20th February 2024

Basics of genetics and its abnormalities

Basics of genetics

DNA

The nucleus of the human cells contains 46 chromosomes, two pairs of autosomal chromosomes with two sex chromosomes, known as diploid. Human chromosomes consist of deoxyribonucleic acid (DNA) wound in a double helix. Ribonucleic acid (RNA) is a single-stranded molecule that mediates protein formation from DNA. Three main subtypes exist:

• Messenger RNA (mRNA) – Formed during transcription and forms the template for protein synthesis.
• Transfer RNA (tRNA) – Transport molecules that interact with the mRNA within the ribosome. An amino acid is attached to one end of the tRNA molecule. During translation, tRNA adds the amino acid to the polypeptide chain.
• Ribosomal RNA (rRNA) – Component of the ribosome organelle. Aids in the binding of mRNA to tRNA during translation.

There are several types of DNA. Single-copy DNA accounts for half of the human genome and accounts for the introns and exons. The remainder of the human genome consists of repetitive DNA. Repetitive DNA can be divided into:

• Dispersed repetitive DNA – Found as short, interspersed elements and long interspersed elements. They function as polymorphisms and are randomly distributed within the genome.
• Satellite DNA – Clustered repetitive segments of tandem repeats with varying lengths (tens to thousands of base pairs). Useful for genetic mapping due to variable sizes between individuals.

Mitochondrial DNA is a circular genome that encodes proteins in the mitochondrial respiratory chain and specific transfer RNAs. Mitochondrial DNAs are derived from the ovum as no mitochondria are transferred from the spermatozoa during fertilisation.

Cell cycle

Normal cell division occurs by mitosis, resulting in 2 genetically identical daughter cells.

Mitosis occurs in 4 distinct phases: prophase, metaphase, anaphase, and telophase.

Image Source: Wikimedia Commons (2022). Mitosis schematic diagram, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Mitosis_schematic_diagram-en.svg (Accessed: 4 January 2024).

Reproductive cells divide by meiosis, resulting in daughter cells containing one chromosome of each chromosome pair, known as the haploid daughter cells. Genetic diversity occurs through a process of “crossing-over”, where segments of homologous chromosomes are exchanged. Meiosis occurs in 2 distinct steps, meiosis I and II. Homologous chromosomes are divided during meiosis I, forming the haploid cells, while sister chromatids are separated during meiosis II.

Image Source: Wikimedia Commons (2016). Meiosis Stage, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Meiosis_Stages.svg (Accessed: 4 January 2024).

Further details can be obtained from the cell cycle section.

Genetic abnormalities

Chromosomal abnormalities or base-pair mutations can cause genetic mutations. Chromosomal abnormalities can be broadly divided into numerical abnormalities and structural abnormalities.

Numerical abnormalities are caused by the failure of chromosomal separation during meiosis and can manifest as:

• Error in ploidy – Failure of the division of the entire set of homologous chromosomes during anaphase I or failure of the division of all sister chromatids during anaphase II, resulting in a diploid gamete. Fertilisation with a normal gamete results in a triploid cell and is usually incompatible with life.
• Aneuploidy – Occurs due to a failure to separate a single chromosome pair during anaphase, resulting in monosomic or trisomic cells following fertilisation.

Structural abnormalities occur during prophase I as chromosomes undergo crossing over. This can manifest as:

• Reciprocal translocation – 2 non-homologous chromosomes swapped segments. This can result in trisomy or monosomy of the translocated segments.
• Robertsonian translocation – Translocation affects acrocentric chromosomes (chromosomes with centromeres close to the end of the chromosome), forming fusion chromosomes. Carriers of such translocations can be asymptomatic due to the balanced nature of the translocation. Increased risk of monosomy or trisomy for their offspring.
• Deletion – Segments of chromosomes are lost during crossing-over, which usually results in significant abnormalities.
• Insertion – Chromosome segments are added during crossing-over, usually resulting in less significant abnormalities.
• Inversion – Error in chromosomal rearrangement where a segment within the chromosome is reversed.

Base-pair mutations occur during DNA replication errors or by environmental factors, resulting in a change in the DNA sequence, and can result in single-gene disorders. This manifests in several ways:

• Base-pair substitution – Single substitution of a nucleotide with a different base-pair. This does not typically result in a phenotype change due to nonsense DNA and redundancies within the codons that encode amino acids. This can result in a missense mutation, resulting in the premature termination of a polypeptide sequence.
• Frame-shift mutation – Occurs following insertion or deletion of a nucleotide, resulting in alteration of the amino acid sequence downstream from the mutation.
• Trinucleotide expansion mutation – Characterised by amplification of a sequence of 3 nucleotides. Dynamic mutations can increase with gametogenesis, affecting the phenotypic presentation.

References

• Trent, R. J. (2012). Chapter 1 – Genes to Personalised Medicine. In R. J. Trent (Ed.), Molecular Medicine (Fourth Edition) (pp. 1–37). Boston/Waltham: Academic Press.
• Read, A., & Donnai, D. (2021). Chapter 2: How do genes work? In New Clinical Genetics: A guide to genomic medicine (4ᵗʰ ed.). United Kingdom: Scoin Publishing Limited.
• Strachan, T., & Read, A. P. (2019). Part 1: Basics of DNA, Chromosomes, Cells, Development, and Inheritance. In Human Molecular Genetics (5ᵗʰ ed.). United States: CRC Press.
• Jorde, L. B., Carey, J. C., & Bamshad, M. J. (2016). Chapter 1: Basic Cell Biology. In Medical Genetics (5ᵗʰ ed.). United States: Elsevier.
• Maitra, A., Kumar, V., Abbas, A. K., & Aster, J. C. (2013). Genetic and Paediatric Diseases. In Robbin’s Basic Pathology (9ᵗʰ ed.): Elsevier.
• Kelsell, D., Bryne, C., & Linton, K. (2012). Molecular cell biology and human genetics. In P. Kumar & M. Clark (Eds.), Kumar and Clark’s Clinical Medicine. Spain: Elsevier Saunders.