ABO Blood Groups and Inheritance

Introduction

• Genotypic traits exhibit simple inheritance, examples include blood groups, hemoglobin variants, proteins, and enzymes
• Polygenic traits exhibit a more complex inheritance pattern, examples include skin, hair, and eye color, and height

Earliest Blood Transfusions

• Ancient Greek physicians performed the earliest blood transfusions
• These transfusions sometimes benefitted the patients, but were often fatal

ABO Blood Group

• The different types are A, B, and O
• The first human polymorphism discovered was in 1900 by Landsteiner
• Polymorphism is a trait that exists in at least 2 forms
• The ABO gene is the most studied simple genetic trait in humans
• The ABO gene is located on chromosome 9 and has 3 alleles
• The alleles are A, B, and O
• A and B are codominant
• O is recessive to both A and B

Antigen – Antibody Reactions

• An antigen is a protein on a substance/molecule of foreign origin
• An antigen triggers the production of an antibody
• An antibody is a protein that recognizes an antigen

Agglutination

• Agglutination is the clumping of cells
• Agglutination occurs when antigens are found on whole cells
• Agglutinogens are antigens on the surface of the RBC that are the basis for blood typing. They include Antigen A and Antigen B, which is a Glycolipid on the RBC surface
• Agglutinins are antibodies in the plasma that bring about transfusion mismatch and include Anti-A, Anti-B, and Anti-H

Chemical Basis of ABO Types

• The antigen type is determined by the glycolipid composition/order
• Membrane phospholipids with short carbohydrates are bonded to them via a string of sugars that is attached to the cell membrane
• The string of sugars include: Galactose, N-acetylgalactosamine (GalNac), N-acetylglucosamine (GlcNac) – “GlucNac", and Fucose
• All strings end with a fucose
• H antigen building blocks are used for other antigens
• B antigen chain has a galactose added to it
• A antigen chain has GalNac added to it
• Genes determine the ability to build all of these

ABO Blood Group

• Before you can build an A or B antigen, you must first build the precursor, the H antigen
• H antigen is coded for by the FUT 1 gene (chromosome 19)
• (HH, Hh, or hh)
• The H antigen is found in all blood groups
• It is a "Building block" for other antigens
• A and B alleles (ABO gene) code for additional enzymes that add a sugar to the H antigen

The ABO Blood Group

• Blood type is determined by the presence/absence of antigens (agglutinogens) on RBCs
• Blood type A has A antigens
• Blood type B has B antigens
• Blood type AB has both A and B antigens
• Blood type O has neither A or B antigen, but does have H antigens
• Type O is the most common, type AB is the rarest

The ABO Blood Group

• Based on agglutinogens on RBCs, you can predict what type of antibodies (agglutinins) will be present in plasma
• Blood type A has A antigens and Anti-B agglutinins
• Blood type B has B antigens and Anti-A agglutinins
• Blood type AB has both A and B antigens and no agglutinins
• Blood type O has neither antigen and BOTH Anti A and B agglutinins

Blood

• Blood has 2 components, fluid (plasma) and formed elements
• The fluid (plasma) contains Proteins, Nutrients/Gases, and Antibodies
• The formed elements contain RBC/WBC/Platelets

ABO Blood Group

• Blood transfusion involves Red Blood Cell ONLY (packed) vs. Whole Blood (plasma)

H Antigen Variation

• The H antigen (HH, Hh, or hh) is coded for by the FUT 1 gene (chrom 19)
• 99.9% of RBCs in all populations have the H antigen
• H antigen deficiency occurs when there is a Homozygous recessive (hh), also known as the "Bombay Phenotype"

Bombay Phenotype

• The hh genotype codes for inactive FUT1 gene
• Bombay Phenotype results in Lack of H antigen and Results in lack of fucose
• Bombay Phenotype means Other antigens can't be formed
• Bombay Phenotype means a person has Anti-H, Anti-A, Anti-B antibodies
• Incredibly rare as it occurs in 1 in 10,000 individuals in India and 1 in a million in Europe
• No ill effects EXCEPT blood transfusion
• The H antigen gene at 19q13.2 has two alleles. The H allele is dominant and codes for FUT1 which synthesizes the H antigen. The h allele codes for an inactive FUT1 and is recessive. Individuals who are hh have the Bombay phenotype irrespective to the ABO alleles they carry
• Cancels out impact of dominant alleles from ABO gene

Geographical Distribution Early Populations

• B allele (rarest allele) has highest concentration in Central Asia (also high in Africa) and is low in Americas and Australia
• A allele is high in small, unrelated populations (e.g. Blackfoot Indians in Montana, Australia, and northern Scandinavia) and low in Central and South America
• O allele (most common) has the highest concentration in Central, South, and North America (also high in Africa, western Europe, Australia) and is low in Eastern Europe and Central Asia

Distribution and Selection

• The mechanisms of evolution are responsible for the distributions and frequencies of the A, B, O alleles
• Blood groups influence the severity, susceptibility, and mortality rates for many infectious diseases

Natural Selection

• Type O blood type correlates with:
  • Helicobacter pylori infections
    • Gastric and duodenal ulcers
    • Enhanced binding of H. pylori to epithelial cells in gut
  • GI infections caused by Escherichia coli O157
    • 1996 Scottish outbreak, 87.5% of deaths were type O
  • "Traveler's Diarrhea"
    • 2018 study on E. coli
    • Type A vs. Type B or O
  • Cholera (Vibrio cholerae)
    • O people have higher disease severity
    • Peru (1991) O people were more likely to be hospitalized
  • Ganges River Delta (India/Bangladesh)
    • High instances of cholera
    • Low frequency of O allele
    • Lack of A or B antigens?

Rh System

• The Rh system is very polymorphic with over 45 antigens, C, D, and E
• D antigen is the most reactive
• Absence or presence of a functional RHD gene (chrom 1)
• Rh+ = DD, Dd
• Rh- = dd
• Anti-D agglutinins (antibodies) are not normally present
• They form in Rh- person when exposed to Rh+ blood
• Hemolytic disease of the newborn (HDN) occurs if Rh- mother has formed Anti-D antibodies and is more of a problem for second baby as Baby RBC's agglutinate and Agglutination leads to hemolysis (death). The baby is often born anemic
• VERY low Rh- in most populations, but High freq. in Europe
• There are Difficult to determine how one allele could become prevalent in a population with high freq. of the other allele
• There are Issues with maternal/infant incompatibility
• Most likely?
• Historic gene flow between Rh- pop. and Rh+ pop.
• Ancient DNA evidence from Rh- hunter-gatherers, and Rh+ Farmers
• Basque population exhibits a High frequency of Rh- & Hunter-gatherer ancestry