Will an insertion or deletion of three nucleotides result in a frameshift mutation explain why or why not?

The DNA sequence of a gene can be altered in a number of ways. Gene variants (also known as mutations) can have varying effects ­­on health, depending on where they occur and whether they alter the function of essential proteins. Variant types include the following:

Substitution

This type of variant replaces one DNA building block (nucleotide) with another. Substitution variants can be further classified by the effect they have on the production of protein from the altered gene.

• 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. The amino acid change may alter the function of the protein.

• Nonsense: A nonsense variant
  
    is another type of substitution. Instead of causing a change in one amino acid, however, the altered DNA sequence results in a stop signal that prematurely signals the cell to stop building a protein. This type of variant results in a shortened protein that may function improperly, be nonfunctional, or get broken down.

Insertion

An insertion

Deletion

A deletion

Deletion-Insertion

This variant occurs when a deletion and insertion happen at the same time in the same location in the gene. In a deletion-insertion variant, at least one nucleotide is removed and at least one nucleotide is inserted. However, the change must be complex enough to differ from a simple substitution. The resulting protein may not function properly. A deletion-insertion (delins) variant may also be known as an insertion-deletion (indel) variant.

Duplication

A duplication

Inversion

An inversion changes more than one nucleotide in a gene by replacing the original sequence with the same sequence in reverse order.

Frameshift

A reading frame consists of groups of three nucleotides that each code for one amino acid

Repeat expansion

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

1. Acharya S, Wilson T, Gradia S, Kane M F, Guerrette S, Marsischky G T, Kolodner R, Fishel R. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci USA. 1996;93:13629–13634. [PMC free article] [PubMed] [Google Scholar]

2. Alani E. The Saccharomyces cerevisiae Msh2 and Msh6 proteins form a complex that specifically binds to duplex oligonucleotides containing mismatched DNA base pairs. Mol Cell Biol. 1996;17:2436–2447. [PMC free article] [PubMed] [Google Scholar]

3. Bertrand P, Tishkoff D X, Filosi N, Dasgupta R, Kolodner R D. Physical interaction between components of DNA mismatch repair and nucleotide excision repair. Proc Natl Acad Sci USA. 1998;95:14278–14283. [PMC free article] [PubMed] [Google Scholar]

4. Chen W, Jinks-Robertson S. Mismatch repair proteins regulate heteroduplex formation during mitotic recombination in yeast. Mol Cell Biol. 1998;18:6525–6537. [PMC free article] [PubMed] [Google Scholar]

5. Crouse G F. Mismatch repair systems in Saccharomyces cerevisiae. In: Nickoloff J A, Hoekstra M F, editors. DNA damage and repair. 1. DNA repair in prokaryotes and lower eukaryotes. Totowa, N.J: Humana Press; 1998. pp. 411–448. [Google Scholar]

6. Fishman-Lobell J, Haber J E. Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1. Science. 1992;258:480–484. [PubMed] [Google Scholar]

7. Flores-Rozas H, Kolodner R D. The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Proc Natl Acad Sci USA. 1998;95:12404–12409. [PMC free article] [PubMed] [Google Scholar]

8. Greene C N, Jinks-Robertson S. Frameshift intermediates in homopolymer runs are removed efficiently by yeast mismatch repair proteins. Mol Cell Biol. 1997;17:2844–2850. [PMC free article] [PubMed] [Google Scholar]

9. Habraken Y, Sung P, Prakash L, Prakash S. Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. Curr Biol. 1996;6:1185–1187. [PubMed] [Google Scholar]

10. Harfe, B. D., and S. Jinks-Robertson. Unpublished data.

11. Hollingsworth N M, Ponte L, Halsey C. MSH5, a novel MutS homolog, facilitates meiotic reciprocal recombination between homologs in Saccharomyces cerevisiae but not mismatch repair. Genes Dev. 1995;9:1728–1739. [PubMed] [Google Scholar]

12. Iaccarino I, Palombo F, Drummond J, Totty N F, Hsuan J J, Modrich P, Jiricny J. MSH6, a Saccharomyces cerevisiae protein that binds to mismatches as a heterodimer with MSH2. Curr Biol. 1996;6:484–486. [PubMed] [Google Scholar]

13. Jinks-Robertson S, Greene C, Chen W. Genetic instabilities in yeast. In: Wells R D, Warren S T, editors. Genetic instabilities and hereditary neurological diseases. San Diego, Calif: Academic Press; 1998. pp. 485–507. [Google Scholar]

14. Johnson R E, Kivvali G K, Guzder S N, Amin N S, Holm C, Habraken Y, Sung P, Prakash L, Prakash S. Evidence for involvement of yeast proliferating cell nuclear antigen in DNA mismatch repair. J Biol Chem. 1996;271:27987–27990. [PubMed] [Google Scholar]

15. Johnson R E, Kovvali G K, Prakash L, Prakash S. Requirement of the yeast MSH3 and MSH6 genes for MSH2-dependent genomic stability. J Biol Chem. 1996;271:7285–7288. [PubMed] [Google Scholar]

16. Kirkpatrick D T, Petes T D. Repair of DNA loops involves DNA-mismatch and nucleotide-excision repair proteins. Nature. 1997;387:929–931. [PubMed] [Google Scholar]

17. Kolodner R. Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev. 1996;10:1433–1442. [PubMed] [Google Scholar]

18. Kroutil L C, Register K, Bebenek K, Kunkel T A. Exonucleolytic proofreading during replication of repetitive DNA. Biochemistry. 1996;35:1046–1053. [PubMed] [Google Scholar]

19. Kunkel T A, Soni A. Mutagenesis by transient misalignment. J Biol Chem. 1988;263:14784–14789. [PubMed] [Google Scholar]

20. Lea D E, Coulson C A. The distribution of the numbers of mutants in bacterial populations. J Genet. 1949;49:264–285. [PubMed] [Google Scholar]

21. Macpherson P, Humbert O, Karran P. Frameshift mismatch recognition by the human MutSα complex. Mutat Res. 1998;408:55–66. [PubMed] [Google Scholar]

22. Marsischky G T, Filosi N, Kane M F, Kolodner R. Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes Dev. 1996;10:407–420. [PubMed] [Google Scholar]

23. Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination and cancer biology. Annu Rev Biochem. 1996;65:101–133. [PubMed] [Google Scholar]

24. Nicholson, A., M. Hendrix, S. Jinks-Robertson, and G. F. Crouse. Unpublished data.

25. Palomba F, Iaccarino I, Nakajima E, Ikejima M, Shimada T, Jiricny J. hMUTSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol. 1996;6:1181–1184. [PubMed] [Google Scholar]

26. Prolla T A, Christie D-M, Liskay R M. Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene. Mol Cell Biol. 1994;14:407–415. [PMC free article] [PubMed] [Google Scholar]

27. Prolla T A, Pang Q, Alani E, Kolodner R D, Liskay R M. MLH1, PMS1, and MSH2 interactions during the initiation of DNA mismatch repair in yeast. Science. 1994;265:1091–1093. [PubMed] [Google Scholar]

28. Reenan R A G, Kolodner R D. Characterization of insertion mutations in the Saccharomyces cerevisiae MSH1 and MSH2 genes: evidence for separate mitochrondrial and nuclear functions. Genetics. 1992;132:975–985. [PMC free article] [PubMed] [Google Scholar]

29. Ripley L S. Frameshift mutation: determinants of specificity. Annu Rev Genet. 1990;24:189–213. [PubMed] [Google Scholar]

30. Ripley L S, Clark A, deBoer J G. Spectrum of spontaneous frameshift mutations: sequences of bacteriophage T4 rII gene frameshifts. J Mol Biol. 1986;191:601–613. [PubMed] [Google Scholar]

31. Ross-Macdonald P, Roeder G S. Mutation of a meiosis-specific MutS homolog decreases crossing over but not mismatch correction. Cell. 1994;79:1069–1080. [PubMed] [Google Scholar]

32. Rothstein R. Targeting, disruption, replacement, and allele rescue: integrative DNA transformation in yeast. Methods Enzymol. 1991;194:281–301. [PubMed] [Google Scholar]

33. Schaaper R M, Dunn R L. Spontaneous mutation in the Escherichia coli lacI gene. Genetics. 1991;129:317–326. [PMC free article] [PubMed] [Google Scholar]

34. Sherman F. Getting started with yeast. Methods Enzymol. 1991;194:3–20. [PubMed] [Google Scholar]

35. Sia E A, Kokoska R J, Dominska M, Greenwell P, Petes T D. Microsatellite instability in yeast: dependence on repeat unit size and DNA mismatch repair genes. Mol Cell Biol. 1997;17:2851–2858. [PMC free article] [PubMed] [Google Scholar]

36. Singer B S, Westlye J. Deletion formation in bacteriophage T4. J Mol Biol. 1988;202:233–243. [PubMed] [Google Scholar]

37. Strand M, Earley M C, Crouse G F, Petes T D. Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 1995;92:10418–10421. [PMC free article] [PubMed] [Google Scholar]

38. Strand M, Prolla T A, Liskay R M, Petes T D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993;365:274–276. [PubMed] [Google Scholar]

39. Streisinger G, Okada Y, Emrich J, Newton J, Tsugita A, Terzaghi E, Inouye M. Frameshift mutations and the genetic code. Cold Spring Harbor Symp Quant Biol. 1966;31:77–84. [PubMed] [Google Scholar]

40. Tishkoff D X, Filosi N, Gaida G M, Kolodner R D. A novel mutation avoidance mechanism dependent on S. cerevisiae RAD27 is distinct from DNA mismatch repair. Cell. 1997;88:253–263. [PubMed] [Google Scholar]

41. Tran H T, Degtyareva N P, Koloteva N N, Sugino A, Masumoto H, Gordenin D A, Resnick M A. Replication slippage between distant short repeats in Saccharomyces cerevisiae depends on the direction of replication and the RAD50 and RAD52 genes. Mol Cell Biol. 1995;15:5607–5617. [PMC free article] [PubMed] [Google Scholar]

42. Tran H T, Gordenin D A, Resnick M A. The prevention of repeat-associated deletions in Saccharomyces cerevisiae by mismatch repair depends on size and origin of deletions. Genetics. 1996;143:1579–1587. [PMC free article] [PubMed] [Google Scholar]

43. Tran H T, Keen J D, Kricker M, Resnick M A, Gordenin D A. Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol Cell Biol. 1997;17:2859–2865. [PMC free article] [PubMed] [Google Scholar]

44. Umar A, Buermeyer A B, Simon J A, Thomas D C, Clark A B, Liskay R M, Kunkel T A. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell. 1996;87:65–73. [PubMed] [Google Scholar]

45. Umar A, Kunkel T A. DNA-replication fidelity, mismatch repair and genome instability in cancer cells. Eur J Biochem. 1996;238:297–307. [PubMed] [Google Scholar]

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Reversion of the lys2ΔA746 frameshift allele