Blood group genetic

genome

all genetic information of a cell

genomics

study of the entire genome of an organism

Gene

Function unit of heredity (inheritance of characteristics from one generation to the next) of any trait (genetically determined characteristic or condition)

segement of deoxyribonucleic acid (DNA) within a chromosome that codes for a molecule that has a function

locus

fixed position on a chromosome, such as position of a gene or genetic marker

alleles

one of several alternative form of a gene

haplotype

a group of alleles that tend to be inherited together

ex RHD and RHCE

somatic cell

cells in the body except sex cell

46 chromosomes = 22 pairs autosomes + 1 pair sex chromosomes [23 pairs total: each pair from one paternally (dad side) and one maternally (mom side) homologous chromosome]

cell divison through mitosis

Gametes (germ cell)

sex cell: egg or sperm cell

23 chromosomes = 22 autosomes + 1 sex chromosome (male XY and female XX), not pairs.

Gametes are genetically unique because homologous chromosomes undergo crossing over in Prophase I and assort independently in Metaphase I

cell divison through meiosis

homologous chromosomes = chromosome pair

• Same size and shape

• Same genes in the same locations (loci)

• One chromosome came from mom

• One chromosome came from dad

chromosome

contain genetic material (DNA) to maintain the life of cell and the organism

Common: made up of one linear double strand DNA molecule. Each has a centromere (constricted region). Telomeres are protective DNA caps at the ends of chromosomes. p arm (= petite short arm)_ and q arm (long)

Different: in overall size, location of centromere and DNA content

Chromatin => chromasome => 2 chromatid

Pseudoautosomal Region (PAR)

• Pseudoautosomal regions are small matching areas near the ends of the X and Y chromosomes.

• They are located next to the telomeres, but they are not the telomeres themselves.

• Humans have two:

  • PAR1: near the ends of the short arms, Xp and Yp

  • PAR2: near the ends of the long arms, Xq and Yq

• PARs allow the X and Y chromosomes to pair and exchange DNA during male meiosis.

• Genes in PARs are present on both X and Y and usually escape X-inactivation.

• an example of a gene located in PAR1: CD99

karyotype

represent the chromosome complement of a person

Male 46, XY

Female 46, XX

cytogenetics

study of chromosome

heterochromatic (hetero- different; chromatic: color)

regions rich in adenin (A-apple) and thymine (T- tree). Tight pack DNA- gene is mostly inactive and stained dark with giemsa stain

Euchromatic (Eu- true/ good)

rich in guanine (G-garare) and cytosine (C- car). loose pack DNA- gene in active form and stained light with giemsa stain

Mitosis

somatic cells divide for growth and repair

single cell rise to two identical daughter cells (same sets of chromasomes)

Diploid (2N) = 23 pairs

meiosis

occur only in germ cells that are intendeded to become gametes (haploid 1N)

it’s a process of cell division and replication that leads to the formation of haploid gametes

diversity through 2 mechanism: independent assortment and crossing over

independent assortment

each daughter cell randomly receives either maternally or paternally derived homologous chromosomes

crossing over

exchange genetic material between homologous chromosome pairs

X chromosome inactivation (lyonization)

dosage compensation by inactive X chromosome at early stage of embryonic development. only one X cell need for function

example: XK- get shut off like normal X gene, so a carrier female is a mosaic: Kx+ cell and Kx- (McLeod) cell are both appear

escape X inactivation

a gene on the inactive X chromosome stays active and continues producing its protein.

first gene found: XG gene, and CD99

polymorphism

at one locus, there are two or more alleles in the population; each allele carried by > 1% of people ( <1% consider rare variant not polymorphism)

ex: highly polymorphic: RH and MNS

low polymorphic: FY and CO

an allele can be polymorphic in one population and absent in another. Ex FY*02N.01, an allel that swithes off the FYb in red cells is polymorphilic in african (>70%) but not found in other population

mutation- inherited (germline)

present in every cell. Can passed on to offspring

acquired mutation (de-novo)

occur spontaneously or be brought by agent like radiation (UV, X-ray) or chemical

mutation

where: within a gene or intergenic regions (between gene)

How:

Mutation

Type: inherited (germline) or acquired

where: within or between (intergenic region) gene

Effect: silent (no effect) or alter the gene

Mutation rate: how often DNA changes occur. In humans, the average rate is about 1.3 × 10⁻⁸ mutations per base pair per generation, and it varies with parental age, sex, the type of mutation, and where in the genome the DNA is located.

Germline mutation

present in every cell and can passed on to off spring

Acquired mutation

occur spontaneously or be brought by an agent (X-ray, UV) or chemical

genetic variation

• single base-pair (bp) SNV = one DNA base changed. create most blood group antigen differences

• insert/ deletion Indel = DNA bases inserted or deleted.

• Structural variant = large DNA segments deleted, inserted, duplicated, or rearranged.

SNP (Single Nucleotide Polymorphism)

SNP (Single Nucleotide Polymorphism) > 1%

Single Nucleotide Variant (SNV)

A change in one DNA base (nucleotide).

• Most blood group polymorphisms are caused by SNVs.

• One nucleotide change can create a different antigen.

Effects of SNVs in Coding Region

Mutation Type	Effect	Blood Bank Significance
Synonymous (Silent)	DNA changes, amino acid unchanged	Usually no antigen change
Missense (Nonsynonymous)	DNA changes, amino acid changes	Often creates a new antigen
Nonsense	Creates stop codon	Protein shortened or absent create null phenotypes.

allele

Different forms of the same gene at a specific locus

Example:

• ABO has A, B, and O alleles.

Memory Tip:
Gene = recipe
Allele = version of the recipe

How many alleles does a person usually inherit for a blood group gene?

Two

• One from mother

• One from father

genotype

The alleles a person inherits.

Genotype determined by DNA-based testing

Example:

• A/O

• A/B

• KEL01/KEL02

• JKA/JKB

• ABO*A/O

• KEL01/KEL02

phenotype

The antigens expressed on the red cell.

the phenotype is the antigen pattern detected on RBCs by serologic testing.

Example:

Genotype	Phenotype
A/O	Group A
A/B	Group AB
O/O	Group O

What is the relationship between genotype and phenotype?

Genotype produces the phenotype.

Genes → Protein/Antigens → Phenotype

JK*A/JK*A => Jkᵃ antigen produced => Jk(a+b−)

homozygous

Two identical alleles at a locus.

Examples:

• A/A

• JKA/JKA

• KEL02/KEL02

Memory: Homo = same

heterozygous

Two different alleles at a locus.

Examples:

• A/O

• A/B

• JKA/JKB

Memory: Hetero = different

hemizygous

Only one copy of a gene is present.

Example:

• One RHD gene deleted

RHD / deletion

Two alleles are present, but only one works.

Example:

• Normal RHD + RHD pseudogene

antithetical antigens

Antigens encoded by different alleles at the same locus.

Examples:

• K / k

• Jkᵃ / Jkᵇ

• Fyᵃ / Fyᵇ

• M / N

Are genes allelic or antithetical?

Genes = allelic

Antigens = antithetical

Why is "homozygous for k antigen" incorrect?

Because alleles are homozygous, not antigens.

✅ Correct:

• Homozygous for KEL*02 allele

• Double dose of k antigen

What is antigen density?

The number of antigen sites expressed on RBCs.

More gene copies → more antigen expression.

higher antigen density: homozygous. antigen is inherited from both parents.

Example:

Genotype: JK*A/JK*A
Phenotype: Jk(a+b−)

dosage effect

An antibody reacts more strongly with homozygous (double-dose) cells than with heterozygous (single-dose) cells.

Which blood group systems commonly show dosage?

Kidd, Duffy, MNS, and Rh antibodies.

What is a genetic trait?

The observable expression of one or more genes.

Examples:

• Blood type A

• D-positive status

• Jk(a+b−)

What determines how a trait is inherited? What is the first and second question to ask when studying inheritance?

• Location of the gene

  • Autosome → Autosomal inheritance

  • X chromosome (sex-linked) → Sex-linked inheritance

• Pattern of inheritance

  • Dominant → One allele needed

  • Recessive → Two alleles usually needed

What is an autosome?

Any chromosome that is not a sex chromosome.

Humans have:

• 22 pairs of autosomes

• 1 pair of sex chromosomes (XX or XY)

What is an X-linked (sex-linked) gene?

A gene located on the X chromosome.

Inheritance differs between males and females because:

• Females = XX

• Males = XY

Where are most blood group genes located?

On autosomes

Which blood group systems are X-linked?

• Xg blood group system

• XK blood group system

These are inherited through the X chromosome.

What is a dominant trait?

Only one copy of the allele is needed for expression.

exp: A/O => group A

What is a recessive trait?

Two copies of the allele are usually required for expression.

exp O/O => group Oc

Two copies of the allele are usually required for expression.

What does autosomal inheritance mean?

The gene is on an autosome.

Males and females inherit the trait equally.

What does X-linked inheritance mean?

The gene is on the X chromosome.

Inheritance differs between males and females.

males often affected more by X-linked traits because male has only one X. Whatever allele is present on that X chromosome will be expressed.

What is a family study?

A study that follows the inheritance of a genetic trait through family members.

Examples:

• Blood group antigens

• Genetic disorders

• Rare blood group alleles

What is a pedigree?

A diagram showing family relationships and the inheritance of a trait across generations.

Memory Tip: Pedigree = Family Tree for Genetics

What is the purpose of a pedigree?

To determine how a trait is inherited.

Examples:

• Autosomal dominant

• Autosomal recessive

• X-linked inheritance

What information does a pedigree show?

• Family relationships

• Who expresses the trait

• Who does not express the trait

• How the trait is transmitted

What is the "affected" individual in a pedigree?

A person who expresses the trait being studied.

Example:

• Has the antigen

• Has the disease

What does "proband" mean?

The family member whose case initiates genetic investigation.

plural term for probands: Propositi - Used regardless of gender.

What is autosomal dominant inheritance?

A trait is expressed whenever the relevant allele is present, whether the person is homozygous or heterozygous (One copy of the allele is sufficient for expression).

How does an autosomal dominant trait appear in a pedigree?

It appears in every generation.

The trait occurs with equal frequency in males and females.

the chance that a person with an autosomal dominant trait will pass it to a child: 50%

Examples: The B allele is dominant over O.

• B/O → Group B

• B/B → Group B

Autosomal Codominant Inheritance

When two different alleles are present, the products of both alleles are expressed.

example: Antithetical antigen pairs like Ss

Autosomal Recessive Inheritance

expressed only when a person is homozygous for the recessive allele from both parent(obligate carrier) (geno: hemozyous) or one recessive allele and one null allele (geno: heterozygous)

probability that two heterozygous carriers will have a homozygous child: 25% (1/4)

Where is a rare recessive trait usually found in a family?

Among siblings rather than in multiple generations.

In onsanguineous mating (Mating between blood relatives)

What common recessive ABO allele demonstrates this?

The O allele.

What is a null phenotype?

A phenotype in which no blood group product is expressed.

• Lu(a−b−)

• Rhnull

• O phenotype

What is a null allele (Amorph)?

An allele that produces no detectable product.

What is a sex-linked trait?

A trait encoded by a gene located on the X or Y chromosome.

cow many functional blood group genes does the Y chromosome carry, and which one?

Only one known: CD99 of the XG system.

Unlike most X genes, which have no homolog on the Y chromosome, CD99 is present on both X and Y chromosomes, in the pseudoautosomal region.

genes XG and CD99, located in pseudoautosomal region 1 (PAR1) of the sex chromosomes. The Xg glycoprotein is encoded by the X chromosome only, while the CD99 glycoprotein is encoded by both X and Y chromosomes

What does "sex-linked inheritance" generally mean in practice?

Inheritance of genes carried by the X chromosome.

X-linked inheritance can be dominant or recessive

What sex chromosomes does a male have, and where does each come from?

One X chromosome (always maternally derived) and one Y chromosome (always paternally derived).

What does hemizygous mean?

Only one chromosome — and thus one copy of a gene — is present, as in males for genes on the X or Y chromosome.

type of Sex-Linked Inheritance

usually talk about X chromosome as Y chromosome are rare and only CD99 is known of

Type odf X link inheritance

• Sex-Linked Dominant Inheritance

• Sex-Linked Recessive Inheritance

Who expresses an X-linked dominant trait?

Males who are hemizygous (His single X chromosome to all his daughters — all daughters express the trait; none of his sons receive it.)

and females who are heterozygous (50% for each child, whether son or daughter) or homozygous (All her children express the trait) for the gene.

Which blood group antigen is the passage's X-linked dominant example?

The Xg(a) antigen (XG blood group system), encoded by an allele on the X chromosome.

What first suggested Xg(a) was X-linked?

The prevalence of the Xg(a+) phenotype differed by sex: 89% in females and only 66% in males.
Note: Females have two X chromosomes — two chances to carry the dominant allele — while males have one.

Disruption of a GATA-binding motif in the XG gene recently linked to differential expression of Xg(a)

What is sex-linked recessive inheritance?

A trait encoded by a sex chromosome that is not expressed in carriers of a single copy, such as heterozygous females.

Mom is usually a carrier (or homozygous for the trait) pass to son (50%)

An affected male transmits the trait to all of his female offspring. (Affected male → carrier daughters → affected grandsons.)

X-linked recessive traits are usually seen in males because males have only one X chromosome; heterozygous females have one normal X that masks the recessive allele and are typically carriers rather than affected

Which gene is the passage's X-linked recessive example, and what does it encode?

The XK gene, which encodes the Kx protein.

What do deleterious mutations in, or deletions of, XK cause?

The McLeod phenotype — red cells lack the Kx antigen and have reduced expression of KEL antigens.

Late-onset clinical or subclinical myopathy; neurodegeneration and central nervous system manifestations; chronic granulomatous disease; and acanthocytosis, frequently along with compensated hemolytic anemia.

More than 30 different XK gene mutations associated with a McLeod phenotypec

Only Male

What does the principle of independent segregation refer to?

The separation of homologous chromosomes and their random distribution to the gametes during meiosis.

term

Term	What it describes	Human example	Blood bank example
Haploid (1N)	One set of chromosomes	Sperm or egg	A gamete carrying DCe
Diploid (2N)	Two sets of chromosomes	Most body cells	A person with DCe/dce
Haplotype	The allele combination on one chromosome	One HLA haplotype inherited from mom	DCe, Dce, dcE, dce
Genotype	The combination of both haplotypes	HLA-A2/A24	DCe/dce
Homologous chromosomes	Maternal and paternal copies of the same chromosome	Chromosome 1 from mom + chromosome 1 from dad	One chromosome carrying DCe and the other carrying dce
Homozygous alleles of a gene	Same allele on both homologs	AA	FYA/FYA
Heterozygous alleles of a gene	Different alleles on the homologs	Aa	FYA/FYB
Hemizygous	Only one allele present	Male with X-linked gene	XᴴY or XʰY

What is the principle of independent assortment?

Alleles determining various traits are inherited independently from each other.

The inheritance of one allele (e.g., a B allele, on chromosome 9) does not influence the inheritance of another allele (e.g., an M allele, on chromosome 4).

STRUCTURAL VARIATION

Linkage and Crossing Over

Linkage Disequilibrium

What is linkage?

The physical association between two genes located on the same chromosome and inherited together.
Note: Linked genes are the exception to independent assortment — they do not assort independently.

example:

RHD and RHCE, encoding the antigens of the RH system — both on chromosome 1, linked loci that do not assort independently. R1R1, R2R2, R0,…

What is crossing over?

The exchange of genetic material between homologous chromosome pairs. - Shuffle genetic material.

A segment from one chromatid (and any associated genes) changes places with the corresponding part of the other chromatid (and its associated genes); the segments are rejoined, and some genes will have switched chromosomes.

Genes on the same chromosome can still recombine.

• Close genes → low recombination frequency (RHD/RHCE)

• Far-apart genes → higher recombination frequency (FY and KN)

What are recombination and recombinants?

Crossing over is also called recombination because it can result in new gene combinations on the chromosomes involved; the rearranged chromosomes are called recombinants.

What does syntenic mean?

Two gene loci carried by the same chromosome that are not closely linked.

RH and FY, both on chromosome 1 — RH on the short arm and FY on the long arm, far enough apart to undergo crossing over and assort independently.
Note: Syntenic and linked both mean "same chromosome" — the difference is distance: syntenic loci are far apart and act independently, while linked loci are close together and travel together.

What does the frequency of crossing over between two genes measure?

he distance between them, measured in centimorgans (cM).1 cM roughly equals a 1% chance of recombination between the two loci — so a centimorgan is a genetic distance, not a physical length in base pairs.

The greater the distance between two loci, the greater the probability that crossing over (and recombination) will occur; genes located very close together (linked) tend to be transmitted together with no recombination.

What was the first recognized example of autosomal linkage in humans?

Linkage between Lutheran (LU) and ABH secretion (SE or FUT2).

Can recombination happen between very closely linked or adjacent genes?

Rarely, yes — documented examples include the genes encoding the MN (GYPA) and Ss (GYPB) antigens on chromosome 4.

Even very closely linked genes can occasionally undergo recombination.

What is a haplotype?

A combination of alleles at two or more closely linked loci on the same chromosome. DCe
Note: A haplotype is the set of alleles on one chromosome; a genotype is the combination across both chromosomes. DCe/DcE

What are the four MNS haplotypes?

MS, Ms, NS, Ns — in ISBT terminology: GYPA*M-GYPB*S, GYPA*M-GYPB*s, GYPA*N-GYPB*S, GYPA*N-GYPB*s.

Why do the antigens encoded by each haplotype have a different prevalence than random assortment would predict?

Because linked genes do not assort independently.

Expected 17% if M and S were not linked (from frequency calculations); observed 24% for the MS haplotype (from testing and analyzing families).

What is linkage disequilibrium?

The tendency of specific combinations of alleles at two or more linked loci to be inherited together more frequently than would be expected by chance.
Note: The 24% vs 17% gap is the disequilibrium itself — MS shows up more often than chance alone would predict.

Chimera

A chimera is an organism with cells originating from more than one genetic source.

What is mixed-field agglutination often the result of?

Artificially (acquired) induced chimerism — through the transfusion of donor red cells or hematopoietic stem cell transplantation.

Natural chimerism:

• somatic mutation

• true chimera

How can somatic mutations (mosaicism = same zygote) in the marrow explain mixed-field agglutination?

They can lead to the development of two different and persistent cell populations.

They can lead to the development of two different and persistent cell populations.

A somatic mutation means:

A genetic change that happens during life in a body cell, not inherited from mom or dad.Now the person has:

• One population of normal cells

• One population of mutated cells

Both populations continue making RBCs