Instead of the encoded protein being of a certain particular size, it'll end up being much shorter, and it won't be able to accomplish the role that's been set out for it. Elaine A. Ostrander, Ph. Featured Content. Such examples support our method's applicability in the discovery of distant protein homologies and functional frameshifts, without any explicit information about the coding sequences. Future work includes further improvements of the scoring system, for example in order to focus on the detection of short double correcting frameshifts two frameshifts separated by a small number of bases, where the second corrects the reading frame disrupted by the first.
Such cases have been shown to occur frequently [ 37 ], but are often highly penalized by sequence comparison methods, that discard the correct alignment in favor of an ungapped one with a higher score. Some natural extensions of our work include the support for multiple alignments of back-translation graphs. This feature can be useful for confirming frameshifts by similarity of the frameshifted subsequence with the corresponding fragments from several members of a family. Also, for boosting the efficiency, seeding techniques for back-translation graphs could be explored, possibly inspired by the BLASTP score-based seeds.
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PhD thesis. Smith T, Waterman M: Identification of common molecular subsequences. J Mol Bwl. Hirschberg D: A linear space algorithm for computing maximal common subsequences. Communications of the ACM. Molecular Biology and Evolution. Genome Research. Pedersen A, Jensen J: A dependent-rates model and an MCMC-based methodology for the maximum-likelihood analysis of sequences with overlapping reading frames.
BMC bioinformatics. AAAI press. Edited by: Salzberg S, Warnow T. Springer Verlag. Proc of the National Academy of Sciences. Molecular and Cellular Proteomics. Journal of Molecular Evolution. Download references. The authors would like to thank the WABI'09 anonymous reviewers, where a preliminary version of this work [ 40 ] was submitted, for their interesting questions and useful suggestions, that helped to improve some aspects of the work, as well as its presentation.
You can also search for this author in PubMed Google Scholar. GK initiated and guided the project, and proposed the first version of the method. MG refined the method, proposed the initial scoring system, did the implementation and the web interface.
LN contributed to defining and improving the scoring system, and did most of the experimentation and the analysis of the results. MG drafted the manuscript, which was completed by LN with the "Experimental results" section, and then finalized and approved by GK. This article is published under license to BioMed Central Ltd. Reprints and Permissions.
Back-translation for discovering distant protein homologies in the presence of frameshift mutations. Algorithms Mol Biol 5, 6 Download citation. Received : 11 August Accepted : 04 January Published : 04 January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Background Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin.
Results We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences. Conclusions Our approach allows to uncover evolutionary information that is not captured by traditional alignment methods, which is confirmed by biologically significant examples.
Background Context and motivation In protein-coding DNA sequences, frameshift mutations insertions or deletions of one or more bases can alter the translation reading frame, affecting all the amino acids encoded from that point forward. Protein back-translation Back-translation or reverse translation of a protein usually refers to obtaining one of the DNA sequences that encodes the given protein. Similar approaches The idea of using knowledge about coding DNA when aligning amino acid sequences has been explored in several papers.
Methods The problem of inferring homologies between distantly related proteins, whose divergence is the result of frameshifts and point mutations, is approached in this paper by determining the best pairwise alignment between two DNA sequences that encode the proteins. Data structures: back-translation graphs An explicit enumeration and pairwise alignment of all the putative DNA sequences is not an option, since their number increases exponentially with the protein's length, as all amino acids are encoded by 2, 3, 4 or 6 codons, with the exception of M and W , which have a single corresponding codon.
Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Results and Discussion We have proposed a method for aligning protein sequences with frameshifts, by back-translating the proteins into graphs that implicitly contain all the putative DNA sequences, and aligning them with a dynamic programming algorithm that uses a scoring system designed for this particular purpose.
Experimental results We will further discuss several significant frameshifted alignments obtained with our method. Yersinia pestis: Frameshifted transposases Figure 7 displays the alignment of two transposase variants from Yersinia pestis.
In fact, some of the mutations discussed above are the result of spontaneous events during replication, and they are thus known as spontaneous mutations. Slippage of the DNA template strand and subsequent insertion of an extra nucleotide is one example of a spontaneous mutation; excess flexibility of the DNA strand and the subsequent mispairing of bases is another.
Environmental exposure to certain chemicals, ultraviolet radiation, or other external factors can also cause DNA to change. These external agents of genetic change are called mutagens. Exposure to mutagens often causes alterations in the molecular structure of nucleotides, ultimately causing substitutions, insertions, and deletions in the DNA sequence. Mutations are a source of genetic diversity in populations, and, as mentioned previously, they can have widely varying individual effects.
In some cases, mutations prove beneficial to an organism by making it better able to adapt to environmental factors. In other situations, mutations are harmful to an organism — for instance, they might lead to increased susceptibility to illness or disease. In still other circumstances, mutations are neutral, proving neither beneficial nor detrimental outcomes to an organism.
Thus, it is safe to say that the ultimate effects of mutations are as widely varied as the types of mutations themselves.
This page appears in the following eBook. Aa Aa Aa. Where do mutations occur? Germ-line mutations occur in gametes or in cells that eventually produce gametes. In contrast with somatic mutations, germ-line mutations are passed on to an organism's progeny.
As a result, future generations of organisms will carry the mutation in all of their cells both somatic and germ-line. What kinds of mutations exist?
Base substitution. Base substitutions are the simplest type of gene-level mutation, and they involve the swapping of one nucleotide for another during DNA replication. For example, during replication, a thymine nucleotide might be inserted in place of a guanine nucleotide. With base substitution mutations, only a single nucleotide within a gene sequence is changed, so only one codon is affected Figure 1.
Figure 1: Only a single codon in the gene sequence is changed in base substitution mutation. The nitrogenous bases are paired so that blue and orange nucleotides are complementary and red and green nucleotides are complementary. However, the 5 th nucleotide from the right on both the bottom and top strand form a mismatched pair: an orange nucleotide pairs with a red nucleotide.
This mismatched pair is highlighted in cyan. The sugar molecules of each individual nucleotide in the chain are connected to adjacent sugar molecules, which are represented by gray horizontal cylinders. The nitrogenous bases hang down from the sugar molecules and look like vertical bars that are twice as long and half as wide as the gray cylinders; the bases are either blue, red, green, or orange. A second chain of 12 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right.
Here, the nitrogenous bases point upward from the sugar-phosphate chain, nearly meeting the ends of the nitrogenous bases from the upper strand.
Because there are only 12 nucleotides in the lower strand and 16 nucleotides in the upper strand, four nucleotides on the left side of the upper strand are not bound to a complementary nucleotide on the lower strand.
A 13 th nucleotide is shown joining the left end of the lower replicating strand. Although a base substitution alters only a single codon in a gene, it can still have a significant impact on protein production. In fact, depending on the nature of the codon change, base substitutions can lead to three different subcategories of mutations.
The first of these subcategories consists of missense mutations , in which the altered codon leads to insertion of an incorrect amino acid into a protein molecule during translation; the second consists of nonsense mutations , in which the altered codon prematurely terminates synthesis of a protein molecule; and the third consists of silent mutations , in which the altered codon codes for the same amino acid as the unaltered codon. Insertions and deletions. A second chain of 13 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right.
The sixth nucleotide from right to left has slipped out of place, causing a bulge in the DNA strand. The presence of this bulge causes a misalignment of nucleotide pairs; therefore, an extra nucleotide has been added to complete the remaining DNA strand with correct base pairs. This extra nucleotide in position 8 from the right has a cyan aura around it.
A 14 th nucleotide is shown joining the left end of the lower replicating strand. These amino acids are then joined together by the ribosomes in a process known as ribosome translocation.
Synthesis of protein is a cyclic process wherein, after joining one amino acid to the growing chain of the polypeptide, the ribosome moves forward by three bases i. The movement of ribosomes has disproportionate effects on protein or polypeptide function.
In case mutation occurs in the above sequence and an A nucleotide is added or inserted after the start codon AUG. This will completely change the reading frame to:. Thus, we can see, the addition of only a single nucleotide in the RNA sequence completely altered the base sequence that resulted in the formation of completely different amino acids during the translation process.
The reading frame of any mRNA is the coding sequence for a given polypeptide and is read continuously from the start codon AUG to one of the three stop codons. In translation, the ribosome moves down the mRNA three bases at a time and reads whatever codons follow the start codon. Adding or subtracting one or two bases or any other number that is not a multiple of 3 can disrupt the normal reading frame and lead to the production of a completely nonfunctional protein.
Frame shifts may also accidentally introduce an early stop codon. Original coding sequence: atggtgc at ctgactcctgaggagaagtct. Frameshift remove underlined at : atggtgcctgactccTGAggagaagtct.
Mutations are a source of variation; however certain mutations can be deleterious and results in a disease condition. Some of the known diseases that are caused due to frameshift mutations are-. Let us compare and understand the difference between point mutation and frameshift mutation.
In point mutation , one base is replaced by another base in the nucleotide sequence. Thus, the sequence of the nucleotide or the reading frame of the nucleic acid remains unchanged. Due to this reason, point mutation is also known as single base substitution.
The point mutation can be — transition and transversion. DNA is made up of purines and pyrimidines. Transition point mutation occurs when a purine base is substituted into another purine base whereas transversion occurs when a pyrimidine or vice versa substitutes a purine base. In the case of frameshift mutation insertion or deletion of the base, it results in a modification in the reading frame of the nucleotide in a nucleic acid.
Further differences between point mutation and frameshift mutation are enlisted in the table below. Based on the above details, let us attempt to answer a few questions by answering the quiz below.
This tutorial looks at the mutation at the gene level and the harm it may bring. Learn about single nucleotide polymorphisms, temperature-sensitive mutations, indels, trinucleotide repeat expansions, and gene duplication Read More.
This tutorial is a continuation of the first lesson on chromosomal mutation. Here, find out the chromosomal aberrations involving the genes.
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