Blood Group Genetics

Objectives

Blood group genetics Dr. Veera Sekaran Nadarajan

1. Describe the genetic basis of blood group nomenclature and polymorphisms 2. Describe and apply the principles of mendelian genetics in blood group inheritance 3. Describe the principles of linkage disequilibrium in blood group inheritance

Blood group antigens

Polymorphism

• Products residing on the RBC surface • Occurs in polymorphic forms

• means “many forms” • A gene is defined as polymorphic if it has 2 or more different allelic forms in a frequency greater than can be explained by mutation, arbitrarily taken as 1%. • A genetic locus is monomorphic if there is only one common allele and all other alleles individually have a frequency less than 1%

1

From DNA to proteins • DNA forms the basic building blocks – genomics • DNA transcription to RNA controlled at several levels - transcription complexes, gene inactivation, methylation, other epigenetic phenomena – transcriptomics

From DNA to proteins • RNA is translated to protein and controlled at pre and post transcriptional levelssplicing, miRNAs • Final phenotypic expression is determined directly by the proteins produced or via enzymatic pathways proteomics

Blood group antigens

Single nucleotide polymorphism

• Due to mutations involving various genes – Single nucleotide polymorphisms (SNP) • Missense • Nonsense • Silent – Insertions/ deletions – Gene rearrangements • Recombinations • Gene conversions • Gene crosovers – Gene deletions

• SNPs occur every 100 to 300 bases in the normal genome • Most blood groups generated by SNPs

• Generates polymorphisms by – Missense SNPs encoding an aa change – Nonsense SNPs causing aa change to a premature stop codon – Forming a new splice site or abolishing an existing splice site – Altering transcriptional control at regulatory regions

2

3

ISBT • 29 blood group systems – A system of blood group antigens which are genetically distinct and coded by a single loci or very closely linked loci • 40 genes • 962 alleles • Multiple alleles may confer a single phenotype • Single allele confers a single phenotype

ISBT • • • •

29 systems 5 collections – 205 – 210 700 series - low incidence antigens 900 series – high incidence antigens

4

Genetic principles Principle of Independent Assortment

• Blood groups are inherited according to mendelian principles • Generally exhibits independent assortment except for closely linked loci

When gametes are formed in diploid organisms, the segregation of each gene pair does not affect the segregation of other gene pairs as long as the gene pairs are on separate chromosomes.

Human Blood Group

Red Cell Antigens

Serum Antibodies

Possible Genotype

A

A  antigen

Anti-B

AA or AO

 B

B  antigen

Anti-A

BB  or BO

O

None

Anti A and Anti-B

OO only

AB

 A and B antigen

None

   AB only

5

Dihybrid crosses involving 2 independent alleles

The HLA complex Jack DP 1

2

Jill 3

4

Linkage disequilibrum • Closely linked loci (e.g. RHD, RHCe, MHC) show linkage and do not segregate independantly

RHD and RHCE are closely linked loci Bo 1

3

Kim 1

4

Mo 2

3

Lee 2

4

DQ DR B C

A

6

7