You may be surprised to know that mutations keep happening in the trillions of cells in our body, all the time. Contrary to what Superhero movies would have us believe though (looking at you - Marvel Universe), most of the mutations are insignificant to deal any damage or lead to disease occurrence, this is because our cells have extraordinary repair mechanisms to prevent the mutations from causing any harm to us, the body's role is to keep us and our organs healthy, right? Another reason is that most mutations occur in the somatic cells (cells present in the body, like muscle or skin cells). Mutations that occur in germline cells (egg and sperm), will be present in all the cells that develop from it (so, the entire organism).
Let's have a look at some of the mutations:
Point Mutations: These are the most common type, involving the substitution of a single nucleotide base for another. These substitutions can occur through various mechanisms, such as base pair mismatches during DNA replication or exposure to mutagenic agents like radiation or chemicals. Point mutations can be classified into three main categories: a. Silent Mutations: Silent mutations occur when a nucleotide substitution does not result in any change to the amino acid sequence of the encoded protein. This often happens due to the redundancy of the genetic code, where multiple codons code for the same amino acid. As a result, silent mutations typically have no visible effect on the phenotype. b. Missense Mutations: Missense mutations occur when a nucleotide substitution leads to the replacement of one amino acid with another in the encoded protein. Depending on the nature of the amino acid change, missense mutations can have varying effects on protein structure, function, and stability. Some missense mutations may result in mild alterations with minimal impact on phenotype, while others can disrupt protein function. c. Nonsense Mutations: Nonsense mutations occur when a nucleotide substitution introduces a premature stop codon (UAA, UAG, or UGA) in the mRNA sequence, truncating the protein prematurely. As a result, translation is terminated before it is completed, leading to the production of a truncated, non-functional protein or triggering the degradation of the mRNA through nonsense-mediated decay. Nonsense mutations often lead to loss-of-function phenotypes and are associated with various genetic disorders.
Insertions and deletions (Indels) involve the addition or removal of one or more nucleotide bases from the DNA sequence. These mutations can occur spontaneously during DNA replication or as a result of errors in DNA repair mechanisms. Indels can have significant consequences on gene function, leading to frameshift mutations and alterations in the reading frame of the mRNA transcript.
Frameshift Insertions and Deletions: Frameshift mutations occur when the addition or deletion of nucleotides disrupts the reading frame of the mRNA transcript, altering the amino acid sequence of the encoded protein. This often results in the production of a non-functional or truncated protein with altered structure and function. Frameshift mutations can have severe phenotypic consequences and are associated with numerous genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy.
Repeat Expansions: Involve the expansion of repetitive DNA sequences within the genome, leading to the amplification of specific nucleotide motifs. These repetitive sequences, also known as microsatellites or minisatellites, are prone to expansion due to DNA replication errors or aberrant DNA repair mechanisms. Repeat expansions can occur in both coding and non-coding regions of the genome and are associated with a diverse range of genetic disorders, including Huntington's disease, fragile X syndrome, and myotonic dystrophy.
Inversions and Translocations: Involve the rearrangement of chromosomal segments within the genome. a. Inversions: Occur when a segment of DNA is flipped in orientation relative to the rest of the chromosome, they can occur through various mechanisms, such as chromosomal breakage and rejoining. Depending on the location and size of the inversion, it can have variable effects on gene expression and phenotype. Inversions are often benign but can occasionally lead to genetic disorders or reproductive abnormalities. b. Translocations: Involve the transfer of chromosomal segments between different chromosomes, leading to the fusion of unrelated genetic material. Translocations can be classified into two main types: i. Reciprocal translocations: Two non-homologous chromosomes exchange segments. ii. Robertsonian translocations: Two acrocentric chromosomes fuse at their centromeres. Translocations can disrupt gene function, alter gene expression patterns, and contribute to the development of cancer and genetic disorders.
Splice site mutations: Occur at the junctions between introns and exons in pre-mRNA transcripts. These mutations disrupt the precise splicing process, which removes intronic sequences and joins exons together to generate mature mRNA transcripts. Splice site mutations can occur at the 5' (donor) or 3' (acceptor) ends of introns, affecting the recognition and binding of spliceosomal complexes and leading to aberrant splicing patterns. The consequences of splice site mutations can vary widely, ranging from exon skipping and intron retention to the activation of cryptic splice sites and the production of aberrant mRNA isoforms. These splicing errors can disrupt protein-coding sequences, alter protein structure and function, and contribute to the pathogenesis of genetic disorders. Splice site mutations are associated with a broad spectrum of diseases, including inherited disorders like cystic fibrosis, β-thalassemia, and spinal muscular atrophy, as well as various cancers.
-Written by Sohni Tagore
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