Mendelian Genetics (Mod. 5)

What is the definition of “mendelian genetics”?

The study of inherited single gene disorders and overall autosomal inheritance

What is the most common kind of genetic disorder?

Autosomal RECESSIVE inheritance

What are the three main classes of gene mutations?

1) Insertions

2) Deletions

3) Point mutations

What is the main difference between insertion/deletion mutations and point mutations?

Deletion/insertions involve and effect hundreds of genes… point mutations only effect a single gene

What are the three different kinds of point mutations?

1) Change in amino acid

2) Stop codon

3) Silent mutation

What is the difference between germ line mutations and somatic cell mutations? Which one is more significant?

Germ line mutations - means that the mutation is carried in a germ cell (gamete; egg or sperm)

• The mutation carried in the sperm or egg will be passed down to EVERY cell throughout the body

Somatic cell mutations - Mutation arises in one cell and is passed only to those daughter cells

• Will either result in apoptosis of the cell, or give rise to a tumor

Germ line mutations are much more significant clearly

Terminology time!! Define allele:

The two copies of a gene that arises from mutation

Define phenotype:

The physical appearance of the animal

Define Genotype:

Genetic makeup of the animal

Define Homozygous:

When both alleles at a locus are the same (AA, aa)

Define Heterozygous:

When the alleles on the same locus are different (Aa)

Gene dosage is the number of copies of a particular gene present in a genome. In the cases of X-linked genes, males only have 1 copy of every X-linked gene (XY) whereas females have 2 copies of every X-linked gene (XX)… how do we overcome this dosage difference between sexes?

Dosage compensation

• The process by which organisms equalize the expression of genes between members of different biological sexes

  • Does this by silencing (inactivating) one of the X chromosomes in females (whether it is the maternal or paternal X that is silenced is randomly chosen initially)

  • All cells descending from that cell with the silenced X will silence the SAME X chromosome as it is passed down

This ensures that the product levels for genes of the X chromosome are similar in both sexes

What is a real world example of the gene compensation effect (X inactivation)?

Calico cats

Explain WHY calico cats are generally only females and how their coat color works.

POSSIBLE EXAM Q

The allele that expresses orange hair in cats is an X-linked allele, Xa

The allele that expresses NON-orange hair is ALSO an X-linked allele, Xb

• In order for a cat to have both of these alleles, it MUST be a heterozygous female (XaXb)

The calico coloration is caused by the RANDOM inactivation of either X chromosome

• Approx. 50% will deactivate Xa, and the others will deactivate Xb, giving the coat color a “patchy” appearance

What is the definition of aneuploid? (also from last genetics lecture)

Aneuploid: an animal with a change in normal chromosome number (X0, XXX, XXY)

Why is X chromosome aneuploidy usually tolerated well, and not a deadly abnormality?

Because of the X chromosome inactivation mechanism… will inactivate all X chromosomes except for 1

• These inactivated X chromosomes can be detected as Barr bodies (dark-staining bodies) in cells

So therefore:

• XX = one Barr body

• XXX aneuploidy = TWO Barr bodies

• XXY aneuploidy = one Barr body

If X chromosome inactivation makes X chromosome aneuploidy tolerable, why does it still result in disease?

Because of pseudochromosomal regions found on both X and Y chromosomes

• These contain genes that ESCAPE CHROMOSOMAL INACTIVATION

So in a normal individual, whether they are XX or XY, they will both express 2 copies of these genes found in the pseudochromosomal regions

But in cases of X chromosome aneuploidy, they will express an abnormal number of these genes found in the pseudochromosomal regions

• X0 = one dose of pseudochromosomal region genes expressed

• XXY = THREE doses of pseudochromosomal region genes expressed

THIS causes the disease

Describe what the results would be in a simple monohybrid cross. For example, in cattle:

Say P= polled, dominant trait; p = horned, recessive

If a homozygous, horned cow (pp) mates a homozygous, polled cow (PP), what will the genotypic and phenotypic ratio of the calves be?

PP = 25%

Pp = 75%

So 100% of the calves in this breeding pair will be POLLED

Describe what happens in Autosomal Recessive (AR) Inheritance (the most common genetic disorder) from a genetic perspective.

In this case, the mutation occurs on the recessive allele of the individual

• For the disease to actually be present (and not just be carried in an individual) that person must inherit BOTH mutant alleles from BOTH parents

  • Essentially, both parents have to be carriers

Say you have heterozygous male and female carriers: Aa* and Aa*

Their offspring would be:

• AA = unaffected (25% chance)

• Aa* = carriers (50% chance)

• a*a* = AFFECTED (25% chance)

What are the 4 key features of Autosomal Recessive Inheritance?

1) Both males and females have the condition with equal frequency

2) 1 in 4 chance of the offspring being affected by the disease

3) Appears in one generation and NOT in the parents (horizontal pattern)

4) Both parents of affected offspring MUST be carriers (assumed to be heterozygous)

Why is inbreeding of animals dangerous from a genetic perspective?

Because it brings together recessive alleles, which increases the incidence/chances of genetic disease

What is an example of AR inheritance disease in horses? What is the cause of the mutation, and what effects does it have on the individual?

Severe Combined Immunodeficiency Disease (SCID)

• Cause of disease: frameshift deletion

  • DNA-dependent kinase gene mutated

Effects:

• This gene functions to manufacture B and T lymphocytes

• The mutation totally inactivates the gene’s function; results in lack of immunity

• Lethal inability to fight infections causing death within first few months of life

What is an example of an AR inheritance disease in dogs? What is the cause of the mutation, and what effects does it have on the individual?

Pyruvate kinase deficiency

• Cause of disease: mutation in pyruvate kinase gene

• RESULTS IN: shortened lifespan of the RBC, leading to severe hemolytic anemia

Symptoms:

• Begin to show symptoms between 4 months and 1 year… weakness, lack of energy, rapid heart rate, heart murmurs, pale gums, and stunted growth

• Animal will die before 4 years of age

What is genetic heterogeneity?

Where a single disease or condition can be caused by any number of gene mutations in a species

• Example: Pyruvate kinase deficiency is caused by a single nucleotide deletion in Basenjis, but in Pugs, its caused by a T>C insertion

What is an example of an AR inheritance disease in cows? What is the cause of the mutation, and what effects does it have on the individual?

Double muscling / muscle hypertrophy

• An overdevelopment of the muscles in beef breeds… THIS IS SELECTIVELY BRED FOR

Caused by:

• Myostatin gene mutation

  • Results in NO myostatin, which allows for an increase in muscle with little fat deposition

What is Autosomal Dominant Inheritance?

A genetic disease wherein the mutation is in the DOMINANT allele

• In this, ALWAYS ASSUME THE MALE IS AFFECTED WHILE THE FEMALE IS UNAFFECTED

Male = A*a (affected)

Female = aa (unaffected)

Offspring would be:

• A*a (affected; 50%)

• aa (unaffected; 50%)

What is an example of an AD inheritance disease in horses? What is the cause of the mutation, and what effects does it have on the individual?

Hyperkalemic periodic paralysis (HYPP)

• Cause: missense mutation in sodium ion channel gene on muscle cells

  • Results in uncontrolled sodium influx into muscle cells

Effects:

• Muscle paralysis, intermittent muscle weakness, spasms, profuse sweating, and increased respiratory rate

What is an example of an AD inheritance disease in cats? What is the cause of the mutation, and what effect does it have on the individual?

Polycystic Kidney Disease

• Cause: C>A mutation in the PKD1 gene, results in a stop codon

  • Causes los of part of the PKD1 protein

Effects:

• Causes death due to kidney failure

• Symptoms appear later in life, so don’t know NOT to breed affected cats until its too late

• Most are heterozygous, but those that are homozygous die before birth (LETHAL)

• MOST COMMONLY INHERITED CONDITION IN CATS

What are the 4 key features of AD inheritance disease?

1) Males and females have the condition with equal frequency

2) Each child of an affected individual has a 50% chance of being affected

3) Affected offspring have an affected parent (means EVERY generation affected; vertical transmission)

4) Unaffected individuals do not have children with the condition

Describe the key characteristics of X-linked RECESSIVE Inheritance

NO MALE TO MALE TRANSMISSION… for a son to have it, mother needs to be affected (or a carrier; son gets X chromosome from mother)

Despite this being a RECESSIVE disease, sons only need ONE diseased X chromosome to be affected

• For daughters, though, need both X chromosomes to be diseased for them to be affected (both father and mother need to be affected/carriers)

  • Otherwise, are just carriers

X*Y affected father, X*X carrier mother =

• X*X* affected daughter

• X*X carrier daughter

• X*Y affected son

• XY normal son

Describe the key characteristics of X-linked DOMINANT Inheritance

AGAIN, NO MALE TO MALE TRANSMISSION

• Son MUST get affected chromosome from mother

NO FEMALE CARRIERS… ALL DAUGHTERS ARE AFFECTED

• Since its dominant, only need 1 affected X chromosome

Males are usually more severely affected by the disease, but there are more affected females than males

******* Very few actual examples, very rare in animals

What is mitochondrial inheritance?

A MATERNALLY inherited genetic condition (remember… mt → MaTernal)

• Mitochondria is only present in the egg, and not in the sperm, so mtDNA is only in the mother

ALL offspring of an affected mother have this disease… on the other side, affected males CANNOT spread the disease (no mitochondria in sperm)

What is incomplete penetrance?

Incomplete penetrance = when an individual CARRIES a DOMINANT inherited disease, but DOESN’T EXPRESS IT

Is an “all or none” phenomena amongst dominant genetic conditions

What is an example of co-dominance / incomplete dominance?

Both alleles are expressed at the same time in a heterozygous individual

• ex: roan coloration in animals

  • One allele codes for white hairs, another for colored hairs, and both are expressed in the individual despite one being dominant and one being recessive