## asymmetric events
for (k in seq_along(list_ae_type_1)) {
event_1 <- list_ae_event_1[k]
event_2 <- list_ae_event_2[k]
type_1 <- list_ae_type_1[k]
type_2 <- list_ae_type_2[k]
i_1 <- unique(togroup0(path_type)[grep(type_1, unlist(path_type))])
i_2 <- unique(togroup0(path_type)[grep(type_2, unlist(path_type))])
event_id <- intersect(path_event_id[i_1], path_event_id[i_2])
i_1 <- i_1[path_event_id[i_1] %in% event_id]
i_2 <- i_2[path_event_id[i_2] %in% event_id]
path_event[i_1] <- pc(path_event[i_1],
as(rep(event_1, length(i_1)), "CharacterList"))
path_event[i_2] <- pc(path_event[i_2],
as(rep(event_2, length(i_2)), "CharacterList"))
}
## symmetric events
for (k in seq_along(list_se_type)) {
event <- list_se_event[k]
type <- list_se_type[k]
i <- unique(togroup0(path_type)[grep(type, unlist(path_type))])
if (event == "AFE") { i <- i[grep("^S", from(variants)[i])] }
if (event == "ALE") { i <- i[grep("^E", to(variants)[i])] }
if (length(i) > 0) {
event_id_n <- table(path_event_id[i])
event_id <- names(which(event_id_n >= 2))
i <- i[path_event_id[i] %in% event_id]
path_event[i] <- pc(path_event[i],
as(rep(event, length(i)), "CharacterList"))
}
}
## alternative start/end
i <- intersect(grep("^S", from(variants)),
which(!any(path_event == "AFE")))
path_event[i] <- pc(path_event[i],
as(rep("AS", length(i)), "CharacterList"))
i <- intersect(grep("^E", to(variants)),
which(!any(path_event == "ALE")))
path_event[i] <- pc(path_event[i],
as(rep("AE", length(i)), "CharacterList"))
variantType(variants) <- path_event
return(variants)
}
expandString <- function(x, event = NULL, maxnvariant = NA,
return_full = FALSE)
{
if (length(grep("(\\[|\\]|:)", x)) > 0) {
stop("x contains characters '[', ']' or ':'")
}
x_index <- seq_along(x)
x_nesting <- as(x, "CharacterList")
i <- grep("(", x, fixed = TRUE)
skipped <- 0
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_index <- x_index[i][togroup0(b)]
y_nesting <- pc(x_nesting[i][togroup0(b)],
as(unlist(b), "CharacterList"))
## update x, x_index, x_nesting
x <- c(x[-i], y)
x_index <- c(x_index[-i], y_index)
x_nesting <- c(x_nesting[-i], y_nesting)
if (!is.null(event) && !is.na(maxnvariant)) {
event_n <- table(event[x_index])
excl_events <- as.integer(names(which(event_n > maxnvariant)))
excl <- which(x_index %in% which(event %in% excl_events))
if (length(excl) > 0) {
x <- x[-excl]
x_index <- x_index[-excl]
x_nesting <- x_nesting[-excl]
}
skipped <- skipped + length(unique(excl_events))
}
i <- grep("(", x, fixed = TRUE)
}
if (skipped > 0) {
warning(paste("skipped", skipped, "events exceeding maxnvariant"),
call. = FALSE, immediate. = TRUE)
}
if (return_full) {
out <- DataFrame(index = x_index, expanded = x,
nesting = as(x_nesting, "CharacterList"))
} else {
out <- split(x, x_index)
}
return(out)
}
expandType <- function(x, max_n_J = NA)
{
x_f <- seq_along(x)
i <- grep("(", x, fixed = TRUE)
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
if (!is.na(max_n_J)) {
u2 <- sub("\\[\\S+$", "", u)
v2 <- sub("^\\S+\\]", "", v)
min_n_J <- elementNROWS(gregexpr("J", paste0(u2, v2)))
excl <- which(min_n_J > max_n_J)
if (length(excl) > 0) {
x[i][excl] <- ""
i <- i[-excl]
u <- u[-excl]
b <- b[-excl]
v <- v[-excl]
}
}
if (length(i) > 0) {
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_f <- x_f[i][togroup0(b)]
## update x, x_f
x <- c(x[-i], y)
x_f <- c(x_f[-i], y_f)
}
i <- grep("(", x, fixed = TRUE)
}
out <- split(x, x_f)
return(out)
}
getTerminalFeatureIDs <- function(x, start = TRUE)
{
x_f <- seq_along(x)
i <- grep("(", x, fixed = TRUE)
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
if (start) {
terminal <- u
} else {
terminal <- v
}
done <- which(nchar(terminal) > 0)
if (length(done) > 0) {
x[i][done] <- unmaskEvents(terminal[done])
i <- i[-done]
u <- u[-done]
b <- b[-done]
v <- v[-done]
}
if (length(i) > 0) {
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_f <- x_f[i][togroup0(b)]
## update x, x_f
x <- c(x[-i], y)
x_f <- c(x_f[-i], y_f)
}
i <- grep("(", x, fixed = TRUE)
}
if (start) {
x <- sub(",\\S*$", "", x)
} else {
x <- sub("^\\S*,", "", x)
}
out <- tapply(as.integer(x), x_f, unique, simplify = FALSE)
return(out)
}
maskInnerEvents <- function(x)
{
pattern <- "\\([^\\(\\)]+\\)"
m <- regexpr(pattern, x)
done <- rep(FALSE, length(x))
done[m == -1] <- TRUE
while (!all(done)) {
i <- which(!done)
m <- regexpr(pattern, x[i])
l <- attr(m, "match.length")
p1 <- m
p2 <- m + l - 1
substr(x[i], p1, p1) <- "["
substr(x[i], p2, p2) <- "]"
m2 <- regexpr(pattern, x[i])
i_done <- which(m2 == -1)
i_mask <- which(m2 != -1)
if (length(i_done) > 0) {
done[i][i_done] <- TRUE
substr(x[i][i_done], p1[i_done], p1[i_done]) <- "("
substr(x[i][i_done], p2[i_done], p2[i_done]) <- ")"
}
if (length(i_mask) > 0) {
substr(x[i][i_mask], p1[i_mask], p2[i_mask]) <- gsub("|", ":",
substr(x[i][i_mask], p1[i_mask], p2[i_mask]), fixed = TRUE)
}
}
return(x)
}
unmaskEvents <- function(x)
{
x <- gsub("[", "(", x, fixed = TRUE)
x <- gsub("]", ")", x, fixed = TRUE)
x <- gsub(":", "|", x, fixed = TRUE)
return(x)
}
expandSGVariantCounts <- function(sgvc, eventID = NULL, maxnvariant = NA,
cores = 1)
{
variants <- rowRanges(sgvc)
features <- unlist(variants)
if (is.null(eventID)) {
variants_selected <- variants
} else {
variants_selected <- variants[eventID(variants) %in% eventID]
}
## expand nested variants
expanded <- expandString(featureID(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)
## create new SGVariants object
expanded_featureIDs <- strsplit(expanded$expanded, ",", fixed = TRUE)
expanded_i <- relist(match(unlist(expanded_featureIDs),
featureID(features)), expanded_featureIDs)
rd <- split(features[unlist(expanded_i)], togroup0(expanded_i))
mcols(rd) <- mcols(variants_selected[expanded$index])
rd <- SGVariants(rd)
## update SGVariants object
rd_gr <- unlist(range(rd))
x <- flank(rd_gr, -1, TRUE)
i <- which(substr(from(rd), 1, 1) == "S")
if (length(i) > 0) { from(rd)[i] <- paste0("S:", gr2pos(x[i])) }
x <- flank(rd_gr, -1, FALSE)
i <- which(substr(to(rd), 1, 1) == "E")
if (length(i) > 0) { to(rd)[i] <- paste0("E:", gr2pos(x[i])) }
type(rd) <- expandString(type(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)$expanded
featureID(rd) <- expanded$expanded
segmentID(rd) <- expandString(segmentID(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)$expanded
i <- which(elementNROWS(expanded$nesting) > 1)
featureID5p(rd) <- IntegerList(vector("list", length(rd)))
featureID3p(rd) <- IntegerList(vector("list", length(rd)))
rd <- annotateSGVariants(rd)
variantName(rd) <- makeVariantNames(rd)
rd <- annotatePaths(rd)
## update counts
f <- togroup0(expanded$nesting)
i <- match(unlist(expanded$nesting), featureID(variants))
X <- variantFreq(sgvc)[i, , drop = FALSE]
X <- do.call(cbind, mclapply(seq_len(ncol(X)),
function(j) { tapply(X[, j], f, prod) }, mc.cores = cores))
## create new SGVariantCounts object
M <- matrix(NA_integer_, ncol = ncol(X), nrow = nrow(X))
sgvc_expanded <- SummarizedExperiment(
assays = list(
"countsVariant5p" = M,
"countsVariant3p" = M,
"countsEvent5p" = M,
"countsEvent3p" = M,
"variantFreq" = X),
rowRanges = rd,
colData = colData(sgvc))
colnames(sgvc_expanded) <- colnames(sgvc)
rownames(sgvc_expanded) <- NULL
sgvc_expanded <- SGVariantCounts(sgvc_expanded)
return(sgvc_expanded)
}
##' Create interpretable splice variant names
##' taking format GENE_EVENT_VARIANT/ORDER_TYPE.
##' GENE is based on geneName if available, and geneID otherwise.
##' EVENT and VARIANT enumerate events and variants for the same gene
##' and event, respectively. ORDER indicates the total number of
##' variants in the same event (e.g. 1/2 refers to the first out of two
##' splice variants in the event). TYPE is based on variantType.
##'
##' @title Create interpretable splice variant names
##' @param variants \code{SGVariants} object
##' @return Character vector with splice variant names
##' @examples
##' makeVariantNames(sgv_pred)
##' @keywords internal
##' @author Leonard Goldstein
makeVariantNames <- function(variants)
{
if (all(elementNROWS(geneName(variants)) == 0)) {
GENE <- geneID(variants)
} else {
eventID_geneNames <- sort(splitCharacterList(geneName(variants),
factor(eventID(variants))))
i <- match(eventID(variants), names(eventID_geneNames))
variant_geneNames <- setNames(eventID_geneNames[i], NULL)
GENE <- unstrsplit(variant_geneNames, ",")
GENE[GENE == ""] <- "NA"
}
original_eventID <- as.character(eventID(variants))
tmp <- unique(cbind(GENE, original_eventID))
tmp_index <- reindex(tmp[, 1])
EVENT <- tmp_index[match(original_eventID, tmp[, 2])]
VARIANT <- reindex(original_eventID)
eventID_n <- table(original_eventID)
ORDER <- eventID_n[match(original_eventID, names(eventID_n))]
if (all(elementNROWS(variantType(variants)) == 0)) {
TYPE <- NA
} else {
TYPE <- unstrsplit(variantType(variants), ",")
TYPE <- gsub(":\\S", "", TYPE)
TYPE[TYPE == ""] <- "OTHER"
}
variantName <- paste(GENE, EVENT,
paste0(VARIANT, "/", ORDER), TYPE, sep = "_")
return(variantName)
}
reindex <- function(f)
{
f <- as.character(f)
f_n <- table(f)
f_n <- f_n[order(names(f_n))]
o <- order(f)
i <- unlist(as(IRanges(1, f_n), "IntegerList"))
i[match(seq_along(f), o)]
}
extractIDs <- function(x)
{
x <- gsub("(", "", x, fixed = TRUE)
x <- gsub(")", "", x, fixed = TRUE)
x <- gsub("|", ",", x, fixed = TRUE)
x <- strsplit(x, ",", fixed = TRUE)
x <- lapply(x, setdiff, "NA")
x <- IntegerList(x)
return(x)
}
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Defines functions extractIDs reindex makeVariantNames expandSGVariantCounts unmaskEvents maskInnerEvents getTerminalFeatureIDs expandType expandString annotateSGVariants findAllPaths sortEvents findEvents findVariantsPerGene getRepresentativeFeatureIDs findSGVariantsFromSGFeatures findSGVariants findSGSegmentsPerGene findSGSegments subgraph addSourceAndSinkNodes neighborhood2 edges nodes spliceGraph
Documented in annotateSGVariants findSGVariants makeVariantNames
spliceGraph <- function(features)
{
if (is(features, "SGFeatures")) {
features <- asGRanges(features)
} else if (is(features, "SGSegments")) {
features <- asGRangesList(features)
}
if (is(features, "GRanges")) {
edges <- features[mcols(features)$type %in% c("J", "E")]
i_J <- which(mcols(edges)$type == "J")
i_E <- which(mcols(edges)$type == "E")
d <- cbind(from = NA, to = NA, as.data.frame(mcols(edges)))
## splice junctions -> from nodes
D <- gr2pos(flank(edges[i_J], -1, start = TRUE))
d$from[i_J] <- paste0("D:", D)
## splice junctions -> to nodes
A <- gr2pos(flank(edges[i_J], -1, start = FALSE))
d$to[i_J] <- paste0("A:", A)
## exons -> from nodes
E_5p_int <- gr2pos(flank(edges[i_E], -1, start = TRUE))
E_5p_ext <- gr2pos(flank(edges[i_E], 1, start = TRUE))
i <- which(E_5p_int %in% A)
d$from[i_E][i] <- paste0("A:", E_5p_int[i])
i <- which(is.na(d$from[i_E]) & E_5p_ext %in% D)
d$from[i_E][i] <- paste0("D:", E_5p_ext[i])
i <- which(is.na(d$from[i_E]))
d$from[i_E][i] <- paste0("S:", E_5p_int[i])
## exons -> to nodes
E_3p_int <- gr2pos(flank(edges[i_E], -1, start = FALSE))
E_3p_ext <- gr2pos(flank(edges[i_E], 1, start = FALSE))
i <- which(E_3p_int %in% D)
d$to[i_E][i] <- paste0("D:", E_3p_int[i])
i <- which(is.na(d$to[i_E]) & E_3p_ext %in% A)
d$to[i_E][i] <- paste0("A:", E_3p_ext[i])
i <- which(is.na(d$to[i_E]))
d$to[i_E][i] <- paste0("E:", E_3p_int[i])
} else if (is(features, "GRangesList")) {
d <- as.data.frame(mcols(features))
}
g <- graph.data.frame(d = d, directed = TRUE)
gd <- edges(g)
gv <- nodes(g)
if (is(features, "GRanges")) {
splicesites <- features[mcols(features)$type %in% c("D" ,"A")]
gv$featureID <- mcols(splicesites)$featureID[match(gv$name,
feature2name(splicesites))]
}
gv_cluster <- as.integer(clusters(g)$membership)
gd_cluster <- gv_cluster[match(gd$from, gv$name)]
if (is.null(mcols(features)$geneID)) {
gv$geneID <- gv_cluster
gd$geneID <- gd_cluster
} else {
cluster2geneID <- tapply(gd$geneID, gd_cluster, unique,
simplify = FALSE)
if (any(elementNROWS(cluster2geneID) > 1)) {
stop("splice graph inconsistent with geneIDs")
} else {
cluster2geneID <- unlist(cluster2geneID)
}
gv$geneID <- cluster2geneID[match(gv_cluster, names(cluster2geneID))]
}
## For each gene, reorder nodes 5' to 3' and by type (S -> A -> D -> E)
tmp <- strsplit(gv$name, split = ":", fixed = TRUE)
type <- c(S = 0, A = 1, D = 2, E = 3)[vapply(tmp, "[", character(1), 1)]
pos <- as.integer(vapply(tmp, "[", character(1), 3))
strand <- vapply(tmp, "[", character(1), 4)
i_neg <- which(strand == "-")
pos[i_neg] <- -1 * pos[i_neg]
gv <- gv[order(gv$geneID, pos, type), ]
## For each gene, reorder edges in 5' to 3' direction
split_from <- strsplit(gd$from, split = ":", fixed = TRUE)
split_to <- strsplit(gd$to, split = ":", fixed = TRUE)
start <- as.integer(vapply(split_from, "[", character(1), 3))
end <- as.integer(vapply(split_to, "[", character(1), 3))
strand <- vapply(split_from, "[", character(1), 4)
i_neg <- which(strand == "-")
tmp_start_neg <- start[i_neg]
tmp_end_neg <- end[i_neg]
start[i_neg] <- -1 * tmp_end_neg
end[i_neg] <- -1 * tmp_start_neg
gd <- gd[order(gd$geneID, start, end), ]
## Create splice graph
g <- graph.data.frame(d = gd, directed = TRUE, vertices = gv)
return(g)
}
nodes <- function(g)
{
get.data.frame(g, "vertices")
}
edges <- function(g)
{
get.data.frame(g, "edges")
}
neighborhood2 <- function(graph, order, nodes, mode)
{
n <- neighborhood(graph, order, nodes, mode)
n <- mapply(setdiff, n, nodes, SIMPLIFY = FALSE)
return(n)
}
addSourceAndSinkNodes <- function(g)
{
gd <- edges(g)
gv <- nodes(g)
## Add unique source node and edges
i <- which(degree(g, mode = "in") == 0)
gd_R <- data.frame(matrix(NA, nrow = length(i), ncol = ncol(gd)))
names(gd_R) <- names(gd)
gd_R$from <- "R"
gd_R$to <- gv$name[i]
gv_R <- data.frame(matrix(NA, nrow = 1, ncol = ncol(gv)))
names(gv_R) <- names(gv)
gv_R$name <- "R"
## Add unique sink nodes and edges
i <- which(degree(g, mode = "out") == 0)
gd_K <- data.frame(matrix(NA, nrow = length(i), ncol = ncol(gd)))
names(gd_K) <- names(gd)
gd_K$from <- gv$name[i]
gd_K$to <- "K"
gv_K <- data.frame(matrix(NA, nrow = 1, ncol = ncol(gv)))
names(gv_K) <- names(gv)
gv_K$name <- "K"
## update graph
gd <- rbindDfsWithoutRowNames(gd_R, gd, gd_K)
gv <- rbindDfsWithoutRowNames(gv_R, gv, gv_K)
g <- graph.data.frame(d = gd, directed = TRUE, vertices = gv)
return(g)
}
subgraph <- function(g, geneIDs)
{
gv <- nodes(g)
i <- which(gv$geneID %in% geneIDs)
g <- induced.subgraph(g, i)
return(g)
}
findSGSegments <- function(features, cores = 1)
{
g <- spliceGraph(features)
gv <- nodes(g)
gd <- edges(g)
i_branch <- setNames(which(degree(g, mode = "out") != 1 |
degree(g, mode = "in") != 1), NULL)
geneID_n_branch <- table(gv$geneID[i_branch])
## Collapse graph for geneIDs with single isoform
## NOTE edges must be ordered in 5' to 3' direction
geneIDs_1 <- as.integer(names(which(geneID_n_branch == 2)))
i <- which(gd$geneID %in% geneIDs_1)
segments_1 <- IntegerList(split(gd$featureID[i], gd$geneID[i]))
## Collapse graph for geneID with multiple isoforms
## NOTE nodes must be ordered in 5' to 3' direction
geneIDs_2 <- as.integer(names(which(geneID_n_branch > 2)))
list_segments_2 <- mclapply(
geneIDs_2,
findSGSegmentsPerGene,
g = g,
mc.cores = cores)
## error checking only works for mc.preschedule = FALSE
## checkApplyResultsForErrors(
## list_segments_2,
## "findSGSegmentsPerGene",
## geneIDs_2,
## "try-error")
segments_2 <- IntegerList(do.call(c, list_segments_2))
segments <- c(segments_1, segments_2)
segmentID <- togroup0(segments)[match(featureID(features),
unlist(segments))]
return(segmentID)
}
findSGSegmentsPerGene <- function(g, geneID)
{
h <- subgraph(g, geneID)
## Extract nodes and edges
hv <- nodes(h)
hd <- edges(h)
## Find start and end nodes
starts <- setNames(which(degree(h, mode = "out") > 1 |
degree(h, mode = "in") != 1), NULL)
ends <- setNames(which(degree(h, mode = "in") > 1 |
degree(h, mode = "out") != 1), NULL)
list_neighbors <- neighborhood2(h, 1, starts, "out")
s <- starts[togroup0(list_neighbors)]
n <- unlist(list_neighbors)
r <- is.finite(shortest.paths(h, n, ends, "out"))
t <- ends[apply(r, 1, function(x) { min(which(x)) })]
fun <- function(from, to)
{
if (from == to) {
p <- integer()
} else if (edge.connectivity(h, from, to) == 1) {
p <- get.shortest.paths(h, from, to, output = "epath")$epath[[1]]
p <- as.integer(p)
} else {
p <- which(hd$from == hv$name[from] & hd$to == hv$name[to])
p <- as.list(p)
}
return(p)
}
segments_1 <- mapply(fun, s, n, SIMPLIFY = FALSE)
segments_2 <- mapply(fun, n, t, SIMPLIFY = FALSE)
i <- which(vapply(segments_1, is.list, logical(1)))
if (length(i) > 0) {
segments_2 <- c(segments_2[-i],
segments_2[rep(i, elementNROWS(segments_1[i]))])
segments_1 <- c(segments_1[-i],
unlist(segments_1[i], recursive = FALSE))
}
segments <- pc(IntegerList(segments_1), IntegerList(segments_2))
segments <- relist(hd$featureID[unlist(segments)], segments)
return(segments)
}
##' Identify splice variants from splice graph.
##'
##' @title Identify splice variants from splice graph
##' @param features \code{SGFeatures} object
##' @param maxnvariant If more than \code{maxnvariant} variants are
##' identified in an event, the event is skipped, resulting in a warning.
##' Set to \code{NA} to include all events.
##' @param annotate_events Logical indicating whether identified
##' splice variants should be annotated in terms of canonical events.
##' For details see help page for \code{\link{annotateSGVariants}}.
##' @param include Character string indicating whether identified splice
##' variants should be filtered. Possible options are \dQuote{default}
##' (only include variants for events with all variants closed),
##' \dQuote{closed} (only include closed variants) and \dQuote{all}
##' (include all variants).
##' @param cores Number of cores available for parallel processing
##' @return \code{SGVariants} object
##' @examples
##' sgv <- findSGVariants(sgf_pred)
##' @author Leonard Goldstein
findSGVariants <- function(features, maxnvariant = 20, annotate_events = TRUE,
include = c("default", "closed", "all"), cores = 1)
{
include <- match.arg(include)
if (!is(features, "SGFeatures")) {
stop("features must be an SGFeatures object")
}
variants <- findSGVariantsFromSGFeatures(features, maxnvariant, cores)
if (length(variants) == 0) {
return(variants)
}
if (annotate_events) {
message("Annotate variants...")
variants <- annotateSGVariants(variants)
}
variantName(variants) <- makeVariantNames(variants)
open <- !closed5p(variants) | !closed3p(variants)
if (include == "default") {
excl <- which(eventID(variants) %in% eventID(variants)[open])
} else if (include == "closed") {
excl <- which(open)
} else if (include == "all") {
excl <- vector()
}
if (length(excl) > 0) {
variants <- variants[-excl]
}
return(variants)
}
findSGVariantsFromSGFeatures <- function(features, maxnvariant, cores = 1)
{
message("Find segments...")
segments <- convertToSGSegments(features, cores)
message("Find variants...")
g <- spliceGraph(segments)
i <- setNames(which(degree(g, mode = "out") > 1 |
degree(g, mode = "in") > 1), NULL)
geneIDs <- unique(nodes(g)$geneID[i])
if (length(geneIDs) == 0) {
return(SGVariants())
}
list_variant_info <- mclapply(
geneIDs,
findVariantsPerGene,
g = g,
maxnvariant = maxnvariant,
mc.cores = cores)
## error checking only works for mc.preschedule = FALSE
## checkApplyResultsForErrors(
## list_variant_info,
## "findVariantsPerGene",
## geneIDs,
## "try-error")
variant_info <- rbindListOfDFs(list_variant_info, cores)
if (nrow(variant_info) == 0) {
return(SGVariants())
}
## obtain variants in terms of SGFeatures
variant_featureID <- extractIDs(variant_info$featureID)
variants <- split(features[match(unlist(variant_featureID),
featureID(features))], togroup0(variant_featureID))
names(variants) <- NULL
variant_gr <- unlist(range(variants))
## sort by genomic position
i <- order(variant_gr)
variant_info <- variant_info[i, ]
variants <- variants[i]
variant_gr <- variant_gr[i]
## obtain event IDs and variant IDs
ft <- paste(variant_info$from, variant_info$to)
variant_info$eventID <- as.integer(factor(ft, levels = unique(ft)))
variant_info$variantID <- seq_len(nrow(variant_info))
## replace source nodes with corresponding start nodes
x <- flank(variant_gr, -1, TRUE)
i <- which(variant_info$from == "R")
if (length(i) > 0) { variant_info$from[i] <- paste0("S:", gr2pos(x[i])) }
## replace sink nodes with corresponding end nodes
x <- flank(variant_gr, -1, FALSE)
i <- which(variant_info$to == "K")
if (length(i) > 0) { variant_info$to[i] <- paste0("E:", gr2pos(x[i])) }
## obtain representative feature IDs
f5p <- getRepresentativeFeatureIDs(variant_info, features, TRUE)
f3p <- getRepresentativeFeatureIDs(variant_info, features, FALSE)
## set 5' representative feature IDs for 3' closed variants
variant_info$featureID5p <- f5p
i <- which(!variant_info$closed3p)
variant_info$featureID5p[i] <- IntegerList(vector("list", length(i)))
## set 3' representative feature IDs for 5' closed variants
variant_info$featureID3p <- f3p
i <- which(!variant_info$closed5p)
variant_info$featureID3p[i] <- IntegerList(vector("list", length(i)))
## convert eventIDs to factor
eid <- factor(variant_info$eventID)
## set 5' representative feature IDs for 3' closed events
eid_f5p <- split(unlist(f5p), eid[togroup0(f5p)])
eid_f5p <- unique(IntegerList(eid_f5p))
variant_info$featureID5pEvent <- setNames(
eid_f5p[match(eid, names(eid_f5p))], NULL)
i <- which(!variant_info$closed3pEvent)
variant_info$featureID5pEvent[i] <- IntegerList(vector("list", length(i)))
## set 3' representative feature IDs for 5' closed events
eid_f3p <- split(unlist(f3p), eid[togroup0(f3p)])
eid_f3p <- unique(IntegerList(eid_f3p))
variant_info$featureID3pEvent <- setNames(
eid_f3p[match(eid, names(eid_f3p))], NULL)
i <- which(!variant_info$closed5pEvent)
variant_info$featureID3pEvent[i] <- IntegerList(vector("list", length(i)))
## create SGVariants object
mcols(variants) <- variant_info
variants <- SGVariants(variants)
variants <- annotatePaths(variants)
return(variants)
}
getRepresentativeFeatureIDs <- function(variant_info, features, start = TRUE)
{
variant_rep_id <- IntegerList(vector("list", nrow(variant_info)))
if (start) {
index <- grep("^D", variant_info$from)
tmp_info <- variant_info[index, ]
tmp_node <- tmp_info$from
} else {
index <- grep("^A", variant_info$to)
tmp_info <- variant_info[index, ]
tmp_node <- tmp_info$to
}
if (length(index) == 0) {
return(variant_rep_id)
}
tmp_rep_id <- getTerminalFeatureIDs(tmp_info$featureID, start)
## replace exons with splice sites
tmp_rep_id_unlisted <- unlist(tmp_rep_id)
tmp_rep_id_unlisted_i <- match(tmp_rep_id_unlisted, featureID(features))
i_E <- which(type(features)[tmp_rep_id_unlisted_i] == "E")
if (length(i_E) > 0) {
tmp_rep_id_unlisted_i[i_E] <- match(
tmp_node[togroup0(tmp_rep_id)][i_E], feature2name(features))
}
tmp_rep_id_unlisted <- featureID(features)[tmp_rep_id_unlisted_i]
tmp_rep_id <- relist(tmp_rep_id_unlisted, tmp_rep_id)
variant_rep_id[index] <- tmp_rep_id
return(variant_rep_id)
}
findVariantsPerGene <- function(g, geneID, maxnvariant)
{
## Extract subgraph corresponding to geneID
h <- subgraph(g, geneID)
## Add unique source and sink nodes
h <- addSourceAndSinkNodes(h)
## Extract data frames of nodes and edges
hv <- nodes(h)
hd <- edges(h)
## Find events
b <- findEvents(h)
## Sort events
b <- sortEvents(b, h)
## Initialize list of alternative paths
list_path_info <- vector("list", nrow(b))
## Initialize data frame of recursively defined paths
ref <- hd[, c("from", "to", "type", "featureID", "segmentID")]
ref$segmentID <- as.character(ref$segmentID)
n_skipped <- 0
for (k in seq_len(nrow(b))) {
from <- hv$name[b$start[k]]
to <- hv$name[b$end[k]]
paths_index_ref <- findAllPaths(from, to, NULL, ref, hv$name)
if (!is.na(maxnvariant) && (length(paths_index_ref) > maxnvariant ||
(length(paths_index_ref) == 1L && is.na(paths_index_ref)))) {
n_skipped <- n_skipped + 1
if (k < nrow(b)) {
## Include event in data frame of recursively defined events
ref <- rbindDfsWithoutRowNames(ref,
data.frame(
from = from,
to = to,
type = "",
featureID = "",
segmentID = "",
stringsAsFactors = FALSE))
}
next()
}
i <- unlist(paths_index_ref)
f <- togroup0(paths_index_ref)
paths_type <- unstrsplit(split(ref$type[i], f), "")
paths_featureID <- unstrsplit(split(ref$featureID[i], f), ",")
paths_segmentID <- unstrsplit(split(ref$segmentID[i], f), ",")
names(paths_type) <- NULL
names(paths_featureID) <- NULL
names(paths_segmentID) <- NULL
o <- order(nchar(paths_type), paths_type)
paths_type <- paths_type[o]
paths_featureID <- paths_featureID[o]
paths_segmentID <- paths_segmentID[o]
## determine whether variants are closed
paths_segmentIDs <- extractIDs(paths_segmentID)
i <- match(unlist(paths_segmentIDs), hd$segmentID)
paths_all_from <- relist(hd$from[i], paths_segmentIDs)
paths_all_to <- relist(hd$to[i], paths_segmentIDs)
paths_int_nodes <- lapply(pc(paths_all_from, paths_all_to),
setdiff, y = hv$name[c(b$start[k], b$end[k])])
paths_ext_nodes <- lapply(paths_int_nodes, setdiff, x = hv$name)
event_ext_nodes <- setdiff(hv$name, unlist(paths_int_nodes))
hme <- delete.vertices(h, b$end[k])
paths_nodes_out <- lapply(paths_int_nodes,
function(x) { unique(unlist(lapply(x,
function(y) { names(subcomponent(y,
graph = hme, mode = "out")) }))) })
paths_edges_out <- lapply(paths_int_nodes,
function(x) { setdiff(hd$segmentID[hd$from %in% x], NA) })
closed3pVariant <- elementNROWS(mapply(intersect,
paths_nodes_out, paths_ext_nodes, SIMPLIFY = FALSE)) == 0 &
elementNROWS(mapply(setdiff, paths_edges_out,
paths_segmentIDs, SIMPLIFY = FALSE)) == 0
closed3pEvent <- all(elementNROWS(lapply(paths_nodes_out,
intersect, event_ext_nodes)) == 0)
hms <- delete.vertices(h, b$start[k])
paths_nodes_in <- lapply(paths_int_nodes,
function(x) { unique(unlist(lapply(x,
function(y) { names(subcomponent(y,
graph = hms, mode = "in")) }))) })
paths_edges_in <- lapply(paths_int_nodes,
function(x) { setdiff(hd$segmentID[hd$to %in% x], NA) })
closed5pVariant <- elementNROWS(mapply(intersect,
paths_nodes_in, paths_ext_nodes, SIMPLIFY = FALSE)) == 0 &
elementNROWS(mapply(setdiff, paths_edges_in,
paths_segmentIDs, SIMPLIFY = FALSE)) == 0
closed5pEvent <- all(elementNROWS(lapply(paths_nodes_in,
intersect, event_ext_nodes)) == 0)
if (k < nrow(b) && closed3pEvent && closed5pEvent) {
## Include event in data frame of recursively defined paths
ref <- rbindDfsWithoutRowNames(ref,
data.frame(
from = from,
to = to,
type = paste0("(", paste(paths_type, collapse = "|"), ")"),
featureID = paste0("(", paste(paths_featureID,
collapse = "|"), ")"),
segmentID = paste0("(", paste(paths_segmentID,
collapse = "|"), ")"),
stringsAsFactors = FALSE))
ref <- ref[-unique(unlist(paths_index_ref)), ]
}
list_path_info[[k]] <- data.frame(
from = rep(from, length(o)),
to = rep(to, length(o)),
type = paths_type,
featureID = paths_featureID,
segmentID = paths_segmentID,
closed5p = closed5pVariant,
closed3p = closed3pVariant,
closed5pEvent = rep(closed5pEvent, length(o)),
closed3pEvent = rep(closed3pEvent, length(o)),
stringsAsFactors = FALSE)
}
if (n_skipped > 0) {
warning(paste(n_skipped, "events exceed maxnvariant in gene", geneID),
call. = FALSE, immediate. = TRUE)
}
if (all(elementNROWS(list_path_info) == 0)) {
return()
}
path_info <- do.call(rbindDfsWithoutRowNames, list_path_info)
## remove references to artifical source and sink nodes
path_info$type <- gsub("NA", "", path_info$type, fixed = TRUE)
path_info$featureID <- gsub("NA,", "", path_info$featureID, fixed = TRUE)
path_info$featureID <- gsub(",NA", "", path_info$featureID, fixed = TRUE)
path_info$segmentID <- gsub("NA,", "", path_info$segmentID, fixed = TRUE)
path_info$segmentID <- gsub(",NA", "", path_info$segmentID, fixed = TRUE)
## include geneID
path_info$geneID <- geneID
return(path_info)
}
findEvents <- function(g)
{
gv <- nodes(g)
i_start <- setNames(which(degree(g, mode = "out") > 1), NULL)
list_start <- vector()
list_end <- vector()
for (s in i_start) {
## Initialize vector of end nodes completing events from s
t <- vector()
## Consider alternative nodes immediately downstream (proximal) from s
alt_prox <- neighborhood2(g, 1, s, "out")[[1]]
## Proximal nodes with connectivity > 1 complete events
i <- which(vapply(alt_prox, edge.connectivity, numeric(1),
graph = g, source = s) > 1)
t <- c(t, alt_prox[i])
## Consider branchpoints reachable from s (excluding s)
branchpts <- which(is.finite(shortest.paths(g, s, mode = "out")))[-1]
## Keep track of alternative paths in terms of both proximal and
## downstream (distal) nodes when proceeding through branchpoints
alt_dist <- alt_prox
j <- 1
reachable <- is.finite(shortest.paths(g, alt_dist, branchpts[j],
"out"))
while (!all(reachable)) {
i <- which(reachable)
prox <- unique(alt_prox[i])
dist <- neighborhood2(g, 1, branchpts[j], "out")[[1]]
if (length(prox) > 1) {
t <- c(t, branchpts[j])
prox <- branchpts[j]
}
alt_prox <- alt_prox[-i]
alt_dist <- alt_dist[-i]
n_prox <- length(prox)
n_dist <- length(dist)
alt_prox <- c(alt_prox, rep(prox, rep(n_dist, n_prox)))
alt_dist <- c(alt_dist, rep(dist, n_prox))
j <- j + 1
reachable <- is.finite(shortest.paths(g, alt_dist,
branchpts[j], "out"))
}
t <- c(t, branchpts[j])
t <- unique(t)
list_start <- c(list_start, rep(s, length(t)))
list_end <- c(list_end, t)
}
## exclude special case when start and end node are
## source and sink node, respectively (cf. PLEKHA5)
exclude <- intersect(which(gv$name[list_start] == "R"),
which(gv$name[list_end] == "K"))
if (length(exclude) > 0) {
list_start <- list_start[-exclude]
list_end <- list_end[-exclude]
}
events <- data.frame(start = list_start, end = list_end)
return(events)
}
sortEvents <- function(events, g)
{
name_split <- strsplit(nodes(g)$name, ":", fixed = TRUE)
gv_type <- vapply(name_split, "[", character(1), 1)
gv_pos <- as.integer(vapply(name_split, "[", character(1), 3))
st <- setdiff(vapply(name_split, "[", character(1), 4), NA)
start_type <- gv_type[events$start]
start_pos <- gv_pos[events$start]
end_type <- gv_type[events$end]
end_pos <- gv_pos[events$end]
i_I <- which(start_type != "R" & end_type != "K")
i_I <- i_I[order(end_pos[i_I] - start_pos[i_I],
decreasing = (st == "-"))]
i_R <- which(start_type == "R")
i_R <- i_R[order(end_pos[i_R], decreasing = (st == "-"))]
i_K <- which(end_type == "K")
i_K <- i_K[order(start_pos[i_K], decreasing = (st == "+"))]
i <- c(i_I, i_R, i_K)
events <- events[i, ]
return(events)
}
findAllPaths <- function(from, to, path, ref, nodes)
{
if (from == to) {
return(path)
} else {
i <- which(ref$from == from)
i <- i[match(ref$to[i], nodes) <= match(to, nodes)]
if (length(i) > 0) {
if (any(!is.na(ref$type[i]) & ref$type[i] == "")) {
return(NA)
}
paths <- lapply(i, append, path, 0)
paths <- mapply(findAllPaths,
from = ref$to[i],
path = paths,
MoreArgs = list(to = to, ref = ref, nodes = nodes),
SIMPLIFY = FALSE,
USE.NAMES = FALSE)
i <- which(vapply(paths, is.list, logical(1)))
if (length(i) > 0) {
paths <- c(paths[-i], unlist(paths[i], recursive = FALSE))
}
i <- which(elementNROWS(paths) == 0)
if (length(i) > 0) {
paths <- paths[-i]
}
if (any(is.na(paths))) {
return(NA)
} else {
return(paths)
}
} else {
return()
}
}
}
##' Annotate splice variants in terms of canonical events.
##'
##' The following events are considered:
##'
##' \describe{
##' \item{\dQuote{SE}}{skipped exon}
##' \item{\dQuote{S2E}}{two consecutive exons skipped}
##' \item{\dQuote{RI}}{retained intron}
##' \item{\dQuote{MXE}}{mutually exclusive exons}
##' \item{\dQuote{A5SS}}{alternative 5' splice site}
##' \item{\dQuote{A3SS}}{alternative 3' splice site}
##' \item{\dQuote{AFE}}{alternative first exon}
##' \item{\dQuote{ALE}}{alternative last exon}
##' \item{\dQuote{AS}}{alternative start other than \dQuote{AFE}}
##' \item{\dQuote{AE}}{alternative end other than \dQuote{ALE}}
##' }
##'
##' For events \dQuote{SE} and \dQuote{S2E}, suffixes \dQuote{I} and
##' \dQuote{S} indicate inclusion and skipping, respectively.
##' For event \dQuote{RI} suffixes \dQuote{E} and \dQuote{R} indicate
##' exclusion and retention, respectively.
##' For events \dQuote{A5SS} and \dQuote{A3SS}, suffixes \dQuote{P} and
##' \dQuote{D} indicate use of the proximal (intron-shortening) and
##' distal (intron-lengthening) splice site, respectively.
##'
##' All considered events are binary events defined by two alternative
##' variants. A variant is annotated as a canonical event if it coincides
##' with one of the two variants in the canonical event, and there is at
##' least one variant in the same event that coincides with the second
##' variant of the canonical event.
##'
##' @title Annotate splice variants in terms of canonical events
##' @param variants \code{SGVariants} object
##' @return \code{variants} with added metadata column
##' \dQuote{variantType} indicating canonical event(s)
##' @keywords internal
##' @author Leonard Goldstein
annotateSGVariants <- function(variants)
{
## asymmetric events
list_ae_event_1 <- c("SE:I", "S2E:I", "RI:E", "A5SS:P", "A3SS:P")
list_ae_event_2 <- c("SE:S", "S2E:S", "RI:R", "A5SS:D", "A3SS:D")
list_ae_type_1 <- c("^JE+J$", "^JE+JE+J$", "^J$", "^E+J$", "^JE+$")
list_ae_type_2 <- c("^J$", "^J$", "^E+$", "^J$", "^J$")
## symmetric events
list_se_event <- c("AFE", "ALE", "MXE")
list_se_type <- c("^E+J$", "^JE+$", "^JE+J$")
## maximum number of Js in type patterns
t <- c(list_ae_type_1, list_ae_type_2, list_se_type)
max_n_J <- max(elementNROWS(gregexpr("J", t)))
## preliminaries
path_event_id <- eventID(variants)
path_event <- CharacterList(vector("list", length(variants)))
path_type <- expandType(type(variants), max_n_J)
## asymmetric events
for (k in seq_along(list_ae_type_1)) {
event_1 <- list_ae_event_1[k]
event_2 <- list_ae_event_2[k]
type_1 <- list_ae_type_1[k]
type_2 <- list_ae_type_2[k]
i_1 <- unique(togroup0(path_type)[grep(type_1, unlist(path_type))])
i_2 <- unique(togroup0(path_type)[grep(type_2, unlist(path_type))])
event_id <- intersect(path_event_id[i_1], path_event_id[i_2])
i_1 <- i_1[path_event_id[i_1] %in% event_id]
i_2 <- i_2[path_event_id[i_2] %in% event_id]
path_event[i_1] <- pc(path_event[i_1],
as(rep(event_1, length(i_1)), "CharacterList"))
path_event[i_2] <- pc(path_event[i_2],
as(rep(event_2, length(i_2)), "CharacterList"))
}
## symmetric events
for (k in seq_along(list_se_type)) {
event <- list_se_event[k]
type <- list_se_type[k]
i <- unique(togroup0(path_type)[grep(type, unlist(path_type))])
if (event == "AFE") { i <- i[grep("^S", from(variants)[i])] }
if (event == "ALE") { i <- i[grep("^E", to(variants)[i])] }
if (length(i) > 0) {
event_id_n <- table(path_event_id[i])
event_id <- names(which(event_id_n >= 2))
i <- i[path_event_id[i] %in% event_id]
path_event[i] <- pc(path_event[i],
as(rep(event, length(i)), "CharacterList"))
}
}
## alternative start/end
i <- intersect(grep("^S", from(variants)),
which(!any(path_event == "AFE")))
path_event[i] <- pc(path_event[i],
as(rep("AS", length(i)), "CharacterList"))
i <- intersect(grep("^E", to(variants)),
which(!any(path_event == "ALE")))
path_event[i] <- pc(path_event[i],
as(rep("AE", length(i)), "CharacterList"))
variantType(variants) <- path_event
return(variants)
}
expandString <- function(x, event = NULL, maxnvariant = NA,
return_full = FALSE)
{
if (length(grep("(\\[|\\]|:)", x)) > 0) {
stop("x contains characters '[', ']' or ':'")
}
x_index <- seq_along(x)
x_nesting <- as(x, "CharacterList")
i <- grep("(", x, fixed = TRUE)
skipped <- 0
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_index <- x_index[i][togroup0(b)]
y_nesting <- pc(x_nesting[i][togroup0(b)],
as(unlist(b), "CharacterList"))
## update x, x_index, x_nesting
x <- c(x[-i], y)
x_index <- c(x_index[-i], y_index)
x_nesting <- c(x_nesting[-i], y_nesting)
if (!is.null(event) && !is.na(maxnvariant)) {
event_n <- table(event[x_index])
excl_events <- as.integer(names(which(event_n > maxnvariant)))
excl <- which(x_index %in% which(event %in% excl_events))
if (length(excl) > 0) {
x <- x[-excl]
x_index <- x_index[-excl]
x_nesting <- x_nesting[-excl]
}
skipped <- skipped + length(unique(excl_events))
}
i <- grep("(", x, fixed = TRUE)
}
if (skipped > 0) {
warning(paste("skipped", skipped, "events exceeding maxnvariant"),
call. = FALSE, immediate. = TRUE)
}
if (return_full) {
out <- DataFrame(index = x_index, expanded = x,
nesting = as(x_nesting, "CharacterList"))
} else {
out <- split(x, x_index)
}
return(out)
}
expandType <- function(x, max_n_J = NA)
{
x_f <- seq_along(x)
i <- grep("(", x, fixed = TRUE)
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
if (!is.na(max_n_J)) {
u2 <- sub("\\[\\S+$", "", u)
v2 <- sub("^\\S+\\]", "", v)
min_n_J <- elementNROWS(gregexpr("J", paste0(u2, v2)))
excl <- which(min_n_J > max_n_J)
if (length(excl) > 0) {
x[i][excl] <- ""
i <- i[-excl]
u <- u[-excl]
b <- b[-excl]
v <- v[-excl]
}
}
if (length(i) > 0) {
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_f <- x_f[i][togroup0(b)]
## update x, x_f
x <- c(x[-i], y)
x_f <- c(x_f[-i], y_f)
}
i <- grep("(", x, fixed = TRUE)
}
out <- split(x, x_f)
return(out)
}
getTerminalFeatureIDs <- function(x, start = TRUE)
{
x_f <- seq_along(x)
i <- grep("(", x, fixed = TRUE)
while (length(i) > 0) {
z <- maskInnerEvents(x[i])
## find event
m <- regexpr("\\(\\S+\\)", z)
l <- attr(m, "match.length")
## split at event
u <- substr(z, 1, m - 1)
b <- substr(z, m + 1, m + l - 2)
v <- substr(z, m + l, nchar(z))
if (start) {
terminal <- u
} else {
terminal <- v
}
done <- which(nchar(terminal) > 0)
if (length(done) > 0) {
x[i][done] <- unmaskEvents(terminal[done])
i <- i[-done]
u <- u[-done]
b <- b[-done]
v <- v[-done]
}
if (length(i) > 0) {
## expand event
b <- strsplit(b, "|", fixed = TRUE)
n <- elementNROWS(b)
y <- paste0(rep(u, n), unlist(b), rep(v, n))
y <- unmaskEvents(y)
y_f <- x_f[i][togroup0(b)]
## update x, x_f
x <- c(x[-i], y)
x_f <- c(x_f[-i], y_f)
}
i <- grep("(", x, fixed = TRUE)
}
if (start) {
x <- sub(",\\S*$", "", x)
} else {
x <- sub("^\\S*,", "", x)
}
out <- tapply(as.integer(x), x_f, unique, simplify = FALSE)
return(out)
}
maskInnerEvents <- function(x)
{
pattern <- "\\([^\\(\\)]+\\)"
m <- regexpr(pattern, x)
done <- rep(FALSE, length(x))
done[m == -1] <- TRUE
while (!all(done)) {
i <- which(!done)
m <- regexpr(pattern, x[i])
l <- attr(m, "match.length")
p1 <- m
p2 <- m + l - 1
substr(x[i], p1, p1) <- "["
substr(x[i], p2, p2) <- "]"
m2 <- regexpr(pattern, x[i])
i_done <- which(m2 == -1)
i_mask <- which(m2 != -1)
if (length(i_done) > 0) {
done[i][i_done] <- TRUE
substr(x[i][i_done], p1[i_done], p1[i_done]) <- "("
substr(x[i][i_done], p2[i_done], p2[i_done]) <- ")"
}
if (length(i_mask) > 0) {
substr(x[i][i_mask], p1[i_mask], p2[i_mask]) <- gsub("|", ":",
substr(x[i][i_mask], p1[i_mask], p2[i_mask]), fixed = TRUE)
}
}
return(x)
}
unmaskEvents <- function(x)
{
x <- gsub("[", "(", x, fixed = TRUE)
x <- gsub("]", ")", x, fixed = TRUE)
x <- gsub(":", "|", x, fixed = TRUE)
return(x)
}
expandSGVariantCounts <- function(sgvc, eventID = NULL, maxnvariant = NA,
cores = 1)
{
variants <- rowRanges(sgvc)
features <- unlist(variants)
if (is.null(eventID)) {
variants_selected <- variants
} else {
variants_selected <- variants[eventID(variants) %in% eventID]
}
## expand nested variants
expanded <- expandString(featureID(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)
## create new SGVariants object
expanded_featureIDs <- strsplit(expanded$expanded, ",", fixed = TRUE)
expanded_i <- relist(match(unlist(expanded_featureIDs),
featureID(features)), expanded_featureIDs)
rd <- split(features[unlist(expanded_i)], togroup0(expanded_i))
mcols(rd) <- mcols(variants_selected[expanded$index])
rd <- SGVariants(rd)
## update SGVariants object
rd_gr <- unlist(range(rd))
x <- flank(rd_gr, -1, TRUE)
i <- which(substr(from(rd), 1, 1) == "S")
if (length(i) > 0) { from(rd)[i] <- paste0("S:", gr2pos(x[i])) }
x <- flank(rd_gr, -1, FALSE)
i <- which(substr(to(rd), 1, 1) == "E")
if (length(i) > 0) { to(rd)[i] <- paste0("E:", gr2pos(x[i])) }
type(rd) <- expandString(type(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)$expanded
featureID(rd) <- expanded$expanded
segmentID(rd) <- expandString(segmentID(variants_selected),
eventID(variants_selected), maxnvariant, TRUE)$expanded
i <- which(elementNROWS(expanded$nesting) > 1)
featureID5p(rd) <- IntegerList(vector("list", length(rd)))
featureID3p(rd) <- IntegerList(vector("list", length(rd)))
rd <- annotateSGVariants(rd)
variantName(rd) <- makeVariantNames(rd)
rd <- annotatePaths(rd)
## update counts
f <- togroup0(expanded$nesting)
i <- match(unlist(expanded$nesting), featureID(variants))
X <- variantFreq(sgvc)[i, , drop = FALSE]
X <- do.call(cbind, mclapply(seq_len(ncol(X)),
function(j) { tapply(X[, j], f, prod) }, mc.cores = cores))
## create new SGVariantCounts object
M <- matrix(NA_integer_, ncol = ncol(X), nrow = nrow(X))
sgvc_expanded <- SummarizedExperiment(
assays = list(
"countsVariant5p" = M,
"countsVariant3p" = M,
"countsEvent5p" = M,
"countsEvent3p" = M,
"variantFreq" = X),
rowRanges = rd,
colData = colData(sgvc))
colnames(sgvc_expanded) <- colnames(sgvc)
rownames(sgvc_expanded) <- NULL
sgvc_expanded <- SGVariantCounts(sgvc_expanded)
return(sgvc_expanded)
}
##' Create interpretable splice variant names
##' taking format GENE_EVENT_VARIANT/ORDER_TYPE.
##' GENE is based on geneName if available, and geneID otherwise.
##' EVENT and VARIANT enumerate events and variants for the same gene
##' and event, respectively. ORDER indicates the total number of
##' variants in the same event (e.g. 1/2 refers to the first out of two
##' splice variants in the event). TYPE is based on variantType.
##'
##' @title Create interpretable splice variant names
##' @param variants \code{SGVariants} object
##' @return Character vector with splice variant names
##' @examples
##' makeVariantNames(sgv_pred)
##' @keywords internal
##' @author Leonard Goldstein
makeVariantNames <- function(variants)
{
if (all(elementNROWS(geneName(variants)) == 0)) {
GENE <- geneID(variants)
} else {
eventID_geneNames <- sort(splitCharacterList(geneName(variants),
factor(eventID(variants))))
i <- match(eventID(variants), names(eventID_geneNames))
variant_geneNames <- setNames(eventID_geneNames[i], NULL)
GENE <- unstrsplit(variant_geneNames, ",")
GENE[GENE == ""] <- "NA"
}
original_eventID <- as.character(eventID(variants))
tmp <- unique(cbind(GENE, original_eventID))
tmp_index <- reindex(tmp[, 1])
EVENT <- tmp_index[match(original_eventID, tmp[, 2])]
VARIANT <- reindex(original_eventID)
eventID_n <- table(original_eventID)
ORDER <- eventID_n[match(original_eventID, names(eventID_n))]
if (all(elementNROWS(variantType(variants)) == 0)) {
TYPE <- NA
} else {
TYPE <- unstrsplit(variantType(variants), ",")
TYPE <- gsub(":\\S", "", TYPE)
TYPE[TYPE == ""] <- "OTHER"
}
variantName <- paste(GENE, EVENT,
paste0(VARIANT, "/", ORDER), TYPE, sep = "_")
return(variantName)
}
reindex <- function(f)
{
f <- as.character(f)
f_n <- table(f)
f_n <- f_n[order(names(f_n))]
o <- order(f)
i <- unlist(as(IRanges(1, f_n), "IntegerList"))
i[match(seq_along(f), o)]
}
extractIDs <- function(x)
{
x <- gsub("(", "", x, fixed = TRUE)
x <- gsub(")", "", x, fixed = TRUE)
x <- gsub("|", ",", x, fixed = TRUE)
x <- strsplit(x, ",", fixed = TRUE)
x <- lapply(x, setdiff, "NA")
x <- IntegerList(x)
return(x)
}
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