Align Two Sets of Aligned Sequences

Description

Aligns two sets of one or more aligned sequences by first generating representative profiles, then aligning the profiles with dynamic programming, and finally merging the two aligned sequence sets.

Usage

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AlignProfiles(pattern,
              subject,
              p.weight = 1,
              s.weight = 1,
              p.struct = NULL,
              s.struct = NULL,
              perfectMatch = 5,
              misMatch = 0,
              gapOpening = -13,
              gapExtension = -1,
              gapPower = -1,
              terminalGap = -5,
              restrict = -1000,
              anchor = 0.7,
              normPower = 1,
              substitutionMatrix = NULL,
              structureMatrix = NULL,
              processors = 1)

Arguments

pattern

An AAStringSet, DNAStringSet, or RNAStringSet object of aligned sequences to use as the pattern.

subject

A XStringSet object of aligned sequences to use as the subject. Must match the type of the pattern.

p.weight

A numeric vector of weights for each sequence in the pattern to use in generating a profile, or a single number implying equal weights.

s.weight

A numeric vector of weights for each sequence in the subject to use in generating a profile, or a single number implying equal weights.

p.struct

Either NULL (the default), a matrix, or a list of matrices with one list element per sequence in the pattern. (See details section below.)

s.struct

Either NULL (the default), a matrix, or a list of matrices with one list element per sequence in the subject. (See details section below.)

perfectMatch

Numeric giving the reward for aligning two matching nucleotides in the alignment. Only used for DNAStringSet or RNAStringSet inputs.

misMatch

Numeric giving the cost for aligning two mismatched nucleotides in the alignment. Only used for DNAStringSet or RNAStringSet inputs.

gapOpening

Numeric giving the cost for opening a gap in the alignment.

gapExtension

Numeric giving the cost for extending an open gap in the alignment.

gapPower

Numeric specifying the exponent to use in the gap cost function. (See details section below.)

terminalGap

Numeric giving the cost for allowing leading and trailing gaps ("-" or "." characters) in the alignment. Either two numbers, the first for leading gaps and the second for trailing gaps, or a single number for both.

restrict

Numeric specifying the lowest relative score to consider when aligning. The default (-1000) will align most inputs that can reasonably be globally aligned without any loss in accuracy. Input sequences with high similarity could be more restricted (e.g., -500), whereas a pattern and subject with little overlap should be less restricted (e.g., -10000). (See details section below.)

anchor

Numeric giving the fraction of sequences with identical k-mers required to become an anchor point, or NA to not use anchors. Alternatively, a matrix specifying anchor regions. (See details section below.)

normPower

Numeric giving the exponent that controls the degree of normalization applied to scores by column occupancy. A normPower of 0 does not normalize the scores, which results in all columns of the profiles being weighted equally, and is the optimal value for aligning fragmentary sequences. A normPower of 1 normalizes the score for aligning two positions by their column occupancy (1 - fraction of gaps). A normPower greater than 1 more strongly discourages aligning with “gappy” regions of the alignment.

substitutionMatrix

Either a substitution matrix representing the substitution scores for an alignment or the name of the amino acid substitution matrix to use in alignment. The latter may be one of the following: “BLOSUM45”, “BLOSUM50”, “BLOSUM62”, “BLOSUM80”, “BLOSUM100”, “PAM30”, “PAM40”, “PAM70”, “PAM120”, “PAM250”, or “MIQS”. The default (NULL) will use the perfectMatch and misMatch penalties for DNA/RNA or “MIQS” for AA. (See examples section below.)

structureMatrix

A structure matrix if p.struct and s.struct are supplied, or NULL otherwise.

processors

The number of processors to use, or NULL to automatically detect and use all available processors.

Details

Profiles are aligned using dynamic programming, a variation of the Needleman-Wunsch algorithm for global alignment. The dynamic programming method requires order N*M time and memory space where N and M are the width of the pattern and subject. This method works by filling in a matrix of the possible “alignment space” by considering all matches, insertions, and deletions between two sequence profiles. The highest scoring alignment is then used to add gaps to each of the input sequence sets.

Heuristics can be useful to improve performance on long input sequences. The restrict parameter can be used to dynamically constrain the possible “alignment space” to only paths that will likely include the final alignment, which in the best case can improve the speed from quadratic time to linear time. The degree of restriction is important, and if the sequences are not mostly overlapping then restrict should be relaxed (more negative than the default). For example, if aligning a pattern to a much longer subject then restrict should be set to -1e10 to effectively prevent restriction.

The argument anchor can be used to split the global alignment into multiple sub-alignments. This can greatly decrease the memory requirement for long sequences when appropriate anchor points can be found. Anchors are 15-mer (for DNA/RNA) or 7-mer (for AA) subsequences that are shared between at least anchor fraction of pattern(s) and subject(s). Anchored ranges are extended along the length of each sequence in a manner designed to split the alignment into sub-alignments that can be separately solved. For most input sequences, the default anchoring has no effect on accuracy, but anchoring can be disabled by setting anchor=NA.

Alternatively, anchor can be a matrix with 4 rows and one column per anchor. The first two rows correspond to the anchor start and end positions in the pattern sequence(s), and the second two rows are the equivalent anchor region in the subject sequence(s). Anchors specified in this manner must be strictly increasing (non-overlapping) in both sequences, and have an anchor width of at least two positions. Note that the anchors do not have to be equal length, in which case the anchor regions will also be aligned. Manually splitting the alignment into more subtasks can sometimes make it more efficient, but typically automatic anchoring is effective.

The arguments p.struct and s.struct may be used to provide secondary structure probabilities in the form of a list containing matrices or a single matrix. If the input is a list, then each list element must contain a matrix with dimensions q*w, where q is the number of possible secondary structure states, and w is the width of the unaligned pattern sequence. Values in each matrix represent the probability of the given state at that position in the sequence. Alternatively, a single matrix can be used as input if w is the width of the entire pattern or subject alignment. A structureMatrix must be supplied along with the structures. The functions PredictHEC and PredictDBN can be used to predict secondary structure probabilities in the format required by AlignProfiles (for amino acid and RNA sequences, respectively).

The gap cost function is based on the observation that gap lengths are best approximated by a Zipfian distribution (Chang & Benner, 2004). The cost of inserting a gap of length L is equal to: gapOpening + gapExtension*sum(seq_len(L - 1)^gapPower) when L > 1, and gapOpen when L = 1. This function effectively penalizes shorter gaps significantly more than longer gaps when gapPower < 0, and is equivalent to the affine gap penalty when gapPower is 0.

Value

An XStringSet of aligned sequences.

Author(s)

Erik Wright DECIPHER@cae.wisc.edu

References

Chang, M. S. S., & Benner, S. A. (2004). Empirical Analysis of Protein Insertions and Deletions Determining Parameters for the Correct Placement of Gaps in Protein Sequence Alignments. Journal of Molecular Biology, 341(2), 617-631.

Needleman S., Wunsch, C. (1970). A general method applicable to the search for similarities in the amino acid sequence of two proteins. Journal of Molecular Biology, 48(3), 443-453.

ES Wright (2015) "DECIPHER: harnessing local sequence context to improve protein multiple sequence alignment". BMC Bioinformatics, doi:10.1186/s12859-015-0749-z.

See Also

AlignDB, AlignSeqs, AlignSynteny, AlignTranslation, MIQS

Examples

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# align two sets of sequences
db <- system.file("extdata", "Bacteria_175seqs.sqlite", package="DECIPHER")
dna1 <- SearchDB(db, remove="common", limit=100) # the first 100 sequences
dna2 <- SearchDB(db, remove="common", limit="100,100") # the rest
alignedDNA <- AlignProfiles(dna1, dna2)
BrowseSeqs(alignedDNA, highlight=1)

# specify a DNA substitution matrix
subMatrix <- matrix(0,
                    nrow=4, ncol=4,
                    dimnames=list(DNA_BASES, DNA_BASES))
diag(subMatrix) <- 5 # perfectMatch
alignedDNA.defaultSubM <- AlignProfiles(dna1, dna2, substitutionMatrix=subMatrix)
all(alignedDNA.defaultSubM==alignedDNA)

# specify a different DNA substitution matrix
subMatrix2 <- matrix(c(12, 3, 5, 3, 3, 12, 3, 6, 5, 3, 11, 3, 3, 6, 3, 9),
                    nrow=4, ncol=4,
                    dimnames=list(DNA_BASES, DNA_BASES))
alignedDNA.alterSubM <- AlignProfiles(dna1, dna2, substitutionMatrix=subMatrix2)
all(alignedDNA.alterSubM==alignedDNA)

# anchors are found automatically by default, but it is also
# possible to specify anchor regions between the sequences
anchors <- matrix(c(774, 788, 752, 766), nrow=4)
anchors
subseq(dna1, anchors[1, 1], anchors[2, 1])
subseq(dna2, anchors[3, 1], anchors[4, 1])
alignedDNA2 <- AlignProfiles(dna1, dna2, anchor=anchors)

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