ad/ar inheritance

Basic unit of heredity

A specific DNA sequence that codes for a protein or functional RNA.

Gene

A specific copy or variant of a gene. Different versions of a gene found at the same locus.

Allele

The genetic constitution of an individual at a given locus (e.g., AA, Aa, aa).

Genotype

The observable, physical, or clinical trait actually expressed (e.g., detached earlobe, disease symptoms).

Phenotype

Two identical dominant alleles (e.g., AA) can be termed

Homozygous Dominant (Genotype)

Two different alleles (one dominant, one recessive) (e.g., Aa) can be termed

Heterozygous (Genotype)

Two identical recessive alleles (e.g., aa).

Homozygous Recessive (Genotype)

concept that genes occur in pairs, and only one gene (allele) from each pair is transmitted to offspring

Mendel's Principle of Segregation

concept that proves that genes are NOT BLENDED in offspring; they remain intact and distinct

Mendel's Principle of Segregation

concept that says genes at different loci (on different chromosomes or far apart on the same chromosome) are transmitted independently of each other.

Mendel's Principle of Independent Assortment

all traits are NOT LINKED; offspring don't inherit ALL the same traits as a parent.

Mendel's Principle of Independent Assortment

Autosomal Dominant (AD) Inheritance: Key Features

-Vertical Transmission (phenotype seen in every generation).

-Recurrence Risk: 50% for offspring of an affected heterozygous parent.

-Parental Status: Every affected person has an affected parent.

-Carrier Status: Unaffected family members cannot pass the gene on.

-Sex Ratio: Males and females equally affected; male-to-male transmission is possible.

Autosomal Recessive (AR) Inheritance: Key Features

-Transmission: Typically Horizontal (condition found only in siblings, usually not in earlier generations)

-Recurrence Risk: 25% for offspring of two carrier parents.

-Parental Status: Affected individuals usually have unaffected parents (who are typically carriers).

-Sex Ratio: Males and females equally affected.

-Consanguinity: More likely if parents are related (increases chance both carry the same rare recessive gene)

Consanguinity makes these conditions more probable

Autosomal recessive

X-Linked Transmission Pattern

Affected father cannot pass X-linked traits to sons.

Affected father passes X-linked traits to all daughters (who become carriers or affected).

Carrier mother has 50% chance of passing trait to sons (affected) and 50% chance to daughters (carrier).

Males (XY): Express a single recessive allele on the X.

Females (XX): Have two X chromosomes; usually need ___ copies of a recessive allele (or one dominant) to express fully.

two

-a concept that says one gene is not completely dominant over another.

-resulting in a 3rd, intermediate phenotype that is a blending of the two alleles.

ex: Red + white carnations = pink flowers. Human height.

Incomplete Dominance

- describes when both alleles are individually and distinctly expressed (not blended) in the heterozygote.

- resulting in both parent phenotypes showing up together.

ex: Red + white flowers = patches of red and white (mosaic pattern). ABO blood group (A and B alleles are codominant, leading to AB blood type). Calico cats.

Codominance

external factors can significantly influence whether a genetic predisposition manifests as a disease.

Example: Phenylketonuria (PKU) - a specific diet (environmental modification) prevents severe mental retardation despite the genetic mutation.

Environmental Factors (affecting gene expression)

A new mutation occurs spontaneously in the germline of an unaffected parent, leading to an affected child.

- Neither parent is affected.

De Novo Mutation

De novo mutation pedigree clue

A child with an autosomal dominant condition, but no family history in prior generations.

De novo mutation recurrence is low unless

germline mosaicism is present

A parent is phenotypically unaffected, but a mutation is present in a proportion of their germ cells, but not in their other body cells.

Germline Mosaicism

Germline mosaicism pedigree clue

An unaffected parent has multiple offspring with the same autosomal dominant or X-linked condition.

Examples of this transmission pattern are in these diseases: Osteogenesis Imperfecta, Achondroplasia, Duchenne Muscular Dystrophy, Hemophilia A

Germline mosaicism

An 'all or none' phenomenon: A person has the genotype for a condition but does not develop the expected phenotype.

-It is not 100% penetrant.

Reduced (Incomplete) Penetrance

Reduced (Incomplete) Penetrance pedigree clue

A dominant condition may appear to 'skip generations'

Reduced (Incomplete) Penetrance disease examples

Retinoblastoma (10% of carriers never develop a tumor), BRCA1/BRCA2 (carriers have high risk but not 100% certainty of cancer)

A person carries a gene change, but the phenotype for the condition does not develop until later in life.

- Ex: Huntington's Disease (onset typically 30-50 years).

Age-Dependent Penetrance

People with the same genetic disorder can present with a spectrum of symptoms, ranging from few/mild to many/severe, or different combinations of traits.

-Ex: NF1 - wide range of birthmarks, tumors, eye lesions, with varying severity.

Variable Expression

Genes that interact with other genes to modify the phenotype. A change in one gene might not cause disease on its own, but in combination with mutations in other genes, it leads to a more severe phenotype or causes the disease.

Modifier Loci (Modifier Genes)

Different types of mutations within the same gene can lead to different phenotypes, different disease severity, or even different inheritance patterns.

Allelic Heterogeneity

Examples of Allelic Heterogeneity

-Familial Isolated Growth Hormone Deficiency (loss-of-function mutations are recessive; missense/dominant-negative mutations are dominant)

-Cystic Fibrosis (different mutations lead to lung vs. digestive vs. infertility issues)

Mutations in multiple different genes can all result in the same phenotype

Locus Heterogeneity

Examples of Locus Heterogeneity

- Lynch Syndrome (MLH1, MSH2, MSH6, PMS2 mutations all cause increased cancer risk)

- Autosomal Dominant Polycystic Kidney Disease (PKD1, PKD2 mutations both cause ADPKD)

- Osteogenesis Imperfecta (COL1A1, COL1A2 mutations both cause OI)

A mutation in a single gene affects multiple parts of the body or different body systems

- Ex: Marfan Syndrome (affects eye, skeleton, cardiovascular system from one gene).

- NF1 (pigmentary changes and nerve tumors from one gene).

Pleiotropy

Example of diseases with different presentations in their dominant & recessive phenotypes

- Achondroplasia (heterozygous: dwarfism; homozygous: severe/lethal).

- BRCA2 (one copy: cancer risk; two copies: Fanconi Anemia).

Graphical representation of family history; a tool for diagnosis, assessing risk, establishing inheritance patterns, identifying at-risk members, calculating risks, patient education.

Pedigree

Key Info in Pedigree

Names/initials, DOB/age, date/age at death, health conditions, causes of death, incidences of MR/DD, birth defects, genetic test results, ethnic background.

A genetic condition caused by an expansion of a specific three-base DNA sequence that is repeated too many times within a gene, making it unstable and dysfunctional.

Ex: Huntington's Disease (CAG repeat)

Triplet Repeat Disorder

A pattern of inheritance in autosomal recessive conditions where a person with a recessive disorder (homozygous recessive; aa) mates with a person who is a carrier (heterozygous dominant; Aa) making the recurrence risk = 50%

Quasidominant Inheritance

A specific mating pattern for an autosomal recessive condition that makes the pedigree appear to follow a dominant inheritance pattern.

Quasidominant Inheritance

Recurrence Risk in Quasidominant Inheritance

50% chance for each child to be affected.

Parents, children, siblings (share 50% genes) are what degree relatives

1st Degree

Aunts/uncles, nieces/nephews, grandparents, grandchildren (share 25% genes) are what degree relatives

2nd Degree

First cousins (share 12.5% genes) are what degree relatives

3rd Degree

Mating between related individuals.

Consanguinity

Significance of Consanguinity

significantly increases the chance that both parents will carry the same rare recessive mutation, thus increasing the risk of autosomal recessive disorders in offspring

Calculates the probability that two relatives share the same specific gene in common by descent from a common ancestor.

Coefficient of Relationship

Pedigree Symbol: Male vs Female

Male -> square

Female -> circle

A line through the individual symbol (square/circle) on a pedigree means

Deceased

Shaded (filled in) square or circle on pedigree means

Affected Individual

Half-shaded square or circle, or a dot in the center on a pedigree means

Carrier (for recessive traits)

Arrow pointing to the individual symbol on a pedigree means

Proband (Index Case)

Two individual lines originating from the same point on the sibship line, connected by a horizontal line between them on a pedigree means

Identical Twins

Two individual lines originating from the same point on the sibship line, but without the horizontal line connecting them on a pedigree means

Fraternal Twins

A small triangle on a pedigree means

(If affected, it's shaded)

Pedigree Symbol: Spontaneous Abortion (SAB) / Miscarriage

A small triangle with a line through it on a pedigree means

(If affected, it's shaded)

Pedigree Symbol: Termination of Pregnancy (TOP)

history of genetics

principle of segregation and theory of independent assortment

gregor mendel

history of genetics

structure of DNA

Watson & Crick

history of genetics

family and twin studies

Francis Galton

A man who has achondroplasia (which is an autosomal dominant condition) marries a phenotypically normal woman

If they have four children, what is the probability that none of their children will be affected with this disorder?

What is the probability that all of them will be affected?

.

Retinoblastoma is an autosomal dominant condition.

The estimated penetrance for familial retinoblastoma is approximately 90%

If a man has been affected with familial retinoblastoma and mates with a woman who does not have a retinoblastoma mutation, what is the risk that their offspring will develop retinoblastoma?

A 30-year old woman had a sister who died from infantile Tay-Sachs disease, an autosomal recessive disorder that is fatal by age 6 years.

What is the probability that this woman is a heterozygous carrier of the Tay-Sachs mutation?

A man has NF1, which is autosomal dominant. His mother also has this condition.

What is the probability that is sister also has NF1?

In the absence of knowledge of his sister’s phenotype, what is the probability that his sister’s daughter has NF1?

Consider a woman who is a known heterozygous carrier of a mutation that causes PKU (autosomal recessive)

What is the probability that her two grandchildren, who are 1st cousins, are both heterozygous carriers of this PKU-causing allele?

Suppose instead that the woman is affected with PKU. Now what is the probability both of her grandchildren carry the disease-causing allele?