IMED2004 - Gene Interaction I and II (L3 + L4)

What are the eleven learning outcomes for the Gene Interaction lectures?

1. Genotype-phenotype correlation

2. Dominance, incomplete dominance and codominance

3. Inheritance of multiple alleles, including ABO blood groups

4. The level at which phenotype is observed

5. Pleiotropy

6. Polygenic traits

7. Sex-linked characteristics

8. Mosaicism

9. Mitochondrial inheritance

10. Penetrance and expressivity

11. Gene interaction and epistasis, especially recessive epistasis in ABO blood groups

Lecturer emphasis:

All slides marked with a learning-outcome number contain important foundational concepts.

Why do Mendel's principles alone not explain the inheritance of every trait?

Mendel's simple model assumes:

- An individual has two alleles for a trait.

- One allele is dominant.

- A heterozygote has the same phenotype as the dominant homozygote.

However, Mendel knew exceptions existed. For example, crosses involving different flowering times could produce an intermediate phenotype.

Therefore, inheritance may involve incomplete dominance, codominance, multiple alleles, multiple genes, environmental effects and other interactions.

What broad genotype-phenotype relationships can traits display?

Traits may:

- Follow a simple dominant-recessive relationship

- Combine gene effects to produce a completely new phenotype

- Display products or phenotypes from both alleles

- Require multiple genes for full phenotypic expression

DIAGRAM ON SLIDE 4

What is complete dominance?

Complete dominance occurs when the phenotype of a heterozygote is the same as the phenotype of one homozygote.

- True-breeding individuals are homozygous.

- Hybrids are heterozygous.

- The dominant allele masks the phenotypic effect of the recessive allele.

How does a germline mutation present in a fertilising gamete affect the resulting individual?

Example:

- Paternal sperm carries a mutant allele, Mt.

- Maternal ovum carries a wild-type allele, Wt.

- The zygote is Mt/Wt.

- Because the mutation is present from fertilisation, all cells of the embryo are heterozygous Mt/Wt.

- The individual's gametes will carry either Mt or Wt.

A heterozygous cell may produce both normal and abnormal protein.

A homozygous mutant cell produces only abnormal protein.

DIAGRAM ON SLIDE 6

Why might the proportions of normal and mutant protein in a heterozygote differ from a simple 50:50 ratio?

Lecturer explanation:

The two alleles may be transcribed, but their protein products may differ in stability.

A mutant protein may:

- Be degraded more rapidly than the wild-type protein

- Be more stable than the wild-type protein

This can skew the relative amounts of normal and abnormal protein and alter phenotype.

What are the standard expectations for a single-gene dominant disorder?

A dominant disorder commonly involves:

- A heterozygous mutation inherited from an affected parent or arising de novo

- A mutation in only one copy of the gene

- A gain-of-function effect

- A protein that acquires a new or altered function

Some disorders differ from these standard expectations.

What are the standard expectations for a single-gene recessive disorder?

A recessive disorder commonly involves:

- Homozygous or compound-heterozygous mutations

- Mutations inherited from unaffected carrier parents

- Pathogenic variants in both copies of the gene

- Loss of function

- Absent or reduced protein function

A compound heterozygote has two different pathogenic variants at the same locus.

Some disorders differ from these standard expectations.

What is a genotype-phenotype correlation?

A genotype-phenotype correlation is the relationship between:

- A specific genetic mutation or genotype

and

- The resulting disease characteristics or phenotype.

The correlation may sometimes be explained by the mutation's effect on the amount or residual function of the protein.

Why may individuals with the same genotype show different phenotypes?

A clear genotype-phenotype correlation is not always observed because phenotype may also be altered by:

- Modifier genes

- Differences in gene expression

- Environmental factors

- Other interacting biological factors

What did Cuenot's yellow-mouse crosses reveal about simple Mendelian ratios?

Yellow × yellow mice did not produce the expected Mendelian ratio.

The cross produced:

- 1/4 homozygous yellow embryos, YY, which died

- 1/2 heterozygous yellow offspring, Yy

- 1/4 non-yellow offspring, yy

Among surviving offspring, the ratio was therefore:

- 2/3 yellow

- 1/3 non-yellow

DIAGRAM ON SLIDE 9

What broader genetic ideas did Cuenot propose?

Cuenot was among the first to suggest that:

- More than two alleles may exist at one locus

- Genes at different loci may interact

- Cancer may be inherited

- Genes encode enzymes

Why does the lethal-yellow mouse allele demonstrate that Mendel's principles are not sufficient by themselves?

The lethal genotype removes one expected class of offspring before it can be observed.

Therefore:

- The observed phenotypic ratio differs from the basic Mendelian prediction.

- Viability and effects at other loci can modify expected ratios.

- One allele may also have several phenotypic effects.

Lecturer explanation:

The yellow allele was associated not only with coat colour but also with additional effects such as obesity-like features and tumour susceptibility.

What is the difference between biallelic and monoallelic expression?

Biallelic expression:

- Both alleles of a gene are transcribed.

- This is the more prevalent form of expression.

Monoallelic expression:

- Only one of the two alleles is active.

- The other allele is silent.

- The choice is often established early in development and then stably maintained.

DIAGRAM ON SLIDE 11

What forms of epigenetically driven monoallelic expression were shown?

Deterministic monoallelic expression:

- Genomic imprinting

Random monoallelic expression:

- X-chromosome inactivation

- Immunoglobulin expression

- Odorant-receptor expression

- Interleukin expression

- Widespread random autosomal monoallelic expression

DIAGRAM ON SLIDE 12

What non-Mendelian inheritance patterns were introduced in the lecture?

- Multiple alleles, although each individual carries only two

- Incomplete dominance

- Codominance

- Polygenic traits

- Pleiotropy

- Sex-linked characteristics

- Environmental modification of phenotype

Environmental examples included UV exposure, smoking, diet, exercise and alcoholism.

How can genes and environment interact to determine height?

Height is influenced by several genes, but environmental conditions affect whether genetic potential is reached.

Poor nutrition, including inadequate:

- Protein

- Minerals

- Vitamins

can restrict growth.

The lecture noted that average height in the United States has increased by approximately 10 cm since the late 1800s, illustrating environmental effects across generations.

How do complete dominance and incomplete dominance differ?

Complete dominance:

- The heterozygote matches one homozygote.

Incomplete dominance:

- The heterozygote has an intermediate phenotype between the two homozygotes.

- The intermediate phenotype may reflect an intermediate amount of gene product, such as pigment.

DIAGRAM ON SLIDE 15

How does incomplete dominance explain curly, wavy and straight hair in the lecture example?

Using alleles C and S:

- CC → curly hair

- CS → wavy hair

- SS → straight hair

For CS × CS:

- 1/4 CC, curly

- 1/2 CS, wavy

- 1/4 SS, straight

DIAGRAM ON SLIDE 16

What phenotypic ratio results from a heterozygote × heterozygote cross under incomplete dominance?

The phenotypic ratio is 1:2:1 because each genotype has its own phenotype.

Aa × Aa produces:

- 1/4 AA

- 1/2 Aa

- 1/4 aa

Under complete dominance, the same genotypes would usually produce a 3:1 phenotypic ratio.

Dominance affects phenotype, not how alleles segregate or are inherited.

What is a multi-allelic locus?

A multi-allelic locus is a locus for which three or more alleles are observed in the population.

Consequences:

- More possible genotypes

- More possible phenotypes

However, a diploid individual still carries only two alleles at that locus, one on each homologous chromosome.

Why do ABO blood groups demonstrate multiple alleles?

The ABO locus has three major alleles:

- Iᴬ

- Iᴮ

- i

These alleles produce:

- Four blood-group phenotypes

- Six possible genotypes

Each parent still carries and can transmit only two ABO alleles.

What is codominance?

Codominance occurs when two alleles are both expressed in a heterozygote.

The heterozygous phenotype:

- Is not intermediate

- Simultaneously displays the phenotypes or products of both homozygotes

How do ABO genotypes correspond to blood-group phenotypes?

Blood group A:

- Iᴬ/Iᴬ

- Iᴬ/i

Blood group B:

- Iᴮ/Iᴮ

- Iᴮ/i

Blood group AB:

- Iᴬ/Iᴮ

Blood group O:

- i/i

Why are Iᴬ and Iᴮ codominant?

Iᴬ and Iᴮ each encode a transferase that produces a different carbohydrate antigen on the red-cell membrane.

In an Iᴬ/Iᴮ individual:

- The Iᴬ allele produces A antigen.

- The Iᴮ allele produces B antigen.

- Both antigens are present.

The i allele produces no functional A- or B-antigen transferase.

What antigens and naturally occurring antibodies are associated with each ABO blood group?

Blood group A:

- A antigen

- Anti-B antibodies

Blood group B:

- B antigen

- Anti-A antibodies

Blood group AB:

- A and B antigens

- No anti-A or anti-B antibodies

Blood group O:

- No A or B antigens

- Anti-A and anti-B antibodies

What causes ABO-incompatible donor red blood cells to agglutinate?

Recipient antibodies bind matching antigens on donor red blood cells.

- If the donor cells carry an antigen recognised by the recipient's antibodies, the cells clump.

- Donor and recipient blood are incompatible.

- If no antibody-antigen reaction occurs, the donor cells remain dispersed.

The antigens are short carbohydrate chains on the red-cell membrane.

DIAGRAM ON SLIDE 20

What simplified donor-recipient rules were highlighted for ABO red-cell transfusion?

- Type O red cells have no A or B antigens and were described as universal donor red cells.

- Type AB recipients have neither anti-A nor anti-B antibodies and were described as universal recipients.

Lecturer explanation:

These statements concern the simplified ABO red-cell compatibility model shown in the lecture.

How do complete dominance, incomplete dominance and codominance compare?

Complete dominance:

- Heterozygote has the phenotype of one homozygote.

Incomplete dominance:

- Heterozygote has an intermediate phenotype between the two homozygotes.

Codominance:

- Heterozygote includes the phenotypes or products of both homozygotes.

DIAGRAM ON SLIDE 21

What are the main characteristics of dominance?

- Dominance is an allelic interaction at the same locus.

- It reflects interactions between the products of alleles.

- It influences phenotype.

- It does not alter how alleles are inherited.

- Its classification depends on the level at which phenotype is examined.

At what levels can a phenotype be observed?

Phenotype can be examined at:

- Molecular level

- Physiological level

- Anatomical or cellular level

The same pair of alleles may show different apparent dominance relationships at different levels.

What is the molecular change associated with sickle-cell haemoglobin in the lecture?

Haemoglobin is a tetramer containing:

- Two α chains, each 141 amino acids

- Two β chains, each 146 amino acids

The sickle-cell variant involves a change from glutamate to valine in the β chain.

How do HbA/HbA, HbA/HbS and HbS/HbS differ?

HbA/HbA:

- Wild type

- Red blood cells do not sickle

HbA/HbS:

- Usually not anaemic

- Some red blood cells sickle under low oxygen concentration

- Produces both HbA and HbS

HbS/HbS:

- Severe anaemia

- Abnormal haemoglobin

- Sickle-shaped red blood cells

Why does sickle-cell inheritance show different dominance patterns at different phenotypic levels?

With respect to anaemia:

- HbA is dominant because HbA/HbS individuals are generally not anaemic.

With respect to red-cell shape:

- Incomplete dominance occurs because HbA/HbS individuals have some sickled cells under low oxygen.

With respect to haemoglobin protein:

- HbA and HbS are codominant because both protein forms are present.

DIAGRAM ON SLIDE 24

What is pleiotropy?

Pleiotropy is the property by which one gene affects multiple phenotypic characteristics.

Most genes have more than one phenotypic effect.

How does the sickle-cell allele demonstrate pleiotropy?

The haemoglobin allele affects:

- Haemoglobin type

- Red-cell shape

- Anaemia

- Response to low oxygen

- Susceptibility or resistance to malaria

HbA:

- Haemoglobin A

- Round cells

- Susceptibility to malaria

HbS in an HbA/HbS genotype:

- Cells may sickle under low oxygen

- Increased resistance to malaria

DIAGRAM ON SLIDE 25

What human diseases were given as examples of pleiotropy?

- Cystic fibrosis

- Sickle-cell anaemia

In each case, multiple clinical features can be traced back to one defective allele or gene.

What is a polygenic trait?

A polygenic trait is controlled by the combined effects of multiple genes.

Polygenic traits commonly:

- Show many degrees of phenotype

- Produce a continuous distribution

- Form an approximately bell-shaped population curve

What is a multifactorial trait?

A multifactorial trait is influenced by:

- Several genes

and

- Environmental factors

Environmental effects can substantially modify expression of a polygenic trait.

What examples of polygenic or multifactorial traits were given?

Physical and behavioural characteristics:

- Body type

- Height

- Skin colour

- Hair colour

- Eye colour

- Intelligence

- Alcoholism

- Phobias

Disease-related traits:

- Hypertension

- Diabetes

- Cancers

- Allergies

- Cardiovascular diseases

These may have a genetic contribution as well as environmental effects.

Why do polygenic traits not produce simple Mendelian ratios?

Each individual contributing gene may follow Mendel's laws.

However:

- Several loci contribute simultaneously.

- Many genotype combinations are possible.

- Their combined effects produce many phenotypic classes rather than one simple ratio.

What gametes can an AaBbCc individual produce?

Assuming independent assortment:

- ABC

- ABc

- AbC

- Abc

- aBC

- aBc

- abC

- abc

Therefore, an AaBbCc × AaBbCc cross requires an 8 × 8 Punnett square and produces 64 genotype combinations before identical classes are grouped.

How can six contributing alleles create a continuous polygenic phenotype?

In the AaBbCc model:

- Six dominant alleles can produce one extreme, such as very dark pigmentation.

- Six recessive alleles can produce the opposite extreme, such as very light pigmentation.

- Intermediate numbers and combinations produce intermediate phenotypes.

This model was applied to pigmentation, height and eye colour.

DIAGRAM ON SLIDE 30

Why are X-linked recessive traits more commonly expressed in males?

Males have one X chromosome and are hemizygous for X-linked genes.

Therefore:

- A recessive pathogenic allele on their single X cannot be masked.

- A female usually requires pathogenic alleles on both X chromosomes to be affected.

- A heterozygous female can carry a recessive allele while expressing the normal phenotype.

How are X chromosomes inherited by sons and daughters?

Daughters:

- Receive one X chromosome from their mother.

- Receive one X chromosome from their father.

Sons:

- Receive their X chromosome from their mother.

- Receive their Y chromosome from their father.

Therefore, fathers do not transmit X-linked alleles to sons.

What offspring are expected when a carrier female for an X-linked recessive trait mates with an unaffected male?

Possible children:

- Daughter with two normal alleles: unaffected

- Heterozygous daughter: unaffected carrier

- Son with normal maternal X: unaffected

- Son with mutant maternal X: affected

Each outcome represents one of the four equally likely combinations in the simplified cross.

DIAGRAM ON SLIDE 31

What does the normal-female × colour-blind-male cross show for X-linked colour blindness?

Normal homozygous female × colour-blind male:

- All daughters inherit the father's affected X and a normal maternal X, so they have normal colour vision and are carriers.

- All sons inherit the father's Y and a normal maternal X, so they have normal colour vision.

DIAGRAM ON SLIDE 32

What does the reciprocal colour-blind-female × normal-male cross show?

Colour-blind female × normal male:

- All daughters receive a mutant maternal X and a normal paternal X, so they have normal colour vision and are carriers.

- All sons receive a mutant maternal X and the paternal Y, so they are colour blind.

The reciprocal cross gives a different outcome because X-linked inheritance depends on which parent carries the allele.

DIAGRAM ON SLIDE 32

What is X-chromosome inactivation?

X-chromosome inactivation is monoallelic expression in which most genes on one X chromosome are silenced in each cell.

It:

- Occurs early in development

- Is usually random in each cell

- Ensures appropriate dosage of X-linked gene products

- Is stably maintained in all descendants of that cell

Why are human females described as functionally mosaic for X-linked genes?

Different embryonic cells randomly inactivate different X chromosomes.

Consequently:

- Some cell clones express the maternal X.

- Other cell clones express the paternal X.

- A female contains a mixture of cell populations with different active X chromosomes.

What is mosaicism?

Mosaicism is the presence of two or more genetically distinct cell lines derived from one zygote.

It commonly results from a post-zygotic mutation.

How does the developmental timing of a post-zygotic mutation affect mosaicism?

An early mutation:

- Produces many descendant cells

- May be distributed across several tissues

A later mutation:

- Produces fewer descendants

- Is more localised or patchy

DIAGRAM ON SLIDE 34

How does mosaicism influence phenotype?

A mosaic individual contains a mixture of cells producing normal and abnormal gene products.

Phenotype depends on:

- The proportion of mutant cells

- The tissues in which mutant cells are located

- The distribution of those cells

Mosaic disease is often milder than disease present in every cell.

What types of genetic abnormality and tissue can mosaicism involve?

Mosaicism may involve:

- A chromosomal abnormality

- A single-gene mutation

- Somatic tissues

- Germline tissues

- Both somatic and germline tissues

Examples included:

- Mosaic Down syndrome

- Non-inherited cancers

What are the major features of classical monosomy X or Turner syndrome?

Karyotype:

- 45,X

Common classical features:

- Delayed puberty

- Infertility

- Cardiac abnormalities

- Renal abnormalities

Cardiac and renal abnormalities contribute to morbidity.

How does mosaic 45,X/46,XX Turner syndrome differ from non-mosaic 45,X?

A mosaic individual has:

- Some 45,X cells

- Some 46,XX cells

Phenotype usually correlates with the relative proportion and distribution of 45,X cells.

The lecture proposed that some live-born individuals diagnosed with Turner syndrome may be cryptic mosaics because most conceptions consisting entirely of 45,X cells do not survive gestation.

What is a cryptic mosaic?

A cryptic mosaic has a small population of genetically different cells that may be below the detection limit of routine testing.

In the Turner syndrome example:

- Most cells may be 45,X.

- A small, undetected population may be 46,XX.

DIAGRAM ON SLIDE 37

What is skewed X-chromosome inactivation, and why can it cause disease in a female carrier?

Normally, X inactivation is approximately balanced between the two X chromosomes across cells.

In skewed X inactivation:

- One X is active in a much larger proportion of cells.

- For example, expression may be distributed 90:10 rather than 50:50.

- If the X carrying the mutant allele remains active in most cells, a female carrier may express an X-linked disorder.

DIAGRAM ON SLIDE 38

How can somatic mosaicism produce a segmented or patchy phenotype?

The pattern depends on:

- The developmental stage at which the mutation occurred

- The somatic lineage in which it arose

- The descendants of that mutant cell

A mutation before germline and somatic lineages separate may:

- Be expressed mosaically in the individual's tissues

- Also enter the germline

- Be transmitted to offspring in non-mosaic form

What example of somatic mosaicism was given for ornithine transcarbamylase deficiency?

A boy had an unusually mild dysfunction of the hepatic urea cycle caused by ornithine transcarbamylase deficiency.

Molecular testing showed:

- A deletion in the OTC gene

- The deletion was present in only a proportion of his somatic cells

The mosaic distribution explained the milder phenotype.

What is germline mosaicism?

Germline mosaicism occurs when a mutation arises in a germline precursor cell and persists in its clonal descendants.

Consequences:

- A proportion of the parent's gametes carries the mutation.

- The parent's tested somatic cells may not contain the mutation.

- An apparently unaffected parent may transmit the same mutation to more than one child.

Why are there opportunities for new mutations to produce germline mosaicism before meiosis?

The germline undergoes mitotic divisions before meiosis:

- Approximately 30 divisions in females

- Hundreds of divisions in males

A mutation during one of these mitotic stages can be inherited by all descendant germ cells in that clone.

How does osteogenesis imperfecta illustrate germline mosaicism?

Severe lethal osteogenesis imperfecta may result from mutations in type I collagen genes.

Effects include:

- Abnormal collagen

- Brittle bones

- Frequent fractures

The lecture described two affected children with the same collagen-gene point mutation while:

- Their father was unaffected.

- The mutation was absent from examined paternal somatic tissues.

This is consistent with paternal germline mosaicism.

The lecture noted germline mosaicism in approximately 6% of severe lethal cases.

What are the main structural and genetic features of the human mitochondrial genome?

- Circular chromosome

- Approximately 16.5 kb

- 37 genes total:

- 13 protein-coding genes

- 2 rRNA genes

- 22 tRNA genes

- Most cells contain at least 1,000 mtDNA molecules distributed among hundreds of mitochondria.

- A mature oocyte contains more than 100,000 mtDNA copies.

What types of mitochondrial DNA change can cause human disease?

- Point mutations

- Rearrangements

Mitochondrial diseases have distinctive inheritance because of:

1. Replicative segregation

2. Homoplasmy and heteroplasmy

3. Maternal inheritance

What is homoplasmy?

Homoplasmy means the mitochondrial DNA molecules within a cell or individual are all of the same type, such as:

- All normal

or

- All mutant

What is heteroplasmy?

Heteroplasmy means normal and mutant mitochondrial DNA molecules coexist within the same cell or individual.

The proportion of mutant mtDNA is called the mutant load and can vary between cells and tissues.

What is replicative segregation of mitochondrial DNA?

During cell division:

- Mitochondrial DNA molecules replicate clonally.

- Normal and mutant mitochondria are distributed randomly to daughter cells.

- Daughter cells may therefore receive different proportions of mutant mtDNA.

Over successive divisions, cell lineages can develop very different mutant loads.

How does the mitochondrial threshold effect influence disease phenotype?

A cell may remain functionally normal while its mutant mtDNA proportion is below a threshold.

When mutant load exceeds the threshold for phenotypic expression:

- Mitochondrial function becomes inadequate.

- A disease phenotype appears.

Random replicative segregation can therefore produce normal and diseased cells within one individual.

DIAGRAM ON SLIDE 44

Why is mitochondrial DNA maternally inherited?

Sperm mitochondria are generally eliminated from the embryo after fertilisation.

Therefore:

- The embryo's mtDNA is inherited from the mother.

- Females can transmit mitochondrial mutations.

- Affected males do not transmit their mtDNA mutations.

What pedigree pattern suggests mitochondrial inheritance?

- An affected female may transmit the condition to all of her children.

- An affected male does not transmit the condition to any child.

DIAGRAM ON SLIDE 45

Why may a mitochondrial pedigree not show every child of an affected mother with the same phenotype?

Maternal inheritance may be complicated by:

- Heteroplasmy

- Replicative segregation

- Tissue-specific mutant loads

- Threshold effects

- Incomplete penetrance

- Variable expressivity

Therefore, the presence and severity of disease can vary.

What is penetrance?

Penetrance is the proportion or percentage of individuals with a particular genotype who express the expected phenotype.

Formula:

Penetrance = number of people with the phenotype ÷ number of people with the mutation or genotype

What is the difference between full and incomplete penetrance?

Full penetrance:

- 100% of people with the causative genotype express the phenotype.

- Huntington disease was given as an example.

Incomplete penetrance:

- Some people with the causative genotype do not express the expected phenotype.

- Polydactyly was given as an example.

What is expressivity?

Expressivity is the degree to which a phenotype is expressed once it is present.

It includes variation in:

- Number of clinical features

- Severity of clinical features

- Extent of anatomical or physiological abnormality

Expressivity may be influenced by additional genes and environmental factors.

How do penetrance and expressivity differ?

Penetrance asks:

- Does the phenotype appear?

Expressivity asks:

- How strongly or extensively is the phenotype expressed?

Possible patterns include:

- 100% penetrance with uniform expressivity

- 100% penetrance with variable expressivity

- Variable penetrance with variable expressivity

DIAGRAM ON SLIDE 48

What does the polydactyly pedigree demonstrate about incomplete penetrance?

Polydactyly is usually caused by a dominant allele.

In the pedigree:

- Q does not show polydactyly.

- Q has transmitted the dominant allele to two affected children.

- Q must therefore carry the allele despite lacking the phenotype.

For R:

- Phenotype alone cannot establish whether R inherited the allele.

- R could lack the allele or carry it without expressing it because penetrance is incomplete.

DIAGRAM ON SLIDE 49

How is penetrance calculated in the lecture's polydactyly example?

If:

- 50 people carry the polydactyly allele

- 41 show polydactyly

Then:

Penetrance = 41/50 × 100 = 82%

How does polydactyly demonstrate variable expressivity?

Different people carrying the allele may show:

- A fully formed, functional extra digit

- A small or incompletely developed extra digit

- Different numbers or distributions of additional digits

Incomplete penetrance and variable expressivity may result from modifier genes and environmental factors.

What is gene interaction?

Gene interaction occurs when genes at multiple loci determine one phenotype.

The effect of a gene at one locus depends on genes at other loci.

Products of different genes may combine to produce phenotypes that cannot be predicted from either locus alone.

What capsicum phenotypes were shown as an example of interaction between the Y and C loci? (NOT ASSESSABLE)

The four genotype classes shown were:

- Y⁺_ C⁺_ → red

- Y⁺_ cc → peach

- yy C⁺_ → orange

- yycc → cream

Lecturer explanation:

The lecturer said to understand the concept of genes at different loci interacting, but not to memorise the detailed capsicum example.

DIAGRAM ON SLIDE 53

What general biochemical mechanism can explain gene interaction?

Genes at different loci often encode enzymes acting at different steps of one biochemical pathway.

Therefore:

- The product of one reaction becomes the substrate for the next.

- Altering one enzyme can change downstream products.

- Combined activity at several loci determines the final phenotype.

What biochemical pathway was illustrated for capsicum colour? (NOT ASSESSABLE)

The illustrated pathway included:

- A precursor converted to phytoene by phytoene synthase

- Several intermediate enzymatic steps

- Formation of violaxanthin

- Conversion controlled by the C locus and capsanthin-capsorubin synthase

- Production of red and yellow pigments

- Final colour determined by the amount and combination of pigment

Lecturer explanation:

The detailed capsicum pathway was not required; the important concept is that loci can encode enzymes at different pathway steps.

DIAGRAM ON SLIDE 54

What is epistasis?

Epistasis occurs when a gene at one locus masks or modifies expression of a gene at another locus.

- The masking gene is epistatic.

- The masked gene is hypostatic.

- Epistasis may be recessive or dominant.

How does epistasis differ from dominance?

Dominance:

- Interaction between alleles at the same locus

- One allele masks another allele

Epistasis:

- Interaction between genes at different loci

- One locus masks or modifies the phenotypic effect of another locus

What alleles occur at the ABO or I locus in the epistasis example?

The ABO locus has:

- Iᴬ

- Iᴮ

- i

Iᴬ and Iᴮ encode different functional transferases.

The i allele encodes a nonfunctional transferase.

What is the role of the H locus in ABO antigen synthesis?

The H locus encodes a fucosyl transferase.

In HH or Hh individuals:

1. Fucosyl transferase adds fucose to a precursor.

2. This produces substrate H.

3. Substrate H is required before A or B transferase can form an A or B antigen.

DIAGRAM ON SLIDE 56

How are A and B antigens produced from substrate H?

Once substrate H has been produced:

- Transferase A adds the A-specific terminal sugar, forming A antigen.

- Transferase B adds the B-specific terminal sugar, forming B antigen.

Not assessable:

The lecturer explicitly said the individual sugar names do not need to be memorised.

DIAGRAM ON SLIDE 57

What did the lecturer emphasise about the enzymes in the ABO-H pathway?

Lecturer emphasis:

Remember the transferases rather than the individual sugar names.

- The H allele produces fucosyl transferase.

- Iᴬ produces A transferase.

- Iᴮ produces B transferase.

- These enzymes add sugars to the developing carbohydrate antigen.

What is the Bombay phenotype?

The Bombay phenotype occurs in an hh individual.

Because hh produces defective or absent fucosyl transferase:

- Substrate H is not formed.

- A or B transferase has no substrate on which to act.

- No A or B antigen is displayed, regardless of the person's ABO-locus genotype.

DIAGRAM ON SLIDE 58

Why does an ii individual have blood group O when a functional H allele is present?

The i allele encodes a nonfunctional ABO transferase.

In an H_ ii individual:

- Substrate H is produced.

- No functional A or B transferase is produced.

- No A or B sugar is added.

- The phenotype is blood group O.

DIAGRAM ON SLIDE 59

How can an apparent blood group O phenotype arise through two different genetic routes?

1. H_ ii:

- Substrate H is present.

- No functional A or B transferase is present.

- No A or B antigen is added.

2. hh with any ABO genotype:

- Substrate H is absent.

- A or B transferases cannot act, even if Iᴬ or Iᴮ is present.

- This is the Bombay phenotype.

Why is the H locus an example of recessive epistasis over the ABO locus?

The recessive genotype hh prevents production of substrate H.

Without H:

- The products of Iᴬ and Iᴮ cannot be expressed as A or B antigens.

- The ABO alleles are hypostatic to hh.

- The H locus is epistatic to the I locus.

This is recessive epistasis because masking requires homozygosity for h.

What general pathway principle is illustrated by recessive epistasis in ABO blood groups?

A gene acting at an early step in a pathway can be epistatic to genes acting at later steps.

The effects of later genes depend on the product of the earlier reaction.

In the ABO pathway:

1. H_ produces substrate H.

2. Iᴬ or Iᴮ modifies H to form A or B antigen.

3. hh blocks the first step and prevents all downstream A/B expression.

What should you identify in the final H-locus and ABO-locus pathway diagram?

- An intermediate precursor

- H_ producing compound or substrate H

- hh bypassing substrate H formation and producing no A or B antigen

- Iᴬ converting H into A antigen

- Iᴮ converting H into B antigen

- ii leaving H without A or B antigen

- A and B antigens differing in their terminal sugars

- The conclusion that genotypes at both the H and ABO loci determine observed blood type

DIAGRAM ON SLIDE 61

What is the overall relationship between the H and I loci?

H is epistatic to I because it controls whether the I-locus products can be phenotypically expressed.

Full expression of Iᴬ or Iᴮ requires at least one functional H allele.

Therefore, ABO blood type is determined by the combined genotype at:

- The H locus

- The I or ABO locus