Genetic Variation: Protein Polymorphisms and Human Blood Groups

Genetic Variation: Protein Polymorphisms

Definition of Genetic Polymorphism

Genetic polymorphism refers to the occurrence of two or more alleles at a single genetic locus, where the least common allele has a frequency of at least 1% in the population. This concept is fundamental in genetics, as it explains the diversity observed within and between populations.

• Polymorphism: The presence of multiple forms (alleles) of a gene in a population.

• Allele Frequency: The proportion of a specific allele among all alleles at a genetic locus in a population.

• Example: ABO blood group system, HLA system.

Mutation, Variant, and Polymorphism

It is important to distinguish between mutations, variants, and polymorphisms:

• Mutation: Any change in the DNA sequence. Mutations that cause disease are often called mutations, while those that do not are called variants.

• Polymorphism: A DNA sequence variation that is common in a population (frequency ≥ 1%).

• If the frequency of an allele is less than 1%, it is generally considered a mutation or rare variant.

Genetic Polymorphism: Key Points

• Whether a variant is considered a polymorphism depends on its frequency in the population (equal to or greater than 1%).

• Most variants do not result in a phenotypic change.

• Polymorphic sequence variation can influence disease susceptibility and drug response.

• Rare alleles can become polymorphisms if their frequency increases in a population (e.g., sickle cell gene mutation in certain regions).

Polymorphisms in DNA and Protein

Polymorphisms can be studied at both the DNA and protein levels. Historically, protein polymorphisms were identified first, but modern genetics often focuses on DNA sequence variation.

• Examples of protein polymorphisms:

  • Apoprotein E (4 alleles)

  • Cytochrome P450 (many alleles)

  • Blood groups (e.g., ABO, HLA)

  • Many enzymes

• Polymorphisms in drug-metabolizing enzymes can affect individual responses to medications.

Common Pharmacogenetic Polymorphisms

Polymorphisms in genes encoding drug-metabolizing enzymes can lead to significant differences in drug response among individuals and populations.

Enzyme	Phenotype	Frequency in Populations	Examples of Drugs Affected
Cytochrome P450 (CYP2D6)	Poor/Ultra-rapid metabolizer	White: 6-8% poor, Ethiopian: 29% ultra-rapid	Codeine, nortriptyline, debrisoquine, metoprolol
CYP2C9	Reduced activity	White: 8-20%	Warfarin, phenytoin, tolbutamide
N-acetyl transferase	Poor metabolizer	Asian: 21%, White: 50%	Isoniazid, procainamide, hydralazine

Protein Variation

Protein variation is widespread in human populations:

• Any individual is estimated to be heterozygous for alleles coding for structurally different polypeptides at about 20% of all loci.

• Variation is even greater when comparing individuals of different ethnic groups.

Blood Groups and Cell Surface Antigens

Blood Groups: Definition and Classification

A blood group is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids.

• A complete blood type describes a full set of 30+ substances on the surface of RBCs.

• Some antigens are also present on other cell types.

Cell Surface Antigens

Cell surface antigens are molecules found on the exterior of cells, including RBCs. They play a crucial role in immune recognition and compatibility for blood transfusions.

• Antigens can be carbohydrates, proteins, or glycoproteins.

• They are recognized by the immune system and can trigger immune responses if foreign.

Major Blood Group Systems

Blood Group	Year of Discovery	Frequency (%)	Frequency of Most Common Allele (%)
ABO	1900	66	21.7-61.6
Rh	1940	85	20.4-46.4
Kell	1946	9	1.5-14.7
Duffy	1950	8	0.1-0.5
Kidd	1951	8	0.1-0.5
Lutheran	1946	1	0.1-0.5

Additional info: Table simplified to show main blood group systems and their frequencies in the English population.

ABO Blood Group Antigen

• The ABO system is the most important blood group system in transfusion medicine.

• First human blood group discovered (1901).

• Four basic groups: A, B, AB, and O.

• Distribution of these groups varies among populations.

• ABO antigens are integral parts of the red cell membrane and are also present in plasma and other cells.

Genetics of ABO Blood Types

• The ABO gene is located on chromosome 9q34.2.

• It encodes a glycosyltransferase enzyme that modifies the H antigen on the RBC surface.

• Three main alleles: IA, IB, and i (O).

• Genotypes and phenotypes:

  • IAIA or IAi: Type A

  • IBIB or IBi: Type B

  • IAIB: Type AB

  • ii: Type O

Inheritance of ABO Blood Types

• ABO blood types are inherited in a Mendelian fashion.

• Each parent contributes one allele to their offspring.

• Possible combinations determine the child's blood type.

Phenotype and Genotype Table for ABO Blood Types

Phenotype (Blood Type)	Genotype(s)	Antibodies Present	Antigens Present
A	IAIA, IAi	Anti-B	A antigen
B	IBIB, IBi	Anti-A	B antigen
AB	IAIB	None	A and B antigens
O	ii	Anti-A, Anti-B	None

Distribution of ABO Blood Types

• The frequency of ABO blood types varies globally and among ethnic groups.

• Type O is generally the most common worldwide, but the distribution of A and B alleles differs by region.

Clinical Relevance: Blood Transfusions

• ABO compatibility is critical for safe blood transfusions.

• Transfusion of incompatible blood can cause severe immune reactions.

• Type O negative is considered the universal donor; type AB positive is the universal recipient.

Human Leukocyte Antigen (HLA) System

Overview of HLA

The HLA system is another example of a highly polymorphic genetic system. HLA genes encode cell surface proteins essential for immune function and are highly variable among individuals.

• HLA polymorphisms are important in organ transplantation, disease susceptibility, and immune response.

• Each individual inherits a unique combination of HLA alleles from their parents.

Key Concepts and Terms

• Differences between A, B, and O antigens

• Transfusion issues with ABO blood group incompatibility

• Role of polymorphisms in drug metabolism and disease susceptibility

Additional info: Expanded explanations and tables were added for clarity and completeness, as the original slides were brief and sometimes fragmented.