Genetic Variation and Disease Overview

Study Notes

Genetic variation is widespread in DNA, impacting phenotypic expression.
A majority of DNA variation has no adverse consequences.
Small changes in non-coding regions are generally tolerated.
Some genes exist in multiple copies (e.g., rRNA genes), and mutations in one copy may have no effect.
Pathogenic variants can cause disease or increase susceptibility.
Pathogenic variants are not random; specific DNA sequences can be more vulnerable to point mutations leading to ‘hotspots’.
Repetitive DNA arrangements can also increase mutations.
Variants causing diseases act by altering the gene product's sequence, resulting in either loss or gain-of-function.
Mutations can also alter the amount of gene product, such as in duplication, amplification, or deletion.

The HGMD aims to collect all known gene lesions causing inherited diseases.
Originally focused on mutation mechanisms, it's now a comprehensive resource for inherited human gene lesions.
Provides vital diagnostic information for researchers, diagnosticians, physicians and genetic counsellors.
Offers information relating to specific inherited conditions in individuals and families.
Public and professional versions exist.
The database contained 23,800 mutations in 1,084 genes in 2000.
2019: 275,716 mutations in 10,902 genes.
2023: 410,743 mutations in 14,642 genes.
Data is categorized by mutation type (e.g., substitutions, insertions/deletions).
Data includes pathogenic and normal variants, aiding in pathogenicity evaluation.

Mutations can alter the amount of a gene product, leading to either reduced or increased levels.
These mutations can occur in regulatory sequences (e.g., enhancers or silencers) affecting transcription (raising or lowering production).
Changes in gene copy number (duplication, amplification, deletion) can also influence product amounts.
Gene deletions or duplications usually involve larger changes in gene products.
Amplifications are common in cancers.

Missense mutations: Alter a single amino acid in the protein. Sickle cell disease is an example of missense mutations, where a change in the sequence of a protein alters the function of red blood cells.
Nonsense mutations: Introduce a premature stop codon, leading to a truncated protein. Nonsense mutations can have severe consequences, as a full protein is often required for functionality.
Splicing mutations: Affect how exons are combined during mRNA processing. The SMN1 gene is an example demonstrating how splicing mutations affect different genes in various diseases. Frameshift mutations are also discussed with relation to the dystrophin gene.
Frameshift mutations: Alter the reading frame of the mRNA sequence. These mutations often lead to premature termination codons and non-functional proteins.
Variations in short tandem repeats (STRs): Changes in the number of repeating DNA sequences, occurring in non-coding regions. These mutations are sometimes pathogenic leading to diseases.
Polyalanine expansions: Increases in the number of alanine repeats in proteins - some examples are discussed.
Polyglutamine expansions: Increasing repetitions of glutamine repeats in proteins – Huntington disease is a particular example.
Dynamic mutations: Short tandem repeats causing instability and increasing repeat numbers. These mutations typically result in diseases with varying severity across generations.