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In biology, a sequence motif is a
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
or amino-acid
sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is called ...
pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro residue''.


Overview

When a sequence motif appears in the exon of a
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
, it may encode the " structural motif" of a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
; that is a stereotypical element of the overall structure of the protein. Nevertheless, motifs need not be associated with a distinctive secondary structure. " Noncoding" sequences are not
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
into proteins, and nucleic acids with such motifs need not deviate from the typical shape (e.g. the "B-form" DNA double helix). Outside of gene exons, there exist
regulatory sequence A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and ...
motifs and motifs within the " junk", such as satellite DNA. Some of these are believed to affect the shape of nucleic acids (see for example RNA self-splicing), but this is only sometimes the case. For example, many DNA binding proteins that have affinity for specific DNA binding sites bind DNA in only its double-helical form. They are able to recognize motifs through contact with the double helix's major or minor groove. Short coding motifs, which appear to lack secondary structure, include those that label proteins for delivery to particular parts of a cell, or mark them for phosphorylation. Within a sequence or
database In computing, a database is an organized collection of data stored and accessed electronically. Small databases can be stored on a file system, while large databases are hosted on computer clusters or cloud storage. The design of databases ...
of sequences, researchers search and find motifs using computer-based techniques of sequence analysis, such as BLAST. Such techniques belong to the discipline of
bioinformatics Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
. See also consensus sequence.


Motif Representation

Consider the ''N''-glycosylation site motif mentioned above: : ''Asn, followed by anything but Pro, followed by either Ser or Thr, followed by anything but Pro'' This pattern may be written as N T/code> where N = Asn, P = Pro, S = Ser, T = Thr; means any amino acid except X; and Y/code> means either X or Y. The notation Y/code> does not give any indication of the probability of X or Y occurring in the pattern. Observed probabilities can be graphically represented using sequence logos. Sometimes patterns are defined in terms of a probabilistic model such as a
hidden Markov model A hidden Markov model (HMM) is a statistical Markov model in which the system being modeled is assumed to be a Markov process — call it X — with unobservable ("''hidden''") states. As part of the definition, HMM requires that there be an ...
.


Motifs and consensus sequences

The notation YZ/code> means X or Y or Z, but does not indicate the likelihood of any particular match. For this reason, two or more patterns are often associated with a single motif: the defining pattern, and various typical patterns. For example, the defining sequence for the IQ motif may be taken to be: : ILVxxx Kxxx Kx ILVWY/code> where x signifies any amino acid, and the square brackets indicate an alternative (see below for further details about notation). Usually, however, the first letter is I, and both K/code> choices resolve to R. Since the last choice is so wide, the pattern IQxxxRGxxxR is sometimes equated with the IQ motif itself, but a more accurate description would be a '' consensus sequence for the IQ motif''.


Pattern description notations

Several notations for describing motifs are in use but most of them are variants of standard notations for regular expressions and use these conventions: * there is an alphabet of single characters, each denoting a specific amino acid or a set of amino acids; * a string of characters drawn from the alphabet denotes a sequence of the corresponding amino acids; * any string of characters drawn from the alphabet enclosed in square brackets matches any one of the corresponding amino acids; e.g. bc/code> matches any of the amino acids represented by a or b or c. The fundamental idea behind all these notations is the matching principle, which assigns a meaning to a sequence of elements of the pattern notation: : ''a sequence of elements of the pattern notation matches a sequence of amino acids if and only if the latter sequence can be partitioned into subsequences in such a way that each pattern element matches the corresponding subsequence in turn.'' Thus the pattern B DEF matches the six amino acid sequences corresponding to ACF, ADF, AEF, BCF, BDF, and BEF. Different pattern description notations have other ways of forming pattern elements. One of these notations is the PROSITE notation, described in the following subsection.


PROSITE pattern notation

The PROSITE notation uses the
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
one-letter codes and conforms to the above description with the exception that a concatenation symbol, '-', is used between pattern elements, but it is often dropped between letters of the pattern alphabet. PROSITE allows the following pattern elements in addition to those described previously: * The lower case letter 'x' can be used as a pattern element to denote any amino acid. * A string of characters drawn from the alphabet and enclosed in braces (curly brackets) denotes any amino acid except for those in the string. For example, denotes any amino acid other than S or T. * If a pattern is restricted to the N-terminal of a sequence, the pattern is prefixed with '<'. * If a pattern is restricted to the C-terminal of a sequence, the pattern is suffixed with '>'. * The character '>' can also occur inside a terminating square bracket pattern, so that S >/code> matches both "ST" and "S>". * If e is a pattern element, and m and n are two decimal integers with m <= n, then: ** e(m) is equivalent to the repetition of e exactly m times; ** e(m,n) is equivalent to the repetition of e exactly k times for any integer k satisfying: m <= k <= n. Some examples: * x(3) is equivalent to x-x-x. * x(2,4) matches any sequence that matches x-x or x-x-x or x-x-x-x. The signature of the C2H2-type '' zinc finger'' domain is: * C-x(2,4)-C-x(3)- IVMFYWCx(8)-H-x(3,5)-H


Matrices

A matrix of numbers containing scores for each residue or nucleotide at each position of a fixed-length motif. There are two types of weight matrices. * A position frequency matrix (PFM) records the position-dependent frequency of each residue or nucleotide. PFMs can be experimentally determined from SELEX experiments or computationally discovered by tools such as MEME using hidden Markov models. * A
position weight matrix A position weight matrix (PWM), also known as a position-specific weight matrix (PSWM) or position-specific scoring matrix (PSSM), is a commonly used representation of motifs (patterns) in biological sequences. PWMs are often derived from a set ...
(PWM) contains log odds weights for computing a match score. A cutoff is needed to specify whether an input sequence matches the motif or not. PWMs are calculated from PFMs. An example of a PFM from the
TRANSFAC TRANSFAC (TRANScription FACtor database) is a manually curated database of eukaryotic transcription factors, their genomic binding sites and DNA binding profiles. The contents of the database can be used to predict potential transcription facto ...
database for the transcription factor AP-1: The first column specifies the position, the second column contains the number of occurrences of A at that position, the third column contains the number of occurrences of C at that position, the fourth column contains the number of occurrences of G at that position, the fifth column contains the number of occurrences of T at that position, and the last column contains the IUPAC notation for that position. Note that the sums of occurrences for A, C, G, and T for each row should be equal because the PFM is derived from aggregating several consensus sequences.


Motif Discovery


Overview

The sequence motif discovery process has been well-developed since the 1990s. In particular, most of the existing motif discovery research focuses on DNA motifs. With the advances in high-throughput sequencing, such motif discovery problems are challenged by both the sequence pattern degeneracy issues and the data-intensive computational scalability issues.


''De novo'' motif discovery

There are software programs which, given multiple input sequences, attempt to identify one or more candidate motifs. One example is the Multiple EM for Motif Elicitation (MEME) algorithm, which generates statistical information for each candidate. There are more than 100 publications detailing motif discovery algorithms; Weirauch ''et al''. evaluated many related algorithms in a 2013 benchmark. The planted motif search is another motif discovery method that is based on combinatorial approach.


Phylogenetic motif discovery

Motifs have also been discovered by taking a
phylogenetic In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups ...
approach and studying similar genes in different species. For example, by aligning the amino acid sequences specified by the GCM (''glial cells missing'') gene in man, mouse and ''D. melanogaster'', Akiyama and others discovered a pattern which they called the GCM motif in 1996. It spans about 150 amino acid residues, and begins as follows: : WDIND*.*P..*...D.F.*W***.**.IYS**...A.*H*S*WAMRNTNNHN Here each . signifies a single amino acid or a gap, and each * indicates one member of a closely related family of amino acids. The authors were able to show that the motif has DNA binding activity. A similar approach is commonly used by modern protein domain databases such as Pfam: human curators would select a pool of sequences known to be related and use computer programs to align them and produce the motif profile, which can be used to identify other related proteins. A phylogenic approach can also be used to enhance the ''de novo'' MEME algorithm, with PhyloGibbs being an example.


''De novo'' motif pair discovery

In 2017, MotifHyades has been developed as a motif discovery tool that can be directly applied to paired sequences.


''De novo'' motif recognition from protein

In 2018, a Markov random field approach has been proposed to infer DNA motifs from
DNA-binding domains A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
of proteins.


Motif Cases


Three-dimensional chain codes

The '' E. coli'' lactose operon repressor LacI ( chain A) and ''E. coli'' catabolite gene activator ( chain A) both have a ''helix-turn-helix'' motif, but their amino acid sequences do not show much similarity, as shown in the table below. In 1997, Matsuda, ''et al.'' devised a code they called the "three-dimensional chain code" for representing the protein structure as a string of letters. This encoding scheme reveals the similarity between the proteins much more clearly than the amino acid sequence (example from article): The code encodes the torsion angles between alpha-carbons of the
protein backbone In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide or protein ch ...
. "W" always corresponds to an alpha helix.


See also


References


Secondary and tertiary sources


Primary sources


Further reading


Secondary and tertiary sources

* *


Primary sources

* * * {{refend Bioinformatics