diff --git a/BioInf/RNAdesign.hs b/BioInf/RNAdesign.hs new file mode 100644 --- /dev/null +++ b/BioInf/RNAdesign.hs @@ -0,0 +1,255 @@ +{-# LANGUAGE RankNTypes #-} +{-# LANGUAGE NoMonomorphismRestriction #-} +{-# LANGUAGE RecordWildCards #-} + +module BioInf.RNAdesign where + +import qualified Data.Array.IArray as A +import System.IO.Unsafe +import Control.Monad.IO.Class +import Control.Monad.Primitive.Class +import Control.Monad.Primitive +import System.Random.MWC.Monad +import Control.Monad +import qualified Data.Vector.Unboxed as VU +import qualified Data.Vector as V +import Data.List (sort,group) +import qualified Data.Map as M +import qualified Data.Vector.Fusion.Stream.Monadic as SM +import Control.Arrow +import System.IO.Unsafe -- TODO remove +import Data.List +import Data.Tuple.Select + +import Biobase.Primary +import Biobase.Secondary.Diagrams +import Biobase.Secondary +import Biobase.Vienna +import qualified BioInf.ViennaRNA.Bindings as RNA -- NOTE removes the ability to call into ghci! +import BioInf.ViennaRNA.Eval + +import BioInf.RNAdesign.Graph +import BioInf.RNAdesign.OptParser +import BioInf.RNAdesign.Assignment +import BioInf.RNAdesign.LogMultinomial + +import Debug.Trace + + + +-- A single candidate, with its sequence and the score, this sequence receives. +-- Candidates are ordered by their scores. + +data Candidate = Candidate + { candidate :: Primary + , score :: Score + } deriving (Eq,Show) + +instance Ord Candidate where + (Candidate _ a) <= (Candidate _ b) = ropt a <= ropt b + +-- | Create an initial, legal, candidate. Give it a really bad score. + +mkInitial :: (MonadPrim m, PrimMonad m) => Int -> DesignProblem -> Rand m Candidate +mkInitial l dp = do + let z = VU.replicate l nA + c <- foldM mutateOneAssignment z $ assignments dp + return $ Candidate c (Score [] 999999) + +{- +-- | Sum probabilities over base pairs in the structural constraints + +sumProbStructures :: Primary -> [D1Secondary] -> Double +sumProbStructures inp ss = s where + s = sum $ map ((bp A.!) . first (+1) . second (+1)) ps + ps = concatMap snd (map fromD1S ss :: [(Int,[PairIdx])]) + bp = let (_,_,bp') = unsafePerformIO (RNA.part $ concatMap show $ VU.toList inp) in bp' + +sumProbNotStructures :: Primary -> [D1Secondary] -> Double +sumProbNotStructures inp ss = undefined + +probabilityDefect inp str = s where + s = sum (map (bp A.!) ps) - sum (map (bp A.!) ups) + ups = [ (i,j) | i<-[1..l], j<-[i..l] ] \\ ps + (l,ps) = second (map (first (+1) . second (+1))) $ fromD1S str :: (Int,[PairIdx]) + bp = let (_,_,bp') = unsafePerformIO (RNA.part $ concatMap show $ VU.toList inp) in bp' +-} + +probabilityDefectAll inp ss = s where + ca :: A.Array (Int,Int) Double + ca = A.amap (\c -> c / n) . A.accumArray (+) 0 ((1,1),(l,l)) $ zip ps (repeat 1) + n = genericLength ss +-- s = sum (map (abs . (n-) . (bp A.!)) ps) + sum (map (bp A.!) ups) + s = sum (map (\ix -> abs $ ca A.! ix - bp A.! ix) ps) + sum (map (bp A.!) ups) + l = VU.length inp + ups = [ (i,j) | i<-[1..l], j<-[i..l] ] \\ ps + ps = map (first (+1) . second (+1)) $ concatMap snd (map fromD1S ss :: [(Int,[PairIdx])]) + bp = let (_,_,bp') = unsafePerformIO (RNA.part $ concatMap show $ VU.toList inp) in bp' + +ensembleDefect inp str = s where + s = n - 2 * sps - sus + n = fromIntegral $ VU.length inp + sps = sum $ map (bp A.!) ps + sus = sum $ [bp A.! (i,j) | i <- us, j <- [i..n]] + ps = map (first (+1) . second (+1)) $ snd $ (fromD1S str :: (Int,[PairIdx])) + us = [1..n] \\ (map fst ps ++ map snd ps) + (_,_,bp) = unsafePerformIO (RNA.part $ concatMap show $ VU.toList inp) + +-- | Resolve the optimization task. Each possible optimization function is +-- given here. Try to keep the functions defined here in sync with some +-- (non-existent ;-) documentation. + +resolveOpt :: String -> t -> Primary -> [D1Secondary] -> Double +resolveOpt optfun ener inp secs = parseOptString l sops mops gops props optfun where + l = length secs + sops = + [ ("eos" , \k -> unsafePerformIO $ RNA.eos (concatMap show (VU.toList inp)) (fromD1S $ secs !! (k-1))) + , ("ed" , \k -> ensembleDefect inp (secs !! (k-1))) -- ensemble defect +-- , ("pdef" , \k -> probabilityDefect inp (secs !! (k-1))) +-- [ ("EOS",\k -> let (Deka e) = fst $ rnaEval ener inp $ secs !! (k-1) in fromIntegral e / 100) +-- , ("PF" ... + ] + mops = + [ ("sum",sum) + , ("max",maximum) + , ("min",minimum) + ] + gops = + [ ("Ged" , probabilityDefectAll inp secs) -- global ensemble defect a la ``me'' + , ("gibbs" , sel1 . unsafePerformIO $ RNA.part (concatMap show (VU.toList inp))) + , ("mfe" , fst . unsafePerformIO $ RNA.mfe (concatMap show (VU.toList inp))) +-- , ("Pin" , sumProbStructures inp secs) + ] + props = + [ ("logMN", \ps -> lmn ps inp) + ] + +lmn ps inp = logMultinomial l p c where + l = VU.length inp + p = VU.fromList ps + cM = M.fromList . map (\z -> (head z, length z)) . group . sort $ VU.toList inp + c = VU.fromList $ map (\z -> M.findWithDefault 0 z cM) acgu + +data Score = Score + { eoss :: [Deka] + , ropt :: Double + } deriving (Eq,Show,Read) + +instance Ord Score where + (Score _ a) <= (Score _ b) = a<=b + +scoreSequence :: String -> Vienna2004 -> DesignProblem -> Primary -> Score +scoreSequence optfun ener DesignProblem{..} s = score where + score = Score + { eoss = error "don't call this" -- map (fst . rnaEval ener s) structures + , ropt = resolveOpt optfun ener s structures + } + +-- | This structure defines a "design problem" + +data DesignProblem = DesignProblem + { structures :: [D1Secondary] + , assignments :: [Assignment] + } deriving (Eq,Read,Show) + +-- | Given a set of structures, create the set of independent graphs and +-- assignment possibilities. + +mkDesignProblem :: Int -> [String] -> [String] -> DesignProblem +mkDesignProblem asnLimit xs scs = dp where + dp = DesignProblem + { structures = map mkD1S xs + , assignments = as + } + gs = independentGraphs xs + as = map (allCandidates asnLimit sv) gs + ss = M.map fixup . M.unionsWith (++) $ map (M.fromList . zip [0..] . (map ((:[]). mkNuc))) scs + sv = V.fromList $ map (\k -> M.findWithDefault acgu k ss) [0 .. length (head xs) - 1] + fixup zs = filter (/=nN) $ if (all (==nN) zs) then acgu else zs + +unfoldStreamNew + :: forall m . (MonadPrim m, PrimMonad m) + => Int -> Int -> Int -> (Primary -> Score) -> (Candidate -> Candidate -> Rand m Bool) -> DesignProblem -> Candidate -> SM.Stream (Rand m) Candidate +unfoldStreamNew burnin number thin score f dp = go where + go s = SM.map snd -- remove remaining indices from stream + . SM.take number -- take the number of sequences we want + . SM.filter ((==0) . flip mod thin . fst) -- keep only every thin'th sequence + . SM.indexed -- add index + . SM.drop burnin -- drop the burnin sequences + . SM.drop 1 -- drop original input + . SM.scanlM' (mutateOneAssignmentCandidateWith score f) s -- starting with 's', mutate s further and further using cycled assignments + $ SM.unfoldr (Just . first head . splitAt 1) (cycle $ assignments dp) -- create inifinite cycled assignments + +unfoldStream + :: forall m . (MonadPrim m, PrimMonad m) + => Int -> Int -> Int -> (Primary -> Primary -> Rand m Bool) -> DesignProblem -> Primary -> SM.Stream (Rand m) Primary +unfoldStream burnin number thin f dp = go where + go s = SM.map snd -- remove remaining indices from stream + . SM.take number -- take the number of sequences we want + . SM.filter ((==0) . flip mod thin . fst) -- keep only every thin'th sequence + . SM.indexed -- add index + . SM.drop burnin -- drop the burnin sequences + . SM.drop 1 -- drop original input + . SM.scanlM' (mutateOneAssignmentWith f) s -- starting with 's', mutate s further and further using cycled assignments + $ SM.unfoldr (Just . first head . splitAt 1) (cycle $ assignments dp) -- create inifinite cycled assignments + +-- | Mutate the sequence in a candidate + +mutateOneAssignmentCandidateWith + :: (MonadPrim m, PrimMonad m) + => (Primary -> Score) -> (Candidate -> Candidate -> Rand m Bool) -> Candidate -> Assignment -> Rand m Candidate +mutateOneAssignmentCandidateWith score f old Assignment{..} = do + i <- uniformR (0,V.length assignment -1) -- inclusive range for Int + let cs = VU.zip columns (assignment V.! i) + let nw = VU.update (candidate old) cs + let new = Candidate nw (score nw) + b <- f old new + return $ if b then new else old + +-- | Mutate the sequence using one assignment with evaluation function. + +mutateOneAssignmentWith + :: (MonadPrim m, PrimMonad m) + => (Primary -> Primary -> Rand m Bool) -> Primary -> Assignment -> Rand m Primary +mutateOneAssignmentWith f old Assignment{..} = do + i <- uniformR (0,V.length assignment -1) -- inclusive range for Int + let cs = VU.zip columns (assignment V.! i) + let new = VU.update old cs + b <- f old new + return $ if b then new else old + +-- | Create a number of sequences, thinning the list of candidates to yield +-- more independent candidates. The optimization function is used to make the +-- choice between emitting the current candidate again and selecting a new one. + +generateSequences + :: (MonadPrim m, PrimMonad m) + => Int -> Int -> (Primary -> Primary -> Rand m Bool) -> DesignProblem -> Primary -> Rand m [Primary] +generateSequences number thin f dp s = go number thin s where + go n t s + | n < 1 = return [] + | t == 0 = do s' <- mutateSequence f dp s + ss <- go (n-1) thin s' + return $ s' : ss + | otherwise = mutateSequence f dp s >>= go n (t-1) + +-- | Mutate a sequence using the possible assignments. + +mutateSequence + :: (MonadPrim m, PrimMonad m) + => (Primary -> Primary -> Rand m Bool) -> DesignProblem -> Primary -> Rand m Primary +mutateSequence f dp old = do + new <- foldM mutateOneAssignment old $ assignments dp + b <- f old new + return $ if b then new else old + +-- | Mutate the sequence using one assignment. + +mutateOneAssignment + :: (MonadPrim m, PrimMonad m) + => Primary -> Assignment -> Rand m Primary +mutateOneAssignment s Assignment{..} = do + i <- uniformR (0,V.length assignment -1) -- inclusive range for Int + let cs = VU.zip columns (assignment V.! i) + return $ VU.update s cs + diff --git a/BioInf/RNAdesign/Assignment.hs b/BioInf/RNAdesign/Assignment.hs new file mode 100644 --- /dev/null +++ b/BioInf/RNAdesign/Assignment.hs @@ -0,0 +1,71 @@ +{-# LANGUAGE PatternGuards #-} +{-# LANGUAGE ScopedTypeVariables #-} + +module BioInf.RNAdesign.Assignment where + +import Control.Arrow +import Data.Graph.Inductive.Graph +import Data.List (nub,sortBy,sort,genericLength) +import Data.Ord +import qualified Data.Vector as V +import qualified Data.Vector.Unboxed as VU +import Control.Lens.Tuple +import Control.Lens +import Data.Function + +import Biobase.Primary +import Biobase.Secondary.Vienna +import Data.Graph.Inductive.Query.Ear + +import BioInf.RNAdesign.Graph + +import Data.Graph.Inductive.Query +import Debug.Trace + + + +data Assignment = Assignment + { columns :: VU.Vector Int + , assignment :: V.Vector (VU.Vector Nuc) + , isExhaustive :: Bool + , numAssignments :: Integer + } deriving (Eq,Read,Show) + +-- | Given a graph with base pairing constraints, return a 'Assignments' data +-- structure that provides all legal assignments. + +allCandidates :: (DynGraph gr) => Int -> V.Vector [Nuc] -> gr () () -> Assignment +allCandidates maxC sv g + | noNodes g == 1 = let [n] = nodes g + svn = sv V.! n + in Assignment (VU.singleton n) (V.fromList $ map VU.singleton svn) True (genericLength svn) + | noNodes g == 2 = let [n,m] = nodes g + svnm = [[a,b] | a <- sv V.! n, b <- sv V.! m, isViennaPair a b] + in Assignment (VU.fromList [n,m]) (V.fromList $ map VU.fromList $ svnm) True (genericLength svnm) + | noNodes g > 2 = let es :: [(Int,Int)] = nub . filter (uncurry (<)) . map (\(a,b,_) -> (a,b)) . sortBy (compare `on` sel3) . labEdges $ g' -- $ ears g + g' = case bcc g of + [_] -> ears g + xs -> emap (const 0) g + o = sort $ mkEL es + (as,num) = second genericLength . splitAt maxC . map VU.fromList $ mkAssignments sv es + in Assignment (VU.fromList o) (V.fromList $ take maxC as) (num==1) (genericLength as + num) + +mkEL = nub . concatMap (\(a,b) -> [a,b]) + +mkAssignments sv es = map (map snd . sortBy (comparing fst)) $ mkA [] es where + mkA :: [(Int,Nuc)] -> [(Int,Int)] -> [[(Int,Nuc)]] + mkA dones [] = [[]] + mkA dones ((a,b):ds) + | Nothing <- a', Nothing <- b' + = [ (a,n):(b,m):ns | n <- sv V.! a, m <- sv V.! b, isViennaPair n m, ns <- mkA ((a,n):(b,m):dones) ds ] + | Nothing <- a', Just m <- b' + = [ (a,n):ns | n <- sv V.! a, isViennaPair n m, ns <- mkA ((a,n):dones) ds ] + | Just n <- a', Nothing <- b' + = [ (b,m):ns | m <- sv V.! b, isViennaPair n m, ns <- mkA ((b,m):dones) ds ] + | Just n <- a', Just m <- b' + = if isViennaPair n m then mkA dones ds else [] + where + a' = lookup a dones + b' = lookup b dones + +vps = filter (uncurry isViennaPair) [(a,b) | a<-cgau, b<-cgau] diff --git a/BioInf/RNAdesign/Graph.hs b/BioInf/RNAdesign/Graph.hs new file mode 100644 --- /dev/null +++ b/BioInf/RNAdesign/Graph.hs @@ -0,0 +1,61 @@ + +module BioInf.RNAdesign.Graph where + +import Data.Graph.Inductive.Graph +import Data.Graph.Inductive.Basic +import Data.Graph.Inductive.PatriciaTree +import Data.Graph.Inductive.Query +import Data.List (nub,partition) +import Control.Arrow (first,second) + +import Biobase.Secondary.Diagrams + + + +-- | Given the one to many structures, create the independent graphs, where +-- each graph describes a set of dependent edges in the basepairing. + +independentGraphs xs + | null xs = error "You should give at least one structure. If you did, you have found a bug, yeah!" + | any ((/=lx).length) xs = error $ "At least one structure with different length was found" ++ show xs + | otherwise = independentComponents g + where + lx = length $ head xs + g = mkUnionGraph xs + +-- | Union of several graphs, created from secondary structure. + +mkUnionGraph = unions . map (pairlistToGraph . (mkD1S :: String -> D1Secondary)) + +-- | Given k graphs, each with nodes [1..n], provide the union of all edges. + +unions :: Eq b => [Gr a b] -> Gr a b +unions [] = empty +unions xs@(x:_) = mkGraph (labNodes x) (nub $ concatMap labEdges xs) where + +-- | Given a pairlist, generate the secondary structure graph. + +pairlistToGraph :: D1Secondary -> Gr () () +pairlistToGraph d = + let (len, ps) = fromD1S d + in undir $ mkUGraph [0..len -1] ps + +-- | Split the graph into (simple, complex) components. The simple components +-- can trivially be filled with any pair. The complex components require an Ear +-- or Woffle decomposition. Simple components are acyclic. + +independentComponents :: DynGraph gr => gr () () -> [gr () ()] +independentComponents g = map f $ components g where + f ns = mkUGraph ns (edges g) + +-- | Tests if the given graph is bipartite, which is true if the even/odd BST +-- trees contain no edges + +isBipartite :: DynGraph gr => gr a b -> Bool +isBipartite g = e && o where + -- True, if there are no edges + (e,o) = both (null . edges) $ f g + -- generate the (even,odd) distance graphs + f g = both (flip delNodes g . map fst) . partition (even . snd) $ level (fst $ head $ labNodes g) g + both f = second f . first f + diff --git a/BioInf/RNAdesign/LogMultinomial.hs b/BioInf/RNAdesign/LogMultinomial.hs new file mode 100644 --- /dev/null +++ b/BioInf/RNAdesign/LogMultinomial.hs @@ -0,0 +1,15 @@ + +module BioInf.RNAdesign.LogMultinomial where + +import qualified Data.Vector.Unboxed as VU + + +logMultinomial :: Int -> VU.Vector Double -> VU.Vector Int -> Double +logMultinomial n' ps xs' + | VU.length ps /= VU.length xs' = error "logMultinomial: P-vector and count-vector of unequal length" + | otherwise = n - x + p where + n = logSum1k n' + x = VU.sum $ VU.map logSum1k xs' + p = VU.sum $ VU.zipWith (*) (VU.map log ps) (VU.map fromIntegral xs') + logSum1k k = VU.sum . VU.map (log . fromIntegral) $ VU.enumFromTo 1 k + diff --git a/BioInf/RNAdesign/OptParser.hs b/BioInf/RNAdesign/OptParser.hs new file mode 100644 --- /dev/null +++ b/BioInf/RNAdesign/OptParser.hs @@ -0,0 +1,89 @@ + +-- | A simple parser designed to read the optimization string from an argument +-- and together with the input computes the result of the the optimization +-- query. Without 'mkSingleOp' and 'mkMultiOp' this just a trivial parser for +-- simple arithmetic. The addional operations provide access to user-defined +-- functions that can, for example, be used to calculate the energy of a +-- sequence-structure pair. Those functions are not defined here but in the +-- application that uses the parser. + +module BioInf.RNAdesign.OptParser + ( parseOptString + ) where + +import Text.Parsec.Expr +import Text.Parsec hiding ((<|>)) +import Text.Parsec.Language +import Text.Parsec.Token +import Control.Applicative +import Text.Parsec.String + +import Text.Parsec.Numbers + + + +type SingleOp = (String,Int -> Double) +type MultiOp = (String,[Double] -> Double) +type GlobalOp = (String,Double) +type PropOp = (String,[Double] -> Double) +type NumSecStructs = Int + +parseOptString :: NumSecStructs -> [SingleOp] -> [MultiOp] -> [GlobalOp] -> [PropOp] -> String -> Double +parseOptString nss sops mops gops props s = case parse expr "" $ prepString s of + Right res -> res + Left err -> error $ show err + where + prepString = filter (/= ' ') + expr :: GenParser Char st Double + expr + = buildExpressionParser optable term + "expression" + term :: GenParser Char st Double + term + = between (char '(') (char ')') expr + <|> parseSingleOp sops + <|> parseMultiOp nss sops mops + <|> parseGlobalOp gops + <|> parsePropOp props + <|> parseFloat + "term" + +parsePropOp xs = choice $ map mkPropOp xs + +mkPropOp :: PropOp -> GenParser Char st Double +mkPropOp (s,f) = try $ f <$ string s <* string "(" <*> parseFloat `sepBy` string "," <* string ")" where + +mkSingleOp :: SingleOp -> GenParser Char st Double +mkSingleOp (s,f) = try $ g <$ string s <* string "(" <*> many1 digit <* string ")" where + g x = f (read x) + +mkMultiOp :: NumSecStructs -> (SingleOp,MultiOp) -> GenParser Char st Double +mkMultiOp nss ((s,sf),(m,mf)) = {- (\xs -> error $ show (xs, map sf xs, mf $ map sf xs)) <$ -} (\xs -> mf $ map sf xs) <$ + string m <* string "(" <* string s <* string "," <*> secs <* string ")" where + secs = try ([1..nss] <$ string "all") + <|> map read <$> many1 digit `sepBy1` string "," + +mkGlobalOp :: GlobalOp -> GenParser Char st Double +mkGlobalOp (s,f) = try $ f <$ string s + +parseSingleOp xs = choice $ map mkSingleOp xs + +parseMultiOp nss sops mops = choice $ map (try . mkMultiOp nss) [(s,m) | s<-sops, m<-mops] + +parseGlobalOp gops = choice $ map (try . mkGlobalOp) gops + +optable = [ [prefix "-" negate, prefix "+" id] + , [binary "^" (**) AssocLeft] --, binary "**" (**) AssocLeft] + , [binary "*" (*) AssocLeft, binary "/" (/) AssocLeft] + , [binary "+" (+) AssocLeft, binary "-" (-) AssocLeft] + ] + +pow b e + | (fromIntegral $ round e) /= e + = error $ "exponent " ++ show e ++ " needs to be integral, sorry" + | otherwise + = b ^ (round e) + +prefix name fun = Prefix (fun <$ string name) +binary name fun assoc = Infix (fun <$ string name) assoc + diff --git a/LICENSE b/LICENSE new file mode 100644 --- /dev/null +++ b/LICENSE @@ -0,0 +1,675 @@ + GNU GENERAL PUBLIC LICENSE + Version 3, 29 June 2007 + + Copyright (C) 2007 Free Software Foundation, Inc. + Everyone is permitted to copy and distribute verbatim copies + of this license document, but changing it is not allowed. + + Preamble + + The GNU General Public License is a free, copyleft license for +software and other kinds of works. + + The licenses for most software and other practical works are designed +to take away your freedom to share and change the works. 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But first, please read +. + diff --git a/README.md b/README.md new file mode 100644 --- /dev/null +++ b/README.md @@ -0,0 +1,1 @@ + diff --git a/RNAdesign.cabal b/RNAdesign.cabal new file mode 100644 --- /dev/null +++ b/RNAdesign.cabal @@ -0,0 +1,104 @@ +name: RNAdesign +version: 0.0.2.1 +author: Christian Hoener zu Siederdissen +maintainer: choener@tbi.univie.ac.at +category: Bioinformatics +synopsis: Multi-target RNA sequence design +license: GPL-3 +license-file: LICENSE +build-type: Simple +stability: experimental +cabal-version: >= 1.6.0 +description: + The RNA sequence design problem asks for a single sequence that + readily folds into the one or more structural targets that are + given as input. + . + This program expects on standard input a file with one or more + structures and, possibly, additional sequence constraints. It + will then run a Markov chain to find a sequence that is optimal + with regard to the structural targets and the user-defineable + optimization function. + . + The user can give different optimization criteria on the + command line, akin to a simple calculator. + . + . + . + If you find this program useful, please cite: + . + Christian Hoener zu Siederdissen, Stefan Hammer, Ingrid Abfalter, Ivo L. Hofacker, Christoph Flamm, Peter F. Stadler + . + @A Graph Coloring Approach to Designing Multi-Stable Nucleic Acid Sequences@ + . + Biopolymers, 99, 12, 1124-1136, 2013, Wiley + + + +extra-source-files: + changelog + README.md + +library + build-depends: + base >= 4 && < 5 , + array >= 0.4 , + containers , + fgl >= 5.4 , + lens >= 3.9 , + monad-primitive >= 0.1 , + mwc-random-monad >= 0.6 , + parallel >= 3.2 , + parsec >= 3 , + primitive >= 0.5 , + random >= 1.0 , + transformers >= 0.3 , + tuple >= 0.2 , + vector >= 0.10 , + fgl-extras-decompositions >= 0.1.0.0 , + BiobaseTurner >= 0.3.1.1 , + BiobaseVienna >= 0.3 , + BiobaseXNA >= 0.7.0.1 , + ParsecTools >= 0.0.2 && < 0.0.3 , + PrimitiveArray >= 0.5 , + RNAFold >= 1.99.3.3 , + ViennaRNA-bindings >= 0.0.2.3 + exposed-modules: + BioInf.RNAdesign + BioInf.RNAdesign.Assignment + BioInf.RNAdesign.Graph + BioInf.RNAdesign.LogMultinomial + BioInf.RNAdesign.OptParser + ghc-options: + -O2 + +executable RNAdesign + build-depends: + base >= 4 && < 5 , + array >= 0.4 , + cmdargs == 0.10.* , + containers , + fgl >= 5.4 , + lens >= 3.9 , + monad-primitive >= 0.1 , + mwc-random-monad >= 0.6 , + parallel >= 3.2 , + parsec >= 3 , + primitive >= 0.5 , + random >= 1.0 , + transformers >= 0.3 , + tuple >= 0.2 , + vector >= 0.10 , + fgl-extras-decompositions >= 0.1.0.0 , + BiobaseTurner >= 0.3.1.1 , + BiobaseVienna >= 0.3 , + BiobaseXNA >= 0.7.0.1 , + ParsecTools >= 0.0.2 && < 0.0.3 , + PrimitiveArray >= 0.5 , + RNAFold >= 1.99.3.3 , + ViennaRNA-bindings >= 0.0.2.3 + main-is: + RNAdesign.hs + ghc-options: + -O2 -rtsopts + diff --git a/RNAdesign.hs b/RNAdesign.hs new file mode 100644 --- /dev/null +++ b/RNAdesign.hs @@ -0,0 +1,146 @@ +{-# LANGUAGE QuasiQuotes #-} +{-# LANGUAGE BangPatterns #-} +{-# LANGUAGE ScopedTypeVariables #-} +{-# LANGUAGE DeriveDataTypeable #-} +{-# LANGUAGE NoMonomorphismRestriction #-} +{-# LANGUAGE RecordWildCards #-} + +-- | + +module Main where + +import System.Console.CmdArgs +import Data.List +import Data.Char (isAlpha) +import Control.Monad +import System.Random.MWC.Monad +import System.Random.MWC.Distributions.Monad +import qualified Data.Vector.Unboxed as VU +import Text.Printf +import Data.Ord +import qualified Data.Vector.Fusion.Stream.Monadic as SM +import Control.Arrow +import Data.Function +import System.IO + +import Biobase.Primary +import Biobase.Vienna +import qualified Biobase.Turner.Import as TI + +import BioInf.RNAdesign +import BioInf.RNAdesign.Assignment + +import Debug.Trace + + + +-- * configuration + +data Config = Config + { number :: Int + , thin :: Int + , burnin :: Int + , scale :: Double + , optfun :: String + , veclen :: Int + , turner :: String +-- , exhaustive :: Bool -- TODO want to think about this for number of structures > 3, IF the total sequence space size is less than say 100.000 + , initial :: String + , sequenceConstraints :: Bool + , explore :: Bool + } deriving (Show,Data,Typeable) + +config = Config + { number = 50 &= help "Number of candidate sequences to generate (50)" + , thin = 50 &= help "keep only every n'th sequence (50)" + , burnin = 100 &= help "remove the first burnin sequences (100)" + , scale = 1 &= help "acceptance scale parameter (1); exponentially distributed with mean 'scale^(-1)' (smaller scale means longer jumps)" + , optfun = "sum(eos,all)" &= help "optimization function, \"sum(eos,all)\" tries to minimize the sum of the energies" + , veclen = 1000000 &= help "multiple structure constraints lead to large connected components, veclen restricts the number of component solutions to store." + , turner = "./params" &= help "directory containing the Turner 2004 RNA energy tables (with a default of \"./params/\"" +-- , exhaustive = False &= help "exhaustively search the nucleotide space" + , initial = "" &= help "start from this initial sequence" + , explore = def &= help "explore sequences, do not sort of nub list" + , sequenceConstraints = def &= help "activate sequence constraints" + } &= help shortHelp &= details longHelp &= summary "RNAdesign v0.0.2, (C) Christian Hoener zu Siederdissen 2013, choener@tb.univie.ac.at" &= program "RNAdesign" + +shortHelp = "The defaults work acceptably well and produce a results extremely fast. " + +longHelp = + [ "RNAdesign designs RNA sequences given one or more structural targets. The" + , "program offers a variety of optimization functions that each can be used to" + , "optimize candidate sequence towards a certain goal, say, minimal ensemble" + , "defect or small energetic distance to another target structure. By giving a" + , "complex \"--optun\", many different design goals can be tried. The following" + , "functions are available:" + , "binary, combining:" + , "+ - * / :: the four basic operations" + , "^ :: (^) generalized power function" + , "" + , "binary, apply function to many targets:" + , "sum max min :: run function over set of targets: sum(eos,1,2) or sum(eos,all)" + , "" + , "unary, apply to single target:" + , "eos :: energy of a structure: eos(1)" + , "ed :: ensemble defect of a structure: ed(3)" + , "nullary, constant for the current sequence:" + , "Ged :: global, weighted ensemble defect: Ged" + , "gibbs :: gibbs free energy of sequence" + , "mfe :: minimum free energy of sequence" + , "" + , "special:" + , "logMN :: requires four parameters logMN(0.2,0.3,0.3,0.2) penalizes according to given mono-nucleotide distribution" + , "" + , "A good optimization goal is (as an example for three targets):" + , "--optfun \"eos(1)+eos(2)+eos(3) - 3*gibbs +" + , " 1 * ((eos(1)-eos(2))^2 + (eos(1)-eos(3))^2 + (eos(2)-eos(3))^2)\"" + , "This way, the sequence produces close-to-mfe foldings with the targets (left) and the targets are close together in terms of energy. (1 *) scales the two terms according to user choice." + , "\n\n\n" + , "If you find this tool useful, please cite:" + , "" + , "Christian Hoener zu Siederdissen, Stefan Hammer, Ingrid Abfalter, Ivo L. Hofacker, Christoph Flamm, Peter F. Stadler." + , "A Graph Coloring Approach to Designing Multi-Stable Nucleic Acid Sequences." + , "submitted, 2013." + , "" + , "Contact: choener@tbi.univie.ac.at" + , "Given one or more structures in dot-bracket format of the same length, returns a compatible assignment of nucleotides." + , "Compatible nucleotides are those that allow folding of the sequence into all given structures." + ] + +main = do + hSetBuffering stdout NoBuffering + hSetBuffering stderr NoBuffering + cmds@Config{..} <- cmdArgs config + turner <- fmap turnerToVienna $ TI.fromDir turner "" ".dat" + strs' <- fmap lines $ getContents + let (scs,strs) = first (filter ((">"/=) . take 1)) . partition (any isAlpha) $ strs' + unless (length strs > 0) $ error "no structures given!" + let l = length $ head strs + unless (all ((l==) . length) strs) $ error "structures of different size detected" + let dp = mkDesignProblem veclen strs (if sequenceConstraints then scs else []) + let defOpt old new = let oldS = scoreSequence optfun turner dp old + newS = scoreSequence optfun turner dp new + in do t <- exponential scale + return $ ropt newS <= ropt oldS || t >= ropt newS - ropt oldS + let calcScore = scoreSequence optfun turner dp + let walk old new = do t <- exponential scale + let sn = ropt $ score new + let so = ropt $ score old + return $ sn <= so || t >= sn - so + let ini = if null initial -- start from initial sequence or generate one from the ensemble + then mkInitial l dp + else return $ Candidate (mkPrimary initial) (Score [] 999999) + xs <- runWithSystemRandom . asRandIO $ (ini >>= SM.toList . unfoldStreamNew burnin number thin calcScore walk dp) + let pna = product . map numAssignments $ assignments dp + printf "# Size of sequence space: %d %s\n\n" pna {-(product . map numAssignments $ assignments dp)-} (show . map numAssignments $ assignments dp) + unless (pna>0) $ error "empty sequence space, aborting!" + mapM_ (\ys -> printf "%s %4d %8.2f\n" (concatMap show . VU.toList . candidate . head $ ys) (length ys) (ropt . score $ head ys)) + . ( if explore + then map (:[]) + else ( sortBy (comparing (ropt . score . head)) + . groupBy ((==) `on` candidate) + . sortBy (comparing candidate) + ) + ) + $ xs + diff --git a/Setup.hs b/Setup.hs new file mode 100644 --- /dev/null +++ b/Setup.hs @@ -0,0 +1,2 @@ +import Distribution.Simple +main = defaultMain diff --git a/changelog b/changelog new file mode 100644 --- /dev/null +++ b/changelog @@ -0,0 +1,3 @@ +0.0.2.1 + * post-publication version + * allows continuous Markovian walk for special applications