Mendelian Inheritance and Population Genetics

List out the causes of single gene defects

1. missense

   1. sickle cell

2. nonsense

   1. Duchenne muscular dystrophy

3. RNA synthesis/processing mutation

   1. β thalassemia

4. small deletions/insertion

5. large deletions/insertion

6. recombination

   1. Duchenne muscular dystrophy

   2. α thalassemias

7. unequal crossover

   1. hemoglobin a genes

8. abnormal recombination

   1. severe hemophilia A due to inversion of
      coagulation factor VIII gene from exon 1 to exon 22

What is Pleiotropy; describe how this relates to Marfan syndrome

A single variant allele can cause more than one distinct
phenotypic trait. Expression of the distinct traits might differ from one
individual to another.

In the case of Marfan, different patients may exhibit different symptoms

Describe Penetrance vs. Expressivity

Penetrance: The probability that a variant allele has any phenotypic expression.

Expressivity: The severity of the expressed phenotype. (mild versus severe symptoms)

Describe incomplete dominance vs Codominance

Incomplete dominance: homozygotes have more severe symptoms

Codominance: At least two alleles expresses the phenotype

What is the formula to calculate inheritance probabilities

Pchild = Ppunnett X Pmother X Pfather

describe the characteristics of autosomal recessive disorder

Phenotype manifests only homozygotes

Phenotype usually manifests in siblings and not in parents or offspring

Both parents have to be at least heterozygote

Equally affects males and females (most cases)

What are factors that increase incidence of autosomal recessive disorders? Give examples

1. Consanguinity: Union between individuals who are second cousins or closer relatives

2. Founder Effect: Isolated population retains high frequency of a variant allele.

What are the four high yield autosomal recessive diseases for board?

1. Cystic fibrosis (chloride ion channel deficiency)
   

2. Sickle cell disease (hemoglobin mutation)
   

3. Phenylketonuria (phenylalanine metabolism deficiency)
   

4. Tay-Sachs, Gaucher diseases (lysosomal glycolipid degradation deficiencies)

describe the characteristics of autosomal Dominant disorder

The phenotype usually occurs in every generation

One parent of an affect child is usually affected (except nonpenetrant cases and new mutations)

Equally affects males and females (usually). Both sexes can transmit the disease

Frequent cause: New mutations occuring in one the patient’s gamete

Describe the pathology of Achondroplasia and its symptoms

Example of incomplete dominance

Gain of function mutation in fibroblast growth factor receptor 3

Heterozygotes

• Abnormal bone growth

• Short stature (limbs)

• Large head, characteristic face

• Usually normal intelligence

• Usually normal life span
  

Homozygotes

• More severe bone deformities

• Early death

Give an example of how a disease could have different expressivity

What are Well-Known Autosomal Dominant Diseases

• Familial hypercholesterolemia (LDL-receptor mutation)

• Marfan syndrome (fibrillin-1 mutation)

• Achondroplasia (fibroblast growth factor 3 receptor mutation)

• Huntington disease (neurodegenerative disorder)

• Hereditary breast and ovarian cancer

• Familial adenomatous polyposis (colon cancer)

• Retinoblastoma (Rb mutation)

• Neurofibromatosis type 1 (NF-1 mutation)

Describe the characteristics of X-Linked Recessive Disorders

• Much higher incidence in males

• Heterozygote females might be affected depending on the pattern of X-linked inactivation

• No male-to-male transmission

• Daughters of an affected father are obligate carriers

• Isolated cases can be caused by new mutations

explain how females could exhibit symptoms of a X-linked recessive disease despite having one normal allele

if the normal allele is inactivated during X-inactivation, then the female will express only the variant allele in some of her cells (mosaicism) and will have the phenotype (usually less severe)

What are well known X-linked recessive disorders

Hemophilia A and B (coagulation factor VIII and IX deficiency)

Glucose-6-phosphate dehydrogenase deficiency (acute hemolytic anemia)

Ornithine transcarbamoylase deficiency (urea cycle)

Duchenne muscular dystrophy (dystrophin gene defects)

Describe the characteristics of X-linked Dominant Disorders; What are the best known X-linked dominant disorders?

• There is no male-to-male transition

• The daughter of an affected male will be affected

• Affected females can transfer the disease to sons and daughters

• About twice as frequent in females than males

• In affected females, some cells inactivated the mutant gene

• (mosaicism), so the females havemilder symptoms

The best-known X-linked dominant diseases are Rett syndrome,
Fragile X syndrome and the vitamin D resistant rickets.

Describe the symptoms of Rett Syndrome

X-linked Dominant Disorder

• Developmental stagnation

• Intellectual disability

• Characteristic flapping movements of the hand

• Females probably survive this condition because of X inactivation

What is Psuedoautosomal Inheritance and how can they occur

Inheritance of variant alleles in the pseudoautosomal regions of the sex chromosomes (Xp and Yp)

Meiotic recombination can occur between the pseudoautosomal regions on the X and Y chromosomes

differentiate between somatic and germline mosaicism

Somatic: (after conception)

• Can affect large segments of the body (segmental neurofibromatosis)

• The cause of sporadic cancers

• Cannot be inherited (a single affected individual in pedigrees)!!

Germline: (mosaic gametes)

• Produced in germline during development

• Can be inherited (the disease is passed down in the pedigree)

• The same mutation in two children from the same father but
  different women.

• The father does not have the mutation in his somatic cells.

• The father must have germline mosaicism.

Define Carrier Frequency; How do we calculate it?

the portion of the population that are heterozygous for an autosomal
recessive trait.

What are the conditions for Hardy-Weinberg Law

1. population large and random mating

2. allele freq. is constant because

   1. no selection

   2. departing individuals from population have similar allele freq. than original population

   3. no significant rate of new mutations in population

What is the Hardy-weinberg law

p² : 2pq: q² ; P + Q = 1

p2 is the frequency of the genotype homozygous for the P allele
2pq is the frequency of the heterozygotes
q2 is the frequency of the genotype homozygous for the Q allele

Explain how to do weinberg-calculation for X-linked disease

Males: The frequency of the mutant allele in males (q) equals the disease frequency

Females

1. X-linked recessive: q + q2 ≈ q (q2 << q). Disease frequency equals affected male frequency (q).

2. X-linked dominant: Affected total frequency: q + 2q = 3q. Twice as many females (2q) than males (q) are affected.

Explain how the Hardy-Weinberg Law could deviate

1. stratificatoin

   1. Subgroups in a population tend to mate within the subgroup

2. Assortative Mating

   1. Choice of the mate is based on a particular trait

3. Consanguinity and inbreeding

   1. Mating between related individuals
      Mating within genetic isolates (for cultural, geographical, or religious reasons)

4. Impaired reproductive fitness

   1. The variant allele causes infertility, reduced fertility, or death before reproductive age

5. Genetic Drift

   1. Random (non genetic) changes in a small population change allele frequencies

6. Migration and gene flow

   1. Changing of allele frequencies in mixing populations

7. Heterozygote advantage

   1. Positive evolutionary selection for a heterozygote genotype as in how SIckle Cell protects against malaria