This type of variant may alter the function of the protein made from the gene. An inversion changes more than one nucleotide in a gene by replacing the original sequence with the same sequence in reverse order.
A reading frame consists of groups of three nucleotides that each code for one amino acid. A frameshift variant occurs when there is an addition or loss of nucleotides that shifts the grouping and changes the code for all downstream amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift variants. Some regions of DNA contain short sequences of nucleotides that are repeated a number of times in a row.
For example, a trinucleotide repeat is made up of sequences of three nucleotides, and a tetranucleotide repeat is made up of sequences of four nucleotides.
A repeat expansion is a variant that increases the number of times that the short DNA sequence is repeated. This type of variant can cause the resulting protein to function improperly. Other chapters in Help Me Understand Genetics. Genetics Home Reference has merged with MedlinePlus.
Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. What kinds of gene variants are possible? From Genetics Home Reference. Variant types include the following: Substitution This type of variant replaces one DNA building block nucleotide with another. Missense : A missense variant is a type of substitution in which the nucleotide change results in the replacement of one protein building block amino acid with another in the protein made from the gene.
During the next round of replication the missincorporated base would lead to a mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing mismatched base pairs and excising them.
DNA often rearranges itself by a process called recombination which proceeds via a variety of mechanisms. Occasionally DNA is lost during replication leading to a mutation. Many chemical mutagens, some exogenous, some man-made, some environmental, are capable of damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA. Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals which cause chemical damage to DNA.
Damaged DNA can be repaired by several different mechanisms. Sometimes DNA polymerase incorporates an incorrect nucleotide during strand synthesis and the 3' to 5' editing system, exonuclease, fails to correct it.
These mismatches as well as single base insertions and deletions are repaired by the mismatch repair mechanism. Mismatch repair relies on a secondary signal within the DNA to distinguish between the parental strand and daughter strand, which contains the replication error. Human cells posses a mismatch repair system similar to that of E.
Because DNA replication is semi-conservative, the new daughter strand remains unmethylated for a very short period of time following replication. This difference allows the mismatch repair system to determine which strand contains the error. A protein, MutS recognizes and binds the mismatched base pair. DNA polymerase then fills in the gap and ligase seals the nick. The first series shows the frequency distribution for deletions, the second for insertions.
Length distributions of the different types of FS and I-F: a deletions and b insertions. The lengths of indels in nt and their frequency of occurrence are given along the x - and y -axes, respectively. The occurrence of deletions versus insertions suggests that deletions are the preferred mode of mutation; the occurrence of more FS than I-F indels [, ] suggests that the former are preferred, perhaps because they are easier to generate.
A study of small indels in the genomes of 79 humans has shown that healthy humans harbour a number of indels in coding exons coding indels , and The indels are believed to create the genetic variation necessary for biological function in some gene families, to create biological and phenotypic diversity, to have negative effects on gene function and to cause diseases.
In the present study, Insertion of one or more nt into a gene involves a cut and two ligations. In a , the two series show the frequencies with which each nt pair e. In c , the two series show the frequencies with which each nt pair e. Thus, in deletions, the join-pair is often the same as the end-cut. Joint frequencies of cut- and join-sites in deletions and insertions. The first bar in each group gives the total number of mutations FS or I-F deletions or insertions that have cut- and join-sites.
In the first two groups of bars FS and I-F deletions , the second, third, fourth and fifth bars, respectively, give the number of times that: i start-cut, end-cut, join-pair are same, ii start-cut, end-cut, join-pair are different, iii only start-cut, join-pair are same and iv only end-cut, join-pair are same.
The locations in proteins at which indels occur were analysed Supplementary Figure S4. The start and end codon numbers of each deletion in the WT protein, and of each insertion in the mutant protein were used to identify the locations of indels in proteins.
Each protein was divided into three parts—first or N-terminal , second or middle , third or C-terminal —and indels occurring in each part were identified. Thus, in S4A, S4B, while indels occurring in the N-terminal region may abolish protein function, those occurring in the C-terminal region are likely to modify it.
The greater frequency of occurrence of: i deletions in the N- rather than C-terminal regions suggests that deletions often abolish protein function S4A and ii of insertions in the C- rather than N-terminal regions suggests that insertions often modify protein function S4B.
Indels occurring in the middle of the protein are the preferred way to alter or disrupt protein function. The fraction of protein lost as a result of each deletion, and gained or lost as a result of each insertion was calculated for all FS and I-F indels Figure 7.
A deletion may result in the loss of a few amino acids or in the introduction of a PTC, resulting in the loss of a part of the protein. FS insertions may lead to the introduction of a PTC, which causes loss of a part of the protein. As a result of FS indels, while protein segments or fewer residues in length are often lost, the loss of longer segments more than residues is more frequent. On the other hand, the majority of I-F deletions cause modest decreases, and the majority of I-F insertions cause modest increases in protein length or less residues.
After the point of FS deletion or insertion, a change in the gene reading frame occurs. The length distributions of corrupted protein sequences resulting from FS indels [ Supplementary Methods i b ] are shown in Supplementary Figure S6 ; while sequences of shorter lengths 1—10 amino acid residues are the most frequent, those of longer lengths are also common. The figure provides insight into the stretches of protein corrupted by FS indels.
Fractions are given as intervals along the x -axis, and the number of deletions occurring in each interval is given along the y -axis. Fractions are given as intervals along the x -axis range, 0. The number of observations in each interval is given along the y -axis. The three types of substitution, two types of deletion and two types of insertion mutations were sorted gene-wise and tissue-wise Supplementary Table S5.
Genes in which at least one type of mutation had a value more than nine in at least one tissue were short-listed Table 3 ; these were genes in which multiple unique mutations more than nine of at least one type were observed in at least one tissue. Greater the number of unique mutations detected in a gene, greater its significance for cancer 20 , and genes with more than nine unique mutations have a definite significance for cancer.
The table differs from Table 4 in ref. Distribution of substitution, deletion and insertion mutations in 29 TS and 24 PO. The second column gives the basis of the classification of each gene; ts and po refer to the classification of the gene by Swiss-prot 40 , F refers to the classification given in Table 4 in ref. The total numbers of mutations [, ] and missense mutations [, ], observed in the sets of TS and PO, are given.
I-F deletions and I-F insertions are also observed in TS, but in lesser numbers, with the former being more frequent than the latter. Nonsense substitutions are observed far more frequently in TS than PO. This is consistent with the requirement that TS, which inhibit cell proliferation, have to be inactivated for unrestrained cell division and cancer to occur.
In PO, on the other hand, I-F indels are preferred. As these mutations modify, rather than disrupt, protein function, they are well-suited to activate PO cellular genes that promote cell proliferation to oncogenes which promote excessive cell division and cancer.
Mutations in TS cause loss of suppression activity by destabilizing protein structure; mutations in PO also destabilize protein structure, but gain of function results because either the less active form of the protein or the transition to it is destabilized, which increases the population of the active, disease causing state The most frequently occurring mutations in PO are missense mutations, which are also well-suited to modifying function.
The 24 PO and 29 TS, in the table, undergo and missense mutations, respectively; the average number of missense mutations observed per gene is higher for PO [89] than TS [74]. The total number of mutations undergone by TS genes [] is much larger than that undergone by PO []. TS genes undergo large numbers of FS indels, missense and nonsense substitutions, as well as smaller numbers of I-F indels; PO, on the other hand, mainly undergo missense substitutions, and also smaller, but significant, numbers of I-F indels.
Thus, TS genes undergo larger numbers and a greater variety of mutations than PO. One reason for this might be the requirement that both alleles that code for a TS gene be inactivated for tumor formation to occur; to inactivate two alleles, more mutations are recruited. Further, inactivating a protein by mutation is probably easier and less constraining than modifying its activity; therefore, a variety of mutations are employed for the purpose.
On the other hand, for a PO, activation of a single allele is sufficient to turn it into an oncogene. Moreover, activation of a protein requires precise and specific mutations. Hence, the number of ways in which a PO can be mutated into an oncogene is limited. As the types of mutations that target PO e.
KIT differ from those that target TS genes e. An attempt was made to examine if mutation positions in each protein sites of one or more mutations preferred to occur in certain regions of it or if they were randomly distributed over its entire length [ Supplementary Methods ii ].
Figure 8 shows the distribution of mutation positions in each of 40 proteins PO and TS. Thus, mutations in PO tend to occur in selected regions, rather than throughout the length of the protein. The four TS that occur to the left, among the PO, are exceptions discussed below.
Distribution of mutation positions over the lengths of proteins. Genes [40] are listed along the x -axis and each gene name is prefixed by po, ts or b, which indicate, respectively, whether the gene functions as a PO, a TS or as both. For each gene, there is a pair of bars which are related to each other. A tall second bar and a short first bar indicate that the majority of mutations occur in a small segment of the protein; first and second bars of nearly equal length indicate that the mutations occur over the entire length of the protein.
Supplementary Figure S7 a through g shows the distribution of mutation positions for each mutation type. Each type of mutation occurs in specific regions of, rather than throughout the gene. It is possible that the genes have an intrinsic tendency to undergo mutations in these regions; i. Thus, different genes undergo different patterns of mutations, with TS preferring to mutate over the entire length, and PO preferring to mutate in specific regions. Mutations in selected regions of the gene are well-suited to activate PO, and those occurring over the entire length are suitable for inactivating the two alleles of a TS gene.
Cancer of each tissue was considered and genes showing mutations in the cancer were arranged by rank score; likewise, each gene was considered and cancers in which mutations in the gene were observed were ranked Supplementary Table S1a and b. Supplementary Table S1a and b are useful because they list out, in one place, the majority of genes that play a role in cancer of each tissue, and the different cancers in which a gene plays a role.
Supplementary Table 1a shows that cancer is a multiple gene disease: multiple genes undergo mutations, resulting in mal-functioning proteins, which cause cancer.
In most cancers, PO and TS play a role. Considering only marked genes, the largest number play a role in cancers of haematopoietic-and-lymphoid tissue, the reason being the variety of cancers associated with the different cell types of this tissue leukaemias, lymphomas ; different genes play a role in the different cancers. Further, more PO than TS play a role in cancers of this tissue. Genes that have been recognized as playing a role in specific cancers are present in Supplementary Table S1b.
For example, the TS, APC, MEN1, NF1, NF2, RB1, VHL and WT1 have been shown to play roles in colorectal carcinomas, multiple endocrine neoplasia type I, neurofibromatosis types I and II, retinoblastoma, renal cell carcinoma and paediatric kidney cancer 6 , respectively; in the table, appropriately, they appear associated with cancers of the large intestine, pancreas, soft tissue, soft tissue and meninges, eye, kidney and kidney, respectively.
Similarly, the PO, ABL1, EGFR, KIT and RET, are known to play roles in chronic myelogenous leukaemia, squamous cell carcinoma, sarcoma and thyroid cancer, respectively; in the table, appropriately, they appear associated with cancers of haematopoietic-and-lymphoid tissue, lung, soft tissue and thyroid.
In Supplementary Table S1b , genes with a large number of mutated samples third number , a high proportion of mutated samples second number and with high ranks first number may, with confidence, be considered to be playing an important role in the corresponding cancer.
The table also corroborates the well-recognized fact that TP53 plays an important role in a wide range of cancers 6. Some genes appear to be predominantly associated with cancer of a single tissue.
Genes which, in a tissue, undergo few less than ten unique mutations but which undergo a particular mutation repeatedly, are marked in the tables. Mutations in the metabolic enzyme, IDH1, have been linked to glioma and other cancers 46 , The mutated IDH1 samples contain only five unique missense mutations; a single mutation, RH, frequent in human glioma, is observed times.
Most cancer genes play a role in more than one cancer and, in most cancers, more than one gene plays a role. Thus, the scenario is far from the one in which different genes play roles in different cancers. The puzzle also remains as to why genes which function in all tissues, cause cancer only in certain tissues. Funding for open access charge: Waived by the Oxford University Press. The author is grateful to Prof. Joshi for help with statistical analysis and to Prof.
Balaram for helpful discussions during the course of this work. National Center for Biotechnology Information , U. Journal List Nucleic Acids Res v. Nucleic Acids Res. Published online Apr 9. Author information Article notes Copyright and License information Disclaimer. Published by Oxford University Press. This article has been cited by other articles in PMC. Abstract Cancer-associated mutations in cancer genes constitute a diverse set of mutations associated with the disease. Open in a separate window.
Figure 1. Analyses of substitution, deletion and insertion mutations A single mutation may be observed many times.
0コメント