The term mutation or variant is used to designate the process of generating genetic variations as well as the effect of these alterations. A mutation can be defined as any change in the primary nucleotide sequence of DNA regardless of its functional consequences, although it often has a negative connotation. There has been a shift towards using the more neutral term variant to describe sequence changes, and it is now recommended by several professional organizations and guidelines instead of mutation. Some variants may be lethal, others are less deleterious, and some may confer an evolutionary advantage. Variations can occur in the germline (sperm or oocytes); these can be transmitted to progeny. Alternatively, variants can occur during embryogenesis or in somatic tissues. Variations that occur during development lead to mosaicism, a situation in which tis sues are composed of cells with different genetic constitutions. If the germline is mosaic, a mutation can be transmitted to some progeny but not others, which sometimes leads to confusion in assessing the pat tern of inheritance. Somatic mutations that do not affect cell survival can sometimes be detected because of variable phenotypic effects in tissues (e.g., pigmented lesions in McCune-Albright syndrome). Other somatic mutations are associated with neoplasia because they confer a growth advantage to cells. Epigenetic events may also influence gene expression or facilitate genetic damage. With the exception of triplet nucleotide repeats, which can expand (see below), variations are usually stable.

Sequence variants are structurally diverse—they can involve the entire genome, as in triploidy (one extra set of chromosomes), or gross numerical or structural alterations in chromosomes or individual genes. Large deletions may affect a portion of a gene or an entire gene, or, if several genes are involved, they may lead to a contiguous gene syndrome. Unequal crossing-over between homologous genes can result in fusion gene mutations, as illustrated by color blindness. Variations involving single nucleotides are referred to as point mutations.

Substitutions are called transitions if a purine is replaced by another purine base (A ↔ G) or if a pyrimidine is replaced by another pyrimidine (C ↔ T). Changes from a purine to a pyrimidine, or vice versa, are referred to as transversions. If the DNA sequence change occurs in a coding region and alters an amino acid, it is called a missense mutation. Depending on the functional consequences of such a missense mutation, amino acid substitutions in different regions of the protein can lead to distinct phenotypes.

Variants can occur in all domains of a gene (Fig. 1). A point mutation occurring within the coding region leads to an amino acid substitution if the codon is altered (Fig. 2). Point mutations that introduce a premature stop codon result in a truncated or missing protein. Large deletions may affect a portion of a gene or an entire gene, whereas small deletions and insertions alter the reading frame if they do not represent a multiple of three bases. These “frameshift” mutations, also designated as amphigoric amino acid changes, lead to an entirely altered carboxy terminus. Mutations in intronic sequences or in exon junctions may destroy or create splice donor or splice acceptor sites. Variants may also be found in the regulatory sequences of genes, resulting in reduced or enhanced gene transcription.

Fig1. Point mutations causing a thalassemia as example of allelic heterogeneity. The b-globin gene is located in the globin gene cluster. Point mutations occur in the promoter, the CAP site, the 5′-untranslated region, the initiation codon, each of the three exons, the introns, or the polyadenylation signal. Many mutations introduce missense or nonsense mutations, whereas others cause defective RNA splicing. Not shown here are deletion mutations of the β-globin gene or larger deletions of the globin locus that can also result in thalassemia. , promoter mutations; *, CAP site;

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مواضيع ذات صلة

Regulation of Gene Expression

The Human Genome

The Polymerase Chain Reaction (PCR)

Additional Nonhistone Proteins Regulate Transcription and Replication

Nonhistone Proteins Organize Long Chromatin Loops

Modifications of Histone Tails Control Chromatin Condensation and Function

Chromatin Exists in Extended and Condensed Forms

Fetal DNA Sequencing and Fetal Genome Analysis

Globin Gene Clusters

Molecular Analysis of Nucleic Acid Sequences

Genes and Genome Complexity

Structure of Nucleic Acids