Genetic Variations and Nomenclature

Introduction to Genetic Variation

Genetic variation is the basis for differences in drug response among individuals and is central to the field of pharmacogenomics. Understanding the types of genetic variations and their nomenclature is essential for interpreting genetic test results and scientific literature.

• Genetic variation refers to differences in DNA sequences among individuals.

• These variations can affect protein function, drug metabolism, and therapeutic outcomes.

• Standardized nomenclature systems are used to describe and catalog these variations.

Human Genetics: Basic Concepts

DNA Structure and Function

Hereditary information in humans is encoded in DNA, which consists of four nucleotide bases: Adenine (A), Cytosine (C), Thymine (T), and Guanine (G). The sequence of these bases determines the function of DNA and the proteins it encodes.

• DNA is composed of chains of nucleotides (A, C, T, G).

• Proteins are specified by the sequence of DNA bases and perform most cellular functions.

• The genotype is the nucleotide sequence of the genome; the phenotype is the observable expression of the genotype.

Chromosomes and Genomes

The human nuclear genome consists of 22 pairs of homologous chromosomes (autosomes) and one pair of sex chromosomes (X or Y). Each cell also contains mitochondrial DNA, which is much smaller than the nuclear genome.

• Autosomes: Chromosomes numbered 1-22, homologous pairs inherited from each parent.

• Sex chromosomes: X or Y, determine biological sex.

• Mitochondrial genome: Small, circular DNA present in mitochondria.

Alleles, Variants, and Haplotypes

Variations in genes on homologous chromosomes are called alleles. At the molecular level, the term variant is often used, as there can be many sequence variations for a single gene.

• Allele: Specific DNA sequence variation at a gene locus, may affect phenotype.

• Variant: Any sequence variation, often used in molecular genetics.

• Haplotype: Combination of genes inherited together from one parent.

• Homozygous: Two identical alleles for a gene.

• Heterozygous: Two different alleles for a gene.

Types of Genetic Variations

Single Nucleotide Polymorphisms (SNPs) and Single Nucleotide Variants (SNVs)

The most common genetic variation is the SNP, a single base change in the DNA sequence. SNPs are defined as SNVs present in at least 1% of the population, but the terms are sometimes used interchangeably.

• SNP: Single Nucleotide Polymorphism, a single base change found in ≥1% of the population.

• SNV: Single Nucleotide Variant, any single base change regardless of frequency.

• Many SNPs are silent mutations (no phenotypic effect), but some cause defective proteins.

• Example: SNPs in drug metabolism genes can affect therapeutic outcomes.

Structural Variations (SV)

Structural variations include insertions/deletions (indels) and copy number variations (CNVs), which can significantly impact gene function and protein production.

• Indels: Small insertions or deletions in DNA sequence.

• If indel is not a multiple of three base pairs, it causes a frameshift mutation, altering the mRNA and protein.

• Frameshift can introduce a premature STOP codon, resulting in truncated proteins.

• Indels are second only to SNPs in frequency in the human genome.

• CNVs: Copy Number Variations, duplications or deletions of large DNA segments (1 kb to several Mb).

• CNVs can result in multiple gene copies, sometimes leading to increased enzyme production or non-functional genes.

• Example: CYP2D6 gene duplication can cause excessive drug metabolism.

Nomenclature Systems for Genetic Variants

Reference SNP (rs) Numbers

SNPs are cataloged using a unique reference number prefixed by "rs" (Reference SNP). This system is widely used in genetic databases and scientific literature.

• Example: rs28371732 is a SNP in the CYP2D6 gene on chromosome 22.

• Alternative notation: 3829G>A indicates a G to A change at position 3829 in the gene transcript.

Star (*) Nomenclature for Pharmacogenomics Genes

The star nomenclature system is used to classify alleles in pharmacogenomics, especially for cytochrome P450 (CYP) enzymes. The "wild type" allele is denoted as *1, and other variants are assigned distinct star numbers.

• Wild type (WT): Most common genotype/phenotype in a population, denoted as *1.

• Variant alleles: Assigned new star numbers (e.g., CYP2C9*2).

• Example: CYP2C9*2 produces a non-functional enzyme.

• Multiple gene copies: Denoted as "xN" (e.g., CYP2D6*1x4 means four copies of the *1 allele).

• Hundreds of star alleles may be cataloged for pharmacogenomics-related genes.

Illustrative Table: Star Nomenclature for CYP Genes

Additional info: The star nomenclature system is especially important in clinical pharmacogenomics for predicting drug metabolism phenotypes and guiding therapy.

Summary

• Genetic variations include SNPs/SNVs, indels, and CNVs, each with distinct effects on gene function.

• Standardized nomenclature systems (rs numbers, star nomenclature) are essential for cataloging and interpreting genetic variants.

• Understanding these concepts is foundational for applying genetics to clinical pharmacogenomics.