Patterns of inheritance

• Gregor Mendel’s experiments on pea plants in the 1860s: laws of meiosis without knowledge of chromosomes.

• Locus: a unique chromosomal location of a gene or DNA sequence.

• Alleles: alternative versions of a gene.

• Genotype: alleles present at one or more loci.

• Phenotypes, characters, traits: observable properties of an organism.

DEFINITIONS TO REMEMBER:

Monogenic versus multifactorial inheritance:

What is the difference between oligogenic and polygenic inheritance?

Polygenic inheritance

• Many genes are involved (often dozens to hundreds).

🔹 Oligogenic inheritance

• Few genes are involved (usually 2–5).

Great question — this slide is contrasting monogenic vs polygenic traits and introducing the idea of dichotomous vs continuous traits. Let’s break it down clearly.

🔹 What does dichotomous mean?

Dichotomous = two mutually exclusive categories.
There are only two possible outcomes, and you’re either in one or the other.

Think:

• Yes / No

• Affected / Not affected

• Present / Absent

There is no in-between.

Examples of dichotomous traits:

• Huntington's disease (you either have it or you don’t)

• Cleft palate (present or absent)

• Blood type A vs not A

🔹 Mendelian (Monogenic) Traits = Usually Dichotomous

Monogenic traits are caused by one gene with a strong effect.

Because one gene determines the outcome, the trait often looks:

• Clear-cut

• Binary

• Either present or absent

That’s why the slide says:

🔹 Polygenic Traits = Usually Continuous

Polygenic traits involve many genes, each contributing a small effect.

Instead of two categories, you get a range.

Continuous traits (quantitative traits):

• Height

• Weight

• Blood pressure

• Intelligence

You don’t fall into just two groups — you fall somewhere along a spectrum.

These are influenced by:

• Many small-effect genes

• Called Quantitative Trait Loci (QTLs)

🔹 But Some Polygenic Traits Are Still Dichotomous

This is an important point.

Some diseases (like type 2 diabetes) are:

• Influenced by many genes

• BUT still diagnosed as yes/no

You either:

• Have diabetes

• Or don’t

However, genetically, it’s not caused by one gene — it’s due to many susceptibility genes that increase your risk, not guarantee disease.

So genetically → continuous risk
Clinically → dichotomous outcome

This is called a threshold trait.

🔹 Complex Traits

Some conditions (like diabetes) can:

• Be monogenic (rare cases)

• Be polygenic (most cases)

• Be strongly environmentally friendly

• Or a combination

These are called complex traits because:

• Multiple genes

• Environmental factors

• Lifestyle
  all interact.

🔎 Simple Summary

🧠 Big Idea

• Monogenic → usually dichotomous

• Polygenic → usually continuous

• Some polygenic traits are dichotomous in diagnosis but continuous in genetic risk.

DEFINITIONS TO REMEMBER:

WHAT IS A PROBAND?

How do you know it is Autosomal dominant inheritance?

• Autosomal because both sexes are affected equally.

• Dominant because there is an affected individual in every generation.

How to know it is autosomal recessive inheritance:

• Autosomal because both sexes are affected equally.

• Recessive because not every generation has an affected individual in every generation.

Key notes:

• It mainly affects males: a hemizygous state.

• Affected males are usually born to unaffected parents because the parents are heterozygous.

• Females are only affected if their father is affected and their mother is a carrier.

• No male-to-male transmission

  

The males get their X chromosome from the mothers and the Y chromosome from the fathers.

• Affects either sex, but slightly more females.

• At least 1 parent is usually affected.

• Females are more mildly and more variably affected than males.

• Children of affected females.

• Affected males pass the traits to all daughters but none of the sons.

• This is very rare

• Affects only males.

• Affected males always have an affected father; all sons of an affected father are affected.

🔎 1. Why identifying inheritance can be tricky

“Human families are often too small…”

Unlike pea plants (Mendel), human families:

• Have a few children

• Don’t produce clear ratios (like 3:1)

Also, we often study families because someone is affected, which creates ascertainment bias (we’re not sampling randomly).

So patterns are sometimes harder to see.

🔹 2. Dominant diseases: why are most affected people heterozygous?

In autosomal dominant diseases:

• One mutant allele is enough to cause disease.

• Most affected individuals are heterozygous (Aa).

Why not homozygous (AA)?

Because:

• A homozygous dominant is often very severe or lethal.

• Or extremely rare.

📌 Example: Huntington'sis disease

In Huntington's disease:

• Homozygotes and heterozygotes look very similar clinically.

• So it behaves as a classic dominant disorder.

🔹 3. Achondroplasia example

Achondroplasia (short-limbed dwarfism):

• Heterozygous (Aa) → short stature

• Homozygous (AA) → usually lethal shortly after birth

This shows:

• The condition is dominant

• But the homozygous state is much more severe

This helps explain the next concepts.

🔹 4. Incomplete dominance (semi-dominance)

Definition:
The heterozygote has a phenotype between the two homozygotes.

Example pattern:

So the heterozygote is intermediate.

Achondroplasia shows this at the biological level:

• aa = normal

• Aa = dwarfism

• AA = lethal (more severe)

🔹 5. Codominance

Definition:
Both alleles are expressed independently.

Classic example:

• ABO blood group

• IA and IB are both expressed

Here:

• No blending

• Both products are visible

🔹 6. Why is achondroplasia still called dominant

Even though:

• Homozygotes are more severe (lethal)

Clinically:

• If you have one mutant allele, you have the disease.

So in practice:

• It is labelled autosomal dominant.

🧠 Big Concepts From This Slide

1. Dominant diseases usually involve heterozygotes

2. A homozygous dominant may be rare or lethal

3. Incomplete dominance = intermediate phenotype

4. Codominance = both alleles expressed

5. Real human genetics is often more complex than simple Mendelian patterns

Waardenburg Syndrome

Waardenburg syndrome (WS) is a genetic condition that mainly affects:

• 👂 Hearing

• 🎨 Pigmentation (eyes, hair, skin)

It is most commonly autosomal dominant, though some rare types can be autosomal recessive.

🧬What is Variable Expression?

Variable expressivity means:

They all have the mutation.
They all technically “have” the disease.
But the severity and features vary.

Anticipation

• This is the tendency of a disease to become more severe and/ or have an earlier onset in successive generations.

• True anticipation: characteristic of dynamic mutations.

• False impression of anticipation: due to a systematic bias of ascertainment in the dominant conditions showing variable expression (parents only turn to genetic counselling when their child is more severely affected than they are, while severely affected individuals may not have children at all.

• Solutions: statistical methods or direct molecular evidence.

“Inbreeding may make pedigrees less informative”

What is inbreeding?

Mating between relatives (e.g., cousins).

Relatives share genes from common ancestors.

So if there is a harmful recessive allele in the family:

• It becomes more common

• The chance of two carriers mating increases

• More affected children appear

This can make the pattern look misleading.

🔹Why this matters in X-linked recessive disorders

Normally, in X-linked recessive:

• Mostly males affected

• No male-to-male transmission

• Females are usually carriers

But with inbreeding:

🔸 A female can become affected

How?

If:

• Her father is affected (XᵃY)

• Her mother is a carrier (XᵃX)

She can inherit:

• Xᵃ from dad

• Xᵃ from mom

→ XᵃXᵃ = affected female

This is rare in the general population, but more likely with consanguinity.

🔹 False impression of male-to-male transmission

Normally:

• X-linked recessive has NO father → son transmission

But in consanguinity:

You might see:

• An affected male

• His male cousin was also affected

This can look like father → son transmission
But actually:

• The mutation is coming through carrier females

• The males just share the same inherited mutation from a common ancestor

So it can look autosomal recessive, even though it’s X-linked.

🔹Why it may be misinterpreted as autosomal recessive

Autosomal recessive traits:

• Affects males and females equally

• Often appear in consanguineous families

If you see:

• Affected males

• Affected females

• Related parents

You might think: autosomal recessive.

But it could actually be:

• X-linked recessive + consanguinity

🧠 Big Takeaway

Inbreeding increases the chance that:

• Rare harmful alleles meet

• Females become affected in X-linked disorders

• Pedigrees look “non-classical”

So inheritance patterns may be misleading.

PATTERNS OF INHERITANCE II. MOSAICISM, NEW MUTATIONS, NON-MENDELIAN CHARACTERS:

Classification of genetic changes:

• Constitutional: these genetic changes are present in all cells of the body. It originates from a germ-line mutation.

• Mosaic: present only in a particular cell line due to an event at some point during development; may be somatic, gondal or germinal or gonosomal (i.e. involving both somatic and germline cells.

MOSAICISM

🧬 What is Mosaicism?

Mosaicism = one person has two (or more) genetically different cell populations.

This happens when:

• A mutation occurs after fertilisation (not in the egg or sperm),

• During early cell divisions of the embryo.

So some cells carry the mutation, and others don’t.

🔹 “The number and type of affected cells depend on timing”

The earlier the mutation happens:

• More cells will carry it

• A larger part of the body is affected

The later it happens:

• Fewer cells affected

• Maybe only one tissue is

• involved

Example:

• Mutation at 2-cell stage → ~50% of body cells affected

• Mutation later → maybe only skin cells affected

So timing determines:

• How many cells are mutant

• Which tissues are involved

🔹 “Lethal conditions may be compatible with life in mosaic form”

Some mutations are so severe that:

• If every cell had it → the embryo would die

But if only some cells have it:

• The normal cells compensate

• The person survives

So mosaicism can “soften” a lethal mutation.

🔹 Revertant Mosaicism (Back-mutation)

This is fascinating.

If someone has a mutation in all cells (constitutional mutation):

Sometimes:

• A cell randomly “corrects” the mutation

• That corrected cell divides

• It may grow better than the defective cells

So you get patches of normal tissue inside abnormal tissue.

Example:

• Some genetic skin disorders show normal skin patches due to revertant mosaicism.

It’s like the body partially fixes itself.

🔹 Diffusible vs Cell-Autonomous Effects

This is about how the gene product works.

🟢 Diffusible gene product

The protein:

• Can move between cells

• Can help neighbouring cells

Example:

• Hormones

• Some enzymes

If only some cells produce it, nearby cells might still benefit.

→ The mosaicism effect is milder.

🔵 Cell-autonomous gene product

The protein:

• Only works inside the cell, which makes it

• Cannot help neighbouring cells

If a cell has the mutation:

• That cell alone is affected

• No rescue from nearby normal cells

→ The mosaicism effect is more visible.

This slide is about new (de novo) mutations and how they affect inheritance patterns.

Let’s go through it clearly and logically.

🧬 “A normal parent produced a single mutant gamete… or was mosaic”

When a child has a genetic disease, but:

• Both parents are clinically normal

• No family history

We often assume:

That’s called a de novo mutation.

BUT — sometimes:

The parent may actually have germline mosaicism.

Meaning:

• Some of their egg/sperm cells carry the mutation

• Their body cells don’t

• They appear completely normal

This explains:

• More than one affected child

• Despite normal parents

So it wasn’t just “one random sperm” — it may have been mosaic in the parent.

🧬 Natural selection removes severe dominant and X-linked mutations

If a mutation is:

• Very harmful

• Reduces survival or reproduction

Then affected individuals:

• Often don’t reproduce

• Don’t pass it on

So the mutation disappears from the population.

But we still see these diseases.

Why?

Because:

This is calledthe mutation–selectionn balance.

🧬 3⃣ Lethal dominant conditions arise from new mutations

If a dominant mutation is:

• Lethal before reproduction

Then:

• The affected person cannot pass it on

• It must arise as a new mutation each time

Example concept:

• Some severe skeletal dysplasias

So:

No inheritance across generations
Only fresh mutations

🧬 X-linked recessive and selection

In severe X-linked recessive diseases:

• Affected males often have reduced reproduction

• So they don’t pass the mutation on

This means:

• Many cases arise from new mutations

• Especially in severe conditions

🧠 Big Concepts Behind This Slide

🔹 De novo mutation

A mutation that appears for the first time in a child.

🔹 Germline mosaicismThe parentt is normal but has some mutated reproductive cells.

🔹 Mutation–selection balance

Bad mutations are removed by selection,
But new ones constantly appear.

🔹 Lethal dominant disorders

Usually, only seen as new mutations.

✨ Simple Summary

🔎 The Core Message

Even if a disease is genetic:

• It doesn’t always come from a family history.

• Many severe disorders exist because new mutations keep arising.

🧬 Germline (Germinal) Mosaicism

Definition:
A person has a mutation in some of their sperm or egg cells, but not in their body (somatic) cells.

So:

• The parent is healthy.

• Blood test = normal.

• But they can still have affected children.

Why does the slide say:

For fathers:

• You can directly test sperm.

• You might estimate what fraction carries the mutation.

For mothers:

• You cannot test egg cells easily.

• So maternal germline mosaicism is very hard to detect directly.

That’s why it says “not possible to detect in mother.”

🧬 Testing Different Cell Types

If a blood test is negative, that does NOT rule out mosaicism.

Why?

Because:

• The mutation might not be in the blood.

• It might only be in:

  • Skin

  • Brain

  • Gonads

  • A small subset of cells

So sometimes doctors test:

• Blood

• Skin biopsy

• Tumour tissue (in cancer)

Different tissues may show different results.

🧬 Detecting Small Amounts of Mutant DNA

This is a technical problem.

Imagine:

• 95% normal cells

• 5% mutant cells

When you test DNA:

• The normal DNA overwhelms the mutant DNA.

• The mutation signal may be very weak.

So detection depends on:

• Sensitivity of the method

• Depth of sequencing

This is especially important in:

• Cancer tumour cells mixed with normal cells)

• Low-level mosaicism

🧠 Big Challenges in Detecting Mosaicism

✨ Core Message of the Slide

A normal genetic test does NOT always mean:

• No mutation exists.

It might mean:

• The mutation is present in only a small number of cells

• Or only in germ cells

🔎 Clinical Importance

This matters because:

• Parents with normal testing can still have a recurrence risk.

• Cancer detection depends on identifying small mutant clones.

• Negative blood tests don’t always exclude mosaicism.

• Important parameters of Gaussian curves = mean and variance.

• Standard deviation = the square root of variance.

• Variances are additive.

• Vp = V_G + V_E

• Vp = total variance of a phenotype; Vg = genetic variance. Ve = environmental variance.

• h² = Vg/Vp = Vg/Vg+Ve.

WHAT IS HERITABILITY?

It is the proportion of the overall variance of a character that is due to genetic differences.

🌡 Think of it like a cup filling with water

• Everyone has a certain risk level for a disease or trait.

• That risk comes from:

  • Many small-effect genes

  • Environment (diet, stress, smoking, etc.)

This risk builds up gradually — like water filling a cup.

🚨 The “threshold” is the tipping point

• If the water doesn’t reach the top, nothing happens → you’re unaffected.

• If the water crosses the top (threshold) → the disease appears.

So even though the outcome is yes or no (you have it or you don’t),
the underlying risk is gradual and continuous.

🧬 Example 1: Cleft palate

• Many small genetic + environmental factors increase risk.

• But in the end, the baby either:

  • Palatal shelves fuse → normal

  • Don’t fuse → cleft palate

• The fusion only fails if the risk passes a certain threshold.

❤ Example 2: Blood pressure

• Blood pressure varies continuously.

• But we call it hypertension only if it crosses a certain number (e.g., 140/90).

• That number acts like a threshold.

🧠 One-line summary:

What happens to the siblings of an affected person?

Compared to the general population;

• Their entire bell curve is shifted slightly to the right.

Key Note:

• Compared to the general population, the probability for the sibling to be affected is more to the right.

• The probability that the sibling of an affected girl is affected is much higher than the probability that the sibling of an affected boy is affected.