Single Nucleotide Variants (SNVs) in Genetics

Single Nucleotide Variants (SNVs)

• Also known as "point mutations" or "substitutions"
• If they occur in the germline and are variable within individuals in a population, they are often termed "single nucleotide polymorphisms" (SNPs)

Types of SNVs

• Two types are transitions (involving only purines or only pyrimidines respectively)
• Four types are transversions (involving purines converting to pyrimidines or vice versa)

Repair Pathways

• Three cellular DNA repair pathways: nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR)
• NER primarily repairs helix-distorting damage
• BER mainly repairs small, non-helix-distorting lesions
• MMR repairs base-base mismatches

Causes of SNVs

• Exogenous mutational processes: involve exposure to exogenous agents (e.g. cigarette smoke, ultraviolet (UV) light)
• Endogenous mutational processes: derive from mutational activities within the cell (e.g. spontaneous deamination of 5-methylcyosine, causing C>T at CG dinucleotides)

Effects of SNVs

• Most SNVs have no effect on the cell
• A small subset cause disease (e.g. 1799 T>A mutation in the BRAF gene, causing BRAF V600E, present in 60% of human malignant melanomas)
• Mutations in DNA repair factors can cause disease by causing excessive accumulation of mutations (e.g. xeroderma pigmentosum)

Structural Variants

• Large-scale genomic rearrangements that lead to juxtaposition of previously unconnected DNA
• Frequently involve double-stranded DNA breakage, which is repaired by homologous recombination (HR) or non-homologous end joining (NHEJ)

Types of Structural Variants

• Inter-chromosomal: involves two chromosomes
• Intra-chromosomal: involves different parts of the same chromosome

Balanced vs Unbalanced Structural Variants

• Balanced: do not lead to an overall gain or loss of DNA from the cell
• Unbalanced: introduce additional DNA or cause DNA to be lost from the cell, resulting in copy number variants

Visualizing Structural Variants

• Chromosome painting: sorting chromosomes into separate tubes, fluorescently labelling them, and hybridizing them onto a chromosomal karyotype

Examples of Structural Variants

• Philadelphia chromosome: a translocation between human chromosomes 9 and 22, frequently observed in chronic myeloid leukaemia, and an example of a reciprocal translocation (a type of balanced structural variant)
• 22q11.2 deletion syndrome: an example of an unbalanced structural variant, associated with developmental disorders

Clinical Significance

• Unbalanced structural variants and copy number variants are frequently found in cancer
• They can also be found in the germline, where they are frequently associated with developmental disorders

Structural Variants

• Large-scale genomic rearrangements that lead to juxtaposition of previously unconnected DNA
• Frequently involve double-stranded DNA breakage, which is repaired by homologous recombination (HR) or non-homologous end joining (NHEJ)

Types of Structural Variants

• Inter-chromosomal: involves two chromosomes
• Intra-chromosomal: involves different parts of the same chromosome

Balanced vs Unbalanced Structural Variants

• Balanced: do not lead to an overall gain or loss of DNA from the cell
• Unbalanced: introduce additional DNA or cause DNA to be lost from the cell, resulting in copy number variants

Visualizing Structural Variants

• Chromosome painting: sorting chromosomes into separate tubes, fluorescently labelling them, and hybridizing them onto a chromosomal karyotype

Examples of Structural Variants

• Philadelphia chromosome: a translocation between human chromosomes 9 and 22, frequently observed in chronic myeloid leukaemia, and an example of a reciprocal translocation (a type of balanced structural variant)
• 22q11.2 deletion syndrome: an example of an unbalanced structural variant, associated with developmental disorders

Clinical Significance

• Unbalanced structural variants and copy number variants are frequently found in cancer
• They can also be found in the germline, where they are frequently associated with developmental disorders

Cytogenetic Variation

• Involves the gain or loss of one or more entire chromosome(s), leading to aneuploidy
• Can be caused by segregation errors in the germline, resulting in conditions such as Down syndrome (trisomy 21)
• Whole genome duplication can occur, leading to tetraploid cells, as well as additional aneuploidy, frequently in cancer cells
• This can occur via a process of endoreduplication in cancer cells

Cellular Checkpoints

• The spindle assembly checkpoint is a mechanism that prevents aneuploidy
• This checkpoint prevents progression through mitosis if chromosomes are not correctly attached to the spindle apparatus
• If aneuploidy is observed, it indicates that these checkpoints have failed

Germline and Somatic Cells

• The body consists of two distinct cell types: germline cells and somatic cells.
• Germline cells are gametes (sperm and egg cells) or their precursors.
• Germline cells can pass their genetic variation to the next generation.

Germline Variation

• Germline variation occurs in germline cells and is inherited.
• It is important for understanding inherited genetic disease.

Somatic Cells

• Somatic cells are the cells of the body that cannot contribute to the next generation.
• All cells except for germ cells are somatic cells.

Somatic Variation

• Somatic variation is "private" to the individual body and cannot contribute to the next generation.
• It is important in cancer and possibly in ageing.