diff --git a/LICENSE b/LICENSE new file mode 100644 --- /dev/null +++ b/LICENSE @@ -0,0 +1,340 @@ + GNU GENERAL PUBLIC LICENSE + Version 2, June 1991 + + Copyright (C) 1989, 1991 Free Software Foundation, Inc. + 59 Temple Place, Suite 330, Boston, MA 02111-1307 USA + Everyone is permitted to copy and distribute verbatim copies + of this license document, but changing it is not allowed. + + Preamble + + The licenses for most software are designed to take away your +freedom to share and change it. By contrast, the GNU General Public +License is intended to guarantee your freedom to share and change free +software--to make sure the software is free for all its users. This +General Public License applies to most of the Free Software +Foundation's software and to any other program whose authors commit to +using it. (Some other Free Software Foundation software is covered by +the GNU Library General Public License instead.) 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Of course, the commands you use may +be called something other than `show w' and `show c'; they could even be +mouse-clicks or menu items--whatever suits your program. + +You should also get your employer (if you work as a programmer) or your +school, if any, to sign a "copyright disclaimer" for the program, if +necessary. Here is a sample; alter the names: + + Yoyodyne, Inc., hereby disclaims all copyright interest in the program + `Gnomovision' (which makes passes at compilers) written by James Hacker. + + , 1 April 1989 + Ty Coon, President of Vice + +This General Public License does not permit incorporating your program into +proprietary programs. If your program is a subroutine library, you may +consider it more useful to permit linking proprietary applications with the +library. If this is what you want to do, use the GNU Library General +Public License instead of this License. diff --git a/README b/README new file mode 100644 --- /dev/null +++ b/README @@ -0,0 +1,44 @@ + +Simseq - SIMulate SEQuences. Yep, that's real creative. + + Synopsis + -------- + +Generates a bunch of sequences from a set of reference sequences. +For ESTs, NCBI's refseq transcripts are probably good choices. + +The generated sequences are generated using a model that specifies +priming conditions and error generation. + +Currently, this is not very refined, you can try + + simseq --model=sanger:n,d reference.fasta + +Where n indicates the number of sequences to generate, starting points +drawn from a uniform distribution, and d probability of being in the +forward direction. Or, even more experimentally: + + simseq --model=454:n,d + +Which implemets a completely unfounded and baseless model of 454/Roche +pyrosequencing. (Okay, actually based on a paper by Marguiles et al, but +more data is definitely a requirement). + +Solexa will be installed as soon as anybody says something definitive +about the error modes. + +In any case, running out of sequence results in X's, indicating vector, +which I hope makes sense for Sanger, at least. + + Install + ------- + +The usual Cabal routine. Get a working GHC compiler, install +my 'bio' library, and do: + + chmod +x Setup.hs + ./Setup.hs configure + ./Setup.hs build + sudo ./Setup.hs install + +Mail me if it didn't work - . diff --git a/Setup.hs b/Setup.hs new file mode 100644 --- /dev/null +++ b/Setup.hs @@ -0,0 +1,5 @@ +#!/usr/bin/env runhaskell + +import Distribution.Simple +main = defaultMain + diff --git a/idea.txt b/idea.txt new file mode 100644 --- /dev/null +++ b/idea.txt @@ -0,0 +1,35 @@ + +Simple tool to generate simulated ESTs. + +Must support (minimum, generalize?): + + sanger: initial medium/high error rate, + stable low error rate (mostly subst?) + slowly increasing to one from pos 750-900 + + 454: medium error rate, mostly ins/del for monomers + + Solexa: any idea of error rate? + +Generalized: + general error models, training on data sets? + HMM-like? + +** PLAN ** + + primer: determines starting point (initial state) from sequences + transcribe: unfold new sequence, while modifying state + error model: depends on state + terminator: ends transcript + +Specialized: homopolymers for 454 (must be part of state) + + + Terminator = Distribution + Error Model = Distribution + Mutator + Primer = ...? + +Mutators can be 'ins(c,p)', 'del(p)', 'subst(c,p) etc. +Or should the distribution multiplier apply already to distrib? + +-k diff --git a/simseq.cabal b/simseq.cabal new file mode 100644 --- /dev/null +++ b/simseq.cabal @@ -0,0 +1,28 @@ +Name: simseq +Version: 0.0 +License: GPL +License-File: LICENSE + +Author: Ketil Malde +Maintainer: Ketil Malde + +Stability: Alpha +Category: Bioinformatics +Synopsis: Simulate sequencing with different models for priming and errors +Description: This is a simulator that can generate simulated sequences -- primarily EST type sequences, + but quite possibly other types as well. Mail me for further information on usage etc. +Homepage: http://malde.org/~ketil/ + + +Build-Depends: base, bio >= 0.2, random, bytestring + -- add fps for ghc-6.4.2 +Build-Type: Simple + +data-files: README, idea.txt + +Executable: simseq +Main-Is: Simseq.hs +Hs-Source-Dirs: src +Other-modules: Options, R454, UnfoldMut, Sanger + +Ghc-Options: -Wall -funbox-strict-fields diff --git a/src/Options.hs b/src/Options.hs new file mode 100644 --- /dev/null +++ b/src/Options.hs @@ -0,0 +1,151 @@ +{- Handle Options + + Options: + + --prime model for starting points [uniform] + --error error model [uniform,gradient,..] + --terminator termination condition [sigma..] + --model shortcut for useful combinations [sanger|454|solexa] + + -} + +module Options where + +import System.Environment (getArgs) +import System.Exit (exitWith,ExitCode(..)) +import System.Console.GetOpt +import System.IO +import Data.List (unfoldr) +import Control.Monad (when) +import Bio.Sequence + +import UnfoldMut +import Sanger +import R454 + +version, usagemsg :: String +version = "0.0" +usagemsg = "Usage: simseq [options] FILE.." + +data Opts = Opts { primer :: Primer + , errmod :: [Mutator] + , term :: Terminator + } + +getOpts :: IO (Opts,[Sequence]) +getOpts = do + (opt1,fs,err) <- getArgs >>= (return . getOpt Permute options) + opts <- parseargs opt1 + when (not $ null err) (error $ usage err) + when (forceOpts opts) (error "Impossible!") + ss <- if null fs then hReadFasta stdin + else return . concat =<< mapM readFasta fs + return (opts, ss) + where + forceOpts (Opts x y z) = x `seq` y `seq` z `seq` False + +parseargs :: [Opts -> IO Opts] -> IO Opts +parseargs args = foldl (>>=) (return defaultopts) args + +usage :: [String] -> String +usage errs = usageInfo (concat errs ++ usagemsg) options + +------------------------------------------------------------ + +options :: [OptDescr (Opts -> IO Opts)] +options = [ Option [] ["primer"] (ReqArg (setPrimer . processArgs) "p") + ("Model for initiating sequencing "++show (map fst primers)) + , Option [] ["error"] (ReqArg (setMutator . processArgs) "e") + ("Error model "++show (map fst mutators)) + , Option [] ["terminator"] (ReqArg (setTerm . processArgs) "t") + ("Termination condition "++show (map fst terminators)) + , Option [] ["model"] (ReqArg (setModel . processArgs) "m") + ("Shortcut for useful combinations "++show (map fst models)) + , Option ['h'] ["help"] (ReqArg help "option") ("Help with 'option'") + ] + +defaultopts :: Opts +defaultopts = Opts (error "no primer specified") + (error "no error model specified") + (error "no terminator specified") + +help :: String -> Opts -> IO Opts +help arg _ = do putStrLn usagemsg + case arg of + "primer" -> list "specifies when sequence generation starts" primers + "error" -> list "adds an error model for sequence generation" mutators + "terminator" -> list "specifies when sequence generation terminates" terminators + "model" -> list "specifies a complete model including primer, error model, and terminator" models + _ -> putStrLn (" "++arg++": no such option") + exitWith ExitSuccess + + where list str tbl = putStrLn (" "++arg ++ ": "++str++"\n Valid alternatives are: "++unwords (map fst tbl)) + + +------------------------------------------------------------ + +-- | Break a string argument representing a function and arguments +-- into components. Syntax is func:arg1,arg2,.. +processArgs :: String -> (String,[String]) +processArgs ss = let (fn,as) = break (==':') ss + in (fn,splitStr ',' as) + +splitStr :: Char -> String -> [String] +splitStr c = unfoldr (\s -> if null s then Nothing + else let (x,y) = break (==c) (drop 1 s) + in Just (x,y)) + +------------------------------------------------------------ +-- Lookup tables for selecting the desired behavior +------------------------------------------------------------ + +notfound :: String -> [(String,a)] -> String -> String +notfound what whats which = "'"++which++"': no such "++what++".\n"++ + "Available "++what++"s are: "++ (unwords $ map fst whats) + +setPrimer :: (String,[String]) -> Opts -> IO Opts +setPrimer (prim,args) (Opts _ m t) = return (Opts p m t) + where p = maybe (error $ notfound "primer" primers prim) + (\f -> f args) (lookup prim primers) + +primers :: [(String,[String]->Primer)] +primers = [("uniform",p_uniform)] +-- help text? "uniform:n,p","select n random starting points, with probability p of forward direction, 1-p or reverse" + +------------------------------------------------------------ + +setTerm :: (String,[String]) -> Opts -> IO Opts +setTerm (trm,args) (Opts p m _) = return (Opts p m t) + where t = maybe (error $ notfound "terminator" terminators trm) + (\f -> f args) (lookup trm terminators) + +terminators :: [(String,[String]->Terminator)] +terminators = + [("sigma",\args -> case args of + [s,w] -> \ (MS _ _ l) -> sigma (read s) (read w) $ fromIntegral l + _ -> error "terminator 'sigma' needs two arguments") + ] + +------------------------------------------------------------ + +setMutator :: (String,[String]) -> Opts -> IO Opts +setMutator (mut,args) (Opts p m t) = return (Opts p m' t) + where m' = maybe (error $ notfound "mutator" mutators mut) + (\f -> f args : m) (lookup mut mutators) + + +mutators :: [(String,[String]->Mutator)] +mutators = [] -- ("uniform",...)] + +------------------------------------------------------------ + +setModel :: (String,[String]) -> Opts -> IO Opts +setModel (md,args) _ = return (maybe (error $ notfound "model" models md) + (\f -> case f args of (p,m,t) -> Opts {primer=p,errmod=m,term=t}) + (lookup md models)) + +models :: [(String,[String]->Model)] +models = [("sanger",sanger) + ,("stest",\[] -> sanger ["1","1"]) + ,("454",r454) + ] diff --git a/src/R454.hs b/src/R454.hs new file mode 100644 --- /dev/null +++ b/src/R454.hs @@ -0,0 +1,38 @@ +{- Modelling 454 sequencing + (or Roche-something, as it is now called) + + From Marguiles M. et al: + insertion error rate 1.67% + deletion error rate 1.60% + substitution error rate 0.68% + + No quantification of homopolymer length errors. + + Primer is uniform, this is even more so for 454 than for Sanger + (but the paper has a more elaborate stats to be incorporated: TODO) +-} + +module R454 where + +import UnfoldMut +import Bio.Sequence.SeqData (Offset, Sequence) + +r454_dist :: Offset -> Prob +r454_dist = (*0.02) . uniform -- 2% base rate of error + +r454_hp :: MState -> Prob +r454_hp = (*0.2) . homopolymer -- 0-40% chance for 0..20+ equal bases + +basic, hp :: [Mutator] +basic = mkmut r454_dist (subst "ACGTN" ++ ins "ACGTN" ++ (concat $ replicate 5 del)) + +-- | Depending on homopolymer length, duplicate or delete +-- hmm..ugly +hp = [\m -> let (s,m') = (head dup) m in (r454_hp m,s,m') + ,\m -> let (s,m') = (head del) m in (r454_hp m,s,m')] + +terminator :: MState -> Prob +terminator (MS _ _ l) = gradient 90 150 $ fromIntegral l + +r454 :: [String] -> ([Sequence] -> IO [MState], [Mutator], MState -> Prob) +r454 = \[n,d] -> (p_uniform [n,d],basic++hp,terminator) diff --git a/src/Sanger.hs b/src/Sanger.hs new file mode 100644 --- /dev/null +++ b/src/Sanger.hs @@ -0,0 +1,33 @@ +{- Implement Sanger type sequencing + + Random primer position + Terminate after ...850±50 nucleotides(?) + initial errors, uniform errors, terminal errors +-} + +module Sanger (sanger) where +import UnfoldMut + +-- Sanger error distribution. High initial rate, +-- long stretch of high quality, then degradation at the end +sanger_dist :: Distribution +sanger_dist = combine [ (*0.05) . uniform -- 0.5% error rate in HQ region + , (*0.30) . gradient 25 0 -- high initial error rate + , (*0.40) . sigma 700 25] -- terminal degradation + +mods :: [Char] +mods = "ACGTN" + +-- | Relationship of 3:1 between substitutions and indels +s_mutate :: [Mutator] +s_mutate = mkmut ((*0.60) . sanger_dist) (subst mods) -- 3/4 subst + ++ mkmut ((*0.10) . sanger_dist) (ins mods) -- 1/8 insert + ++ mkmut ((*0.10) . sanger_dist) del -- 1/8 delete + ++ mkmut ((*0.30) . sigma 700 25) dup -- terminal duplications + ++ mkmut ((*0.20) . sigma 700 25) del -- ...and deletions + +terminator :: Terminator +terminator (MS _ _ l) = sigma 850 25 $ fromIntegral l + +sanger :: [String] -> Model +sanger = \[n,d] -> (p_uniform [n,d],s_mutate,terminator) diff --git a/src/Simseq.hs b/src/Simseq.hs new file mode 100644 --- /dev/null +++ b/src/Simseq.hs @@ -0,0 +1,31 @@ +{- + Main function for simseq + + Read a set of sequences, apply an error model to generate simulated + sequences. + + Usage: simseq [options] fasta-file.. + + See Options.hs for option details. +-} + +module Main where + +import Bio.Sequence + +import System.IO +import Data.ByteString.Lazy.Char8 (pack) + +import UnfoldMut +import Options + +main :: IO () +main = do + (Opts pri mut trm,ss) <- getOpts + ms <- pri ss + let ts = mkseqs $ map (transcribe mut trm) ms + hWriteFasta stdout ts + +mkseqs :: [String] -> [Sequence] +mkseqs = map ($Nothing) . zipWith Seq [pack (">tr_"++show x) | x <- ([1..]::[Int])] . map pack + diff --git a/src/UnfoldMut.hs b/src/UnfoldMut.hs new file mode 100644 --- /dev/null +++ b/src/UnfoldMut.hs @@ -0,0 +1,160 @@ +{- Transcribe from a base sequence using unfoldr + + Probably more complicated than necessary. + + 'prime' selects starting points (in the form of initial state) + 'transcribe' takes a list of mutators, a terminator, and an + initial state and generates the transcript. +-} + +module UnfoldMut where + +import Bio.Sequence hiding ((!)) +import Data.Char (toUpper) -- for testing +import Data.Int +import Data.List (sort) +import Data.List (unfoldr) +import Data.Maybe (isJust) +import System.Random +import qualified Bio.Sequence as S + +at :: Cursor -> Char +at (s,o,d) | o < 0 || o >= seqlength s = 'X' + | d == Fwd = (S.!) s o + | otherwise = compl $ (S.!) s o + +type Prob = Double + +-- | The cursor tracks position in the sequence (simulating polymerase) +data Direction = Fwd | Rev deriving (Eq,Show) +type Cursor = (Sequence,Offset,Direction) + +-- | A primer determines when to initiate transcripts +type Primer = [Sequence] -> IO [MState] + +------------------------------------------------------------ +-- | A mutator inspects the state, returns the probability of an action, +-- and the action, in the form of a string and a modified state +type Mutator = MState -> (Prob,[Char], MState) +type MutFunc = MState -> ([Char],MState) + +combine :: [Distribution] -> Distribution +combine = foldr (\f g -> \x -> f x + g x) (const 0) + +mkmut :: Distribution -> [MutFunc] -> [Mutator] +mkmut dist fs = + map (\f -> \m -> let (s,m') = f m in (t m, s, m')) fs + where t = (/fromIntegral (length fs)) . dist . tlen + tlen (MS _ _ l) = fromIntegral l + +-- | Uniform probs for substitution and insertion +subst, ins :: String -> [MutFunc] +subst = map (\x -> \m -> ([x],fwd m)) +ins = map (\x -> \m -> ([x],m)) + +-- | Deletion of current base +del :: [MutFunc] +del = [\m -> ([],fwd m)] + +-- | Duplicate current base without forwarding +dup :: [MutFunc] +dup = [\m@(MS _ c _) -> ([toUpper $ at c],m)] + +------------------------------------------------------------ +-- | The terminator examines the state, and the probablity of +-- transcript termination +type Terminator = MState -> Prob + +-- | A Model is shorthand for a complete parameter set +type Model = (Primer,[Mutator],Terminator) + +-- | The state of the current transcription +data MState = MS StdGen Cursor Int +instance Show MState where show = const "xxx" + +------------------------------------------------------------ +-- | A distribution is a probability as a function of length +type Distribution = Offset -> Prob + +-- | The sigmoid function provides a soft threshold +-- center on s, scale by w +sigma :: Double -> Double -> Distribution +sigma s w = \t -> 1/(1+exp ((s-fromIntegral t)/w)) + +uniform :: Distribution +uniform = const 1 + +gradient :: Double -> Double -> Distribution +gradient s e = \t -> max 0 . min 1 $ (fromIntegral t-s)/(e-s) + +-- | For 454 (and other?) sequencing, we need a distribution +-- that depends on sequence content +homopolymer :: MState -> Prob +homopolymer (MS _ c@(s,o,_) _) = + (/20) . fromIntegral . length . takeWhile (== at c) . + map ((S.!) s) $ [o..min (o+19) (seqlength s-1)] + +------------------------------------------------------------ +-- | Increments the cursor in the MState +fwd :: MState -> MState +fwd (MS sg (s,o,d) l) = (MS sg (s,if d == Fwd then o+1 else o-1,d) l) + +transcribe :: [Mutator] -> Terminator -> MState -> [Char] +transcribe ms t is = concat . unfoldr (sequencer ms t) $ is + +-- | walk a list of mutator funcitions, pick one based on p +-- whoa! this is almost :: [Mutator] -> Mutator! +sequencer :: [Mutator] -> Terminator -> MState -> Maybe ([Char],MState) +sequencer ms t = + \m@(MS g c _) -> + let (p,g') = randomR (0,1) g + tp = t m + new = mutate m (p-tp) ms + in if p < tp then Nothing + else update_ms g' $ if isJust new then new + else Just ([at c], fwd m) + +-- | update rndgen and length +update_ms :: StdGen -> Maybe (String,MState) -> Maybe (String,MState) +update_ms g (Just (xs, MS _ c l)) = Just (xs, MS g c (l+length xs)) +update_ms _ Nothing = error "this is impossible" + +-- | try all mutators in a list +mutate :: MState -> Prob -> [Mutator] -> Maybe (String,MState) +mutate st p (m:ms) = let (t,ch,st') = m st + p' = p-t + in if p' < 0 then Just (ch,st') + else mutate st p' ms +mutate _st _p [] = Nothing + +------------------------------------------------------------ +-- | A primer with a uniform (poisson) distribution +p_uniform :: [String] -> Primer +p_uniform [n,d] = \ss -> do + (g,g') <- return . split =<< newStdGen + let l = sum $ map seqlength ss + os = sort . take (read n) . randomRs (0,l-1) $ g + return (gen_ms (read d) g' 0 ss os) +p_uniform _ = error "primer 'uniform' needs two arguments" + +-- | Generate MStates for transcript initiation +gen_ms :: Double -> StdGen -> Offset -> [Sequence] -> [Offset] -> [MState] +gen_ms d g c (s:ss) (p:ps) + | p-c >= seqlength s = gen_ms d g (c+seqlength s) ss (p:ps) + | otherwise = let (g1,g') = split g + (z,g2) = randomR (0,1) g1 + in MS g2 (s,p-c,if z (a,a) -> g -> (a,g) +integralRandomR (a,b) g = case randomR (fromIntegral a :: Integer, + fromIntegral b :: Integer) g of + (x,g') -> (fromIntegral x, g')