Madhavi Bhatia, NIPER Guwahati
Mutations are the changes that occur within the nucleotide sequence of the genetic material present in an organism. The mutation may occur because of various cellular processes, like DNA replication and repair, meiotic recombination and aberrant repair of breaks in sequence-specific contexts. Mutational processes are commonly observed by examining variation present between 2 individuals in a population. Mutation hotspots are highly captivated on the DNA sequences and structure. Mutation within the human genome ends up in three classes of genomic variation -single nucleotide variants (SNVs), short insertions or deletions, and large structural variants (SVs).
DNA sequences susceptible to mutation:
Spontaneous deamination of methylated cytosines and GC-biased gene conversion are samples of mutational mechanisms which occur at recombination hotspots and are majorly driven by base composition heterogeneity. During this process, GC-rich alleles are favoured over AT-rich alleles by meiotic recombination. CpG islands are hotspots for mutation, these are commonly located within and upstream of genes and regulate gene expression via their methylation status.
Microsatellites are repetitive sequences that are susceptible to polymerase slippage and indel formation can give rise to the inherited trinucleotide repeat expansions and contractions seen in Huntington’s disease, Fragile X syndrome. Meiotic recombination occurs at specific GC-rich loci, which contains binding motifs for PR domain zinc finger protein 9 (PRDM9). PRDM9 motifs act as both recombination and mutation hotspots. Nonallelic homologous recombination ends up in structural variant hotspots. This occurs by ectopic recombination at or near repetitive sequences within the human genome during meiosis. Centromeric DNA largely comprises satellite repeat DNAs and transposable elements and acts as a hotspot for rearrangements within the human genome.
Centromeric rearrangements can act as a precursor to aneuploidy in cancer. The large scale of centromeric mutations may result in many gene dosage alterations which are typically seen in the case of cancers. Subtelomeric regions are gene-rich sites for frequent meiotic recombination. Subtelomeric sequences are highly polymorphic in copy number and rearrangement of the same results in intellectual disability, autism, and birth defects. The rate of point mutations along the chromosomes is correlated tightly with the replication timing of the DNA. Late-replicating regions have a 2 and 6-fold increase in transition and transversion SNV mutations. In cancer cells, the late-replicating regions have a 2 to 3 times elevated point mutation rate and loss of DNA methylation. Common fragile sites (CFS) present in DNA can cause SVs in nearby loci and within topologically associated domains.
DNA structures that may cause variation:
Palindromic sequences contain AT-rich repeats form opposing hairpins in DNA, creating a four-way holliday junction that resembles a cruciform. Upon cleavage, the resolution of the cruciform structures may result in translocations, some of which are recurrent. PATRR mediated translocation results in a supernumerary chromosome that contains genetic material from chromosomes 11 and 12, which can lead to Emanuel syndrome (characterized by developmental delay and hypotonia in infants).
Another translocation between PATRRs on chromosomes 17 and 22 disrupts the NF1 gene, results in neurofibromatosis type 1 indicated by patches of darkened skin and benign tumors. G quadruplexes are long stretches of G-nucleotide-rich sequences that can self-stack and also act as common sites for replication stress and fork stalling. These serve as a site where transcription and replication fork may collide. R-loops are the structures where RNA remains hybridized with the transcribed template of the DNA strand. R-loops provide a link between late-replicating large transcription units and SV formation because of CFSs. Along with mutations that occur in DNA sequences and DNA structures there are other focal mutation hotspots which include chromothripsis, kataegis, BIR-mediated SVs.
As technology advances, more large-scale sequencing studies are found to be ongoing. This can give further insights on hotspots of genetic variation, their frequency across the human population and diverse tissues, and how these processes contribute to disease.
Also read: Novel Strategies for Clostridioides Difficile Infection Treatment
Reference:
- Nesta, A. V., Tafur, D., & Beck, C. R. (2021). Hotspots of Human Mutation. Trends in genetics : TIG, 37(8), 717–729. https://doi.org/10.1016/j.tig.2020.10.003
Author info:
Madhavi Bhatia is currently pursuing Master of science in Pharmaceutical Biotechnology from NIPER,Guwahati. Her area of interest lies in understanding the role of gene mutation in development of various diseases and to develop treatment for such diseases.
Publications:
Sputnik V- single dose usage against COVID-19
Kanikah Mehndiratta, MSc, University of Glasgow Amongst so many vaccine options recently developed in different parts of the world, Sputnik V has proven to be a great candidate due to a lot of factors. Firstly, is its high efficacy of about 92% against the coronavirus disease caused by the SARS-CoV2 viral strains. Also known as […]