Types of mutation and their consequences
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P53-56
2025-11-26
15
In this section we consider the nature of different types of mutation and their effect on the genes involved. Each type of mutation discussed here is illustrated by one or more disease examples. Notably, the specificity of the pathogenic variant found in almost all cases of achondroplasia is the exception rather than the rule, and the variants that underlie a single genetic disease are typically heterogeneous among a group of affected individuals. Different cases of a particular disorder will therefore usually be caused by different underlying pathogenic variants in one gene (allelic heterogeneity), sometimes in different genes (locus heterogeneity). In Chapters 11 and 12 we will turn to the ways in which variants in specific disease- associated genes cause these disorders.
Nucleotide Substitutions
Missense Variants
A single nucleotide substitution (or point mutation or SNV) in a gene sequence, such as that in the example of achondroplasia, can alter the code in a triplet of bases and cause the nonsynonymous replacement of one amino acid by another in the gene product (see the genetic code in Table 1 and the example in Fig. 1). Such events are called missense mutations, creating missense variants because they alter the coding (or sense) strand of the gene to specify a different amino acid. Although not all missense variants lead to an observable change in the function of the protein, the resulting protein may fail to work properly, may be unstable and rapidly degraded, or may fail to localize in its proper intracellular position. In many disorders, such as β- thalassemia, most of the variants detected in different patients are missense variants.
Table1. The Genetic Code
Fig1. Examples of mutations in a portion of a hypothetical gene with five codons shown (delimited by the dotted lines). The first base pair of the second codon in the reference sequence (shaded in blue) is mutated by a base substitution, deletion, or insertion. The base substitution of a G for the T at this position leads to a codon change (shaded in green) and, assuming that the upper strand is the sense or coding strand, a predicted nonsynonymous change from a serine to an alanine in the encoded protein (see genetic code in Table 1); all other codons remain unchanged. Both the single base pair deletion and insertion lead to a frameshift mutation in which the translational reading frame is altered for all subsequent codons (shaded in green), until a termination codon is reached.
Nonsense Variants
Point mutation in a DNA sequence that causes the replacement of the normal codon for an amino acid by one of the three termination (or “stop”) codons creates a nonsense variant or premature termination codon (PTC; also called stop gain). Because translation of messenger RNA (mRNA) ceases when a termination codon is reached, a variant that converts a coding codon into a termination codon causes translation to stop prematurely. In general, mRNAs harboring a PTC are targeted for rapid degradation through a cellular process known as nonsense- mediated mRNA decay (NMD), and no translation is possible. Rarely, transcripts harboring a PTC escape NMD, most predict ably if the premature stop codon occurs in last 50 bp of the penultimate exon or anywhere in the final exon of a gene. In this circumstance, a nonsense mutation can often give rise to a truncated protein with altered function.
Rarely, an SNV can alter the normal termination codon (called a stop loss variant), permitting translation to continue until another termination codon in the mRNA is reached further downstream. Such a variant can lead to an abnormal protein product with additional amino acids at its carboxy- terminus. Alternatively, access of a translating ribosome into the 3′ untranslated region downstream of the normal stop codon can displace proteins that regulate mRNA stability and/ or translation.
Variants Affecting RNA Transcription, Processing, and Translation
The normal mechanism by which initial RNA transcripts are made and then converted into mature mRNAs (or final versions of noncoding RNAs) requires a series of modifications, including transcription factor binding, 5′ capping, polyadenylation, and splicing. All of these steps in RNA maturation depend on specific sequences within the RNA. In the case of splicing, two general classes of splicing variants have been described. For introns to be excised from unprocessed RNA and the exons spliced together to form a mature RNA requires particular nucleotide sequences located at or near the exon- intron (5′ donor site) or the intron- exon (3′ acceptor site) junctions. Variants that substitute the required bases at either the splice donor or acceptor site prevent normal RNA splicing. Substitution of less conserved adjacent bases has a variable impact on splicing efficiency. A second class of splicing variants involves base substitutions that do not affect the donor or acceptor site sequences themselves, but instead create alternative donor or acceptor sites that compete with the normal sites during RNA processing. Activation of these so- called cryptic splice sites can lead to inappropriate exclusion or inclusion of exonic or intronic sequences, respectively, in the mature mRNA. Thus at least a proportion of the mature mRNA or noncoding RNA in such cases may contain improperly spliced intron sequences.
For protein- coding genes, even if the mRNA is made, SNVs in the 5′ and 3′ untranslated regions can contribute to disease by changing mRNA stability or translational efficiency, thereby reducing the amount of protein product.
Deletions, Insertions, and Rearrangements
Mutation can also involve the insertion, deletion, or rearrangement of DNA sequences. Some deletions and insertions involve only a few nucleotides and are generally most easily detected by direct sequencing of that part of the genome. In other cases, a substantial segment of a gene or an entire gene is deleted, duplicated, inverted, or translocated to create a novel arrangement of gene sequences— collectively called structural variants. Depending on the exact nature of the deletion, insertion, or rearrangement, a variety of different lab oratory approaches can be used to detect the genomic alteration.
Some deletions and insertions affect only a small number of base pairs. When such a variant occurs in a coding sequence and the number of bases involved is not a multiple of three (i.e., not an integral number of codons), the reading frame will be altered beginning at the point of the insertion or deletion. The results are called frameshift variants (see Fig. 1). From the point of the insertion or deletion, a different sequence of codons is thereby generated that encodes incorrect amino acids followed by a termination codon in the shifted frame. This typically leads to degradation of the altered transcript via activation of NMD or, more rarely, an altered and truncated protein product. In contrast, if the number of base pairs inserted or deleted is a multiple of three, then no frameshift occurs, and there will be a simple insertion or deletion of the corresponding amino acids in the otherwise normally translated gene product. Larger insertions or deletions can affect multiple exons of a gene and cause major disruptions of the coding sequence.
One type of insertion mutation involves insertion of a mobile element, such as those belonging to the LINE family of repetitive DNA (LINE- 1 [L1] elements). Any of the 146 putatively active L1 elements currently recognized in the human genome are capable of movement by retrotransposition (introduced earlier). Such movement not only generates genetic diversity in our species but can cause disease by insertional mutagenesis. For example, in some patients with the severe bleeding disorder hemophilia A (Case 21), LINE sequences several kilobases long are found within an exon in the factor VIII gene, interrupting the coding sequence and inactivating the gene. LINE insertions throughout the genome are also common in colon cancer, reflecting retrotransposition in somatic cells.
As we discussed earlier in this chapter, duplications, deletions, and inversions of a larger segment of a single chromosome are predominantly the result of homologous recombination between DNA segments with high sequence homology (Fig. 2). Disorders arising as a result of such exchanges can be due to a change in the dosage of otherwise wild- type gene products when the homologous segments lie outside the genes themselves. Alternatively, such events can lead to a change in the nature of the encoded protein itself when recombination occurs between different genes within a gene family or between genes on different chromosomes. Abnormal pairing and recombination between two similar sequences in opposite orientation on a single strand of DNA leads to inversion. For example, nearly half of all cases of hemophilia A are due to recombination that inverts a number of exons, thereby disrupting gene structure and rendering the gene incapable of encoding a normal gene product (see Fig. 2).
Fig2. Inverted homologous sequences, labeled A and B, located 500 kb apart on the X chromosome, one upstream of the factor VIII gene, the other in an intron between exons 22 and 23 of the gene. Intrachromosomal mispairing and recombination results in inversion of exons 1 through 22 of the gene, thereby disrupting the gene and causing severe hemophilia.
Repeat Expansion Variants
The pathogenic variant in some disorders involves amplification of a simple nucleotide repeat sequence. For example, simple repeats such as (CCG)n , (CAG)n , or (CCTG)n — located in the coding portion of an exon, in an untranslated region of an exon, or even in an intron— may expand during gametogenesis in repeat expansion or dynamic mutation, and interfere with normal gene expression or protein function. An expanded repeat in a coding region will generate an abnormal protein product; in the untranslated regions or introns of a gene, it may interfere with transcription, mRNA processing, or translation. How repeat expansions occur is not completely understood; they are conceptually similar to microsatellites but expand at a much higher rate.
The involvement of simple nucleotide repeat expansions in disease is discussed further in Chapter 7. In such disorders, marked parent- of- origin effects are well known and appear characteristic of the specific disease and/ or the particular simple nucleotide repeat involved. Such differences may be due to fundamental biologic differences between oogenesis and spermatogenesis but may also result from selection against gametes carrying certain repeat expansions.
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