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HRR Block 1 > Mendelian Genetics I and II & Hardy Weinberg_Foil_NOTES.pdf > Flashcards

Mendelian Genetics I and II & Hardy Weinberg_Foil_NOTES.pdf Flashcards

1
Q

Gregor Mendel (1822‐1884) studied ____#____ of traits, they are ___________.

A

Gregor Mendel (1822‐1884)
 “Father of Modern Genetics”
 Austrian scientist & friar
 Worked in monastery’s experimental garden
 Pea Plant Crosses (& other plants, bees & animals)
 plant height, pod shape and color, seed shape and color, and flower position and color

 Crosses showed that on average, traits occur in fixed & predictable proportions
Mendel’s Laws of Inheritanc

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2
Q

Color of a rose….

 Parental generation (P): True Bred Red (RR) x True Bred White (rr) (homozygotes)

A 
Color of a rose....
 Parental generation (P):
 True Bred Red (RR) x True Bred White (rr)
 (homozygotes)
 F1 generation‐ all heterozygous Rr genotype, all
r r
rrr
RR Rr
Rr rr
P= parental plants

Red phenotype includes RR and Rr genotypes
express dominant Red phenotype (R)
 F2 generation‐ Cross of F1 heterozygotes 1⁄4 RR, 1⁄2 Rr, 1⁄4 rr genotypes
 3:1 Red to White phenotype ratio

***** Red phenotype includes RR and Rr genotype ( they are indistinguishable)

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3
Q

Mendel’s First Law: Law of Segregation

A

Mendel’s First Law:
 Law of Segregation:
 Hereditary traits are determined by discrete factors (genes) that occur in pairs and segregate (separate) during transmission to offspring
 RANDOM segregation: 50‐50 chance which gene is passed on

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4
Q

Mendel’s Second Law:

A

Mendel’s Second Law:
 Law of Independent Assortment:
 Traits at different genetic loci assort independently
 (e.g. wrinkled/smooth pod sorts independently of plant
height, color, etc.)

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5
Q

Exception to 2nd Law

A

Genetic Linkage: Exception to 2nd Law
 If two traits are physically linked by being close to each other on the same chromosome they are not independently assorted.

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6
Q

Modern Mendelian Applications

 “Mendelian” disorders=

 ___#____ genes across __#____ of chromosomes

A

Modern Mendelian Applications  “Mendelian” disorders= single gene disorders
 Occur based on genotype at given locus
 20,000 protein‐coding genes
 Structural, enzymes, ion channels, etc.
 Genes occur on 46 Chromosomes (23 pairs)  22 Autosomal pairs + Sex chromosomes

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7
Q

 Allele= One of two or more forms of a gene at a given locus (e.g. tall vs. short at height locus)

A

 Allele= One of two or more forms of a gene at a given locus (e.g. tall vs. short at height locus)
-Combination of 2 alleles = genotype
- Expression of allelesphenotype
 Mutation = change in the gene that results in abnormality (e.g. dwarf)
 AKA “pathogenic varian

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8
Q

Mutation ***

  • what would be the mutation for height?
  • what do we call mutations todaY?
A

Mutation = change in the gene that results in abnormality (e.g. dwarf)
 AKA “pathogenic variant

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9
Q

Combination of 2 alleles = genotype

A

Combination of 2 alleles = genotype
 Expression of allelesphenotype

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10
Q

 Expression of allelesphenotype

A

 Expression of allelesphenotype

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11
Q

Chromosome to Gene to Protein

A

note

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12
Q

Mendelian Disorders
______diseases with Mendelian inheritance

 _____% of childhood hospitalizations due to single gene disorders
 ____% of single gene disorders present in adolescence or adulthood

A

Mendelian Disorders
 > 7,000 diseases with Mendelian inheritance
 Individually rare but collectively common!
 6‐8% of childhood hospitalizations due to single gene disorders
 10% of single gene disorders present in adolescence or adulthood

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13
Q

Mendelian Inheritance Patterns

  • def: when to use?
  • name them
A 
Mendelian Inheritance Patterns
 Fixed and predictable patterns evident as you study a
disease or study a family
 Autosomal Dominant 
 Autosomal Recessive 
 Co‐Dominant
 X‐linked Recessive
 X‐linked Dominant
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14
Q

Autosomal

A

Autosomal = implicated gene is on autosomes (chromosomes 1‐22)
 Affects M & F equally
 Transmitted by M & F equally
 X‐linked = implicated gene is on X chromosome
 Dominant or Recessive
 Dominant: one mutation sufficient to cause condition; one
normal gene is not protective
 Recessive: one normal gene is enough

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15
Q

Dominant or Recessive

A

Dominant or Recessive
 Dominant: one mutation sufficient to cause condition; one
normal gene is not protective
 Recessive: one normal gene is enough

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16
Q

Mendelian Applications

A 
Mendelian Applications
 All areas of medicine
 Contributes to accurate diagnosis
 Predict natural history and prognosis
 Personalized medicine and treatment
 Assess risk to relatives
 Testing for family members
 Family planning decisions
 Foster research, therapeutics and advances in rare disease
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17
Q

Pedigrees

A

help get to know the patient

 Visualize pattern of transmission in a family
 Shows who is in a family
 Help assess risk to other relatives
 Diagnostic Clues

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18
Q

Common pediggree symbols

  • diamond
  • how to show adopted?
  • who is the patient
A

notes

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19
Q

Autosomal Dominant Inheritance

**be able to recognize this pedigree

A

One copy of the mutation is sufficient to cause disease (other allele is usually normal)
 Vertical transmission
 Both sexes affected in equal proportion and severity
 Equally transmitted by males and females
 Children of parent with AD condition at 50% risk

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20
Q

Autosomal Dominant Inheritance

T/F the sons of females cannot be affected

what is the percent chance a normal parent will pass it on?

A

False

-the daughters of males and the sons of females can be affected

50%

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21
Q

Autosomal Dominant Example
Huntington disease
 Affects ____ persons of European decent
 problems?
 Death usually occurs within _____ years after symptoms develop
 Onset age?

penetrance?

A

Autosomal Dominant Example
Huntington disease
 Affects 1/20,000 persons of European decent
 Progressive loss of motor control (chorea), cognitive and psychiatric problems
 Death usually occurs within 15 years after symptoms develop
 Onset usually age 30 – 45 yrs

substantial loss of neurons in the brain

100% penetrance*****

[every person who has a mutation in the gene will show symptoms of the condition.]

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22
Q

Some other AD Conditions

A

Some other AD Conditions (there are many)
 Marfan syndrome
 Ehlers‐Danlos syndrome
 Achondroplasia
 Osteogenesis Imperfecta
 Craniosynostosis (Apert, Crouzon, Pfieffer)
 Hereditary Breast & Ovarian Cancer (BRCA1/2)
 ADPKD

 Note: Role of de novo mutations in some dominant disorders
—-e.g. Cornelia de Lange
 Note: Chromosomal microduplication/deletion syndromes follow AD pattern of inheritance
—e.g. DiGeorge, VCF (22q‐)

23
Q

Autosomal Recessive Inheritance

-when both parents are carriers?

A

Two germline mutations (one from each parent) to develop disease
Equally transmitted by men and women

 25% risk to each child when both parents are carriers
 Sibs at risk
 Parents & Children of someone affected = “Obligate” carriers

24
Q 
Autosomal Recessive Inheritance
● Parents ?
● Family history? 
● sibs? 
● Males vs females 
● by ethnic group?
A

Autosomal Recessive Inheritance
● Parents usually unaffected, healthy carriers (heterozygotes)
● Family history is usually “negative”
● One or more sibs affected
● Males and females equally affected
● Incidence and carrier rates of many AR disorders vary by ethnic group

 Carrier = heterozygote
 Phenotypically normal
(indistinguishable)
 One normal gene is enough

25
Q

Autosomal Recessive

When disorder is quite rare, consider ____
● _____ increases risk for AR disorders
● Denoted by ____pedigree

A

When disorder is quite rare, consider consanguinity
[the fact of being descended from the same ancestor.]

● ConsanguinityincreasesriskforARdisorders
● Denoted by double line in pedigree

26
Q

consanguinity

A

When disorder is quite rare, consider consanguinity
● ConsanguinityincreasesriskforARdisorders
● Denoted by double line in pedigree

27
Q

Pseudo‐dominance:

A

● Pseudo‐dominance: when AR disease is seen in multiple generations

● Disorderiscommon,ormatingwithinat‐riskgroup

28
Q

AR Examples

A 
AR Examples
 Cystic fibrosis
 Sickle cell disease
 Alpha & beta thalassemia
 Spinal Muscular Atrophy
 Fanconi Anemia
 PKU
 Most inborn errors of metabolism  Most inherited deafness
 Carrier testing available and recommended to be offered for select disorders

(but there is like 300ish that could be tested for)

29
Q

Autosomal Recessive Example- Example of successful population carrier screening

A

Autosomal Recessive Example
Tay‐Sachs Disease
 1/30 carrier frequency in those of Ashkenazi Jewish ancestry
 Also more common in French‐Canadians, Cajuns, and PA Amish
 Progressive neurodegeneration, seizures, blindness, spasticity
 Onset at about 3‐6 months with death usually before age 4
 Example of successful population carrier screening campaigns: incidence in North American Ashkenazi Jewish population reduced by greater than 90%

30
Q

Autosomal Co‐Dominant - blood type example explain
 Two alleles equally affect the phenotype in heterozygotes  ABO Blood Type ‐ 3 alleles
 A & B are co‐dominant, O is recessive

A

Autosomal Co‐Dominant
 Two alleles equally affect the phenotype in heterozygotes  ABO Blood Type ‐ 3 alleles
 A & B are co‐dominant, O is recessive

31
Q

Co‐Dominant
• Alpha‐1 antitrypsin deficiency: Single gene risk for lung & liver disease

explain

A

Co‐Dominant
• Alpha‐1 antitrypsin deficiency: Single gene risk for lung & liver disease
• Allele combination determines quantity of AAT in blood
• Normal allele called “M”, most common mutation called “Z”
• MMnormal AAT level, no increased risk
• MZ heterozygotemildly reduced AAT level, some increased
risks
• ZZSevere AAT deficiency, high risks
COPD Risk – burden due to Alpha-1 genotype

32
Q

X-Linked Inheritance

A

*mutant genes are on the X (sex) chromosome
women typically need to inherit two mutated copies to be affected
all men who inherit the mutation are affected (only one X chormosome)

33
Q

Normal female:
Normal male:

*men are _____ for x genes

A

Normal female: 46,XX Normal male: 46,XY
(2 copies of X genes) (1 copy of X genes – “hemizygous”)

men are hemizygous for x genes

34
Q

X‐linked Recessive Inheritance

  • Unaffected males
  • male to male transmission
  • daughters of affected males
  • Carrier women
A

X‐linked Recessive Inheritance
•Males affected or unaffected (not carriers) •Unaffected males do not transmit the disorder •Never male to male transmission
•Sons get their dad’s Y
• All daughters of affected males are “obligate” carriers •Carrier women have 50% risk to pass mutation to child
daughters at 50% risk of carrier state (not affected due to 2nd X)  sons have a 50% risk of the disease (no 2nd X)

35
Q

X‐linked Recessive Examples

A 
X‐linked Recessive Examples
 Duchenne muscular dystrophy 
 Becker muscular dystrophy
 X‐linked ichthyosis
 Hemophilia
 Most color blindness
36
Q

Duchenne Muscular Dystrophy is an example of ?

 fraction? 
 Expect who to be affected? carriers? 
 problems? 
 Mutations in \_\_\_ gene 
 \_\_\_\_ exons in gene
 *\_\_\_new mutations******
A

Duchenne Muscular Dystrophy: X‐LR
 1/3500 male births
 Expect affected males and unaffected female carriers
(females do not meet the clinical criteria)
 Progressive muscle degeneration and weakness
—-CK, calf enlargement
 Cardiomyopathy
 Mutations in dystrophin gene -> absence of dystrophin
 79 exons in gene
1/3 new mutations (instead of coming from mother)

37
Q

Duchenne Muscular Dystrophy New Treatments

A

DMD New Treatments
• EXONDYS 51 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51 [see Clinical Studies (14)]. A clinical benefit of EXONDYS 51 has not been established

our molecular understading guides treatment

38
Q

Duchenne Muscular Dystrophyfemale carriers

A

DMD female carriers
 Will not meet diagnostic criteria
 But have risk for cardiomyopathy and should be screened

39
Q

X‐linked Dominant
• rate compared to other modes of inheritance?
r

A

X‐linked Dominant

-single is enough

  • Less frequent than other modes of inheritance
  • Both males and females affected
  • May be more severe phenotype in males
  • e.g. hypophosphatemic rickets
  • There are no unaffected “carriers”
  • Often embryonic lethal to males,
  • e.g. Rett syndrome, Aicardi syndrome
  • When father has an X‐linked dominant mutation
  • ALL daughters obligated to inherit mutation – 100% risk
  • ALL sons get his Y – no father‐son transmission
  • Women with an X‐linked dominant mutation
  • 50% risk in any pregnancy for affected son or daughter
40
Q

4 Factors that Impact Pedigree Patterns *****

A

4 Factors that Impact Pedigree Patterns

  1. Pleiotropy
  2. Penetrance
  3. Variable Expressivity
  4. Heterogeneity
    * Many Mendelian disorders exhibit several of these factors
41
Q

Pleiotropy
•def
• AD Example:

  • AR Example:
  • X‐LR Example:
A
  • A single genetic mutation produces diverse manifestations in multiple, seemingly unrelated organs or systems.
  • AD Example: Marfan syndrome - - - FBN1 mutations cause abnormalities of the skeleton, eyes and cardiovascular system.
  • AR Example: Cystic fibrosis
  • CFTR mutations cause pulmonary, gastrointestinal and reproductive disease.

• X‐LR Example: Alport syndrome
—-Mutations cause kidney disease, hearing loss
and eye abnormalities

42
Q

Penetrance

A

Penetrance
• Probability a genotype will express the phenotype.
• Complete penetrance: a disease genotype will certainly result in disease
phenotype
• Everyone with the disease genotype will show some or all
symptoms.
• Reduced penetrance: some with the disease genotype have no
phenotypic manifestations.
• Inherited risk or susceptibility
• Some disorders have age‐related penetrance:
• Examples:
• HNPCC: 52‐82% lifetime risk for colorectal cancer • Huntingtondisease:100%penetrant
• Contrast with variable expressivity

43
Q

• Complete penetrance: **

A

• Complete penetrance: a disease genotype will certainly result in disease
phenotype
• Everyone with the disease genotype will show some or all
symptoms.
• Reduced penetrance: some with the disease genotype have no
phenotypic manifestations.
• Inherited risk or susceptibility
• Some disorders have age‐related penetrance:
• Examples:
• HNPCC: 52‐82% lifetime risk for colorectal cancer • Huntingtondisease:100%penetrant

44
Q

• Reduced penetrance**

A

• Reduced penetrance: some with the disease genotype have no
phenotypic manifestations.
• Inherited risk or susceptibility
• Some disorders have age‐related penetrance:
• Examples:
• HNPCC: 52‐82% lifetime risk for colorectal cancer • Huntingtondisease:100%penetrant

45
Q

Some disorders have age‐related penetrance:

• Examples:

A

Some disorders have age‐related penetrance:
• Examples:
• HNPCC: 52‐82% lifetime risk for colorectal cancer • Huntingtondisease:100%penetrant

46
Q

Variable Expressivity

  • Example**
  • Contrast with Penetrance
A

(range of severity)

• When the type or severity of manifestations differs in individuals with the same genotype.
• Different expression among people with same disease
• Spectrum of severity
• Example: NF1 (Multiple café au lait spots occur in nearly all affected individuals, about half have learning disabilities, few have optic nerve gliomas and brain tumors)
-can be really mild to really severe

  • Contrast with Penetrance
  • Penetrance (all or none)
  • Variable Expressivity (gradient)
47
Q

Heterogeneity

A
  • Mutations in multiple unrelated genes cause the same or similar phenotype.
  • Can’t tell which gene is implicated based on phenotype alone.
  • Example:BRCA1/2
  • BRCA1 and BRCA2 gene mutations both predispose to clinically indistinguishable breast and ovarian cancer

(either of these genes affected can lead to breast cancer ]

48
Q

Mendel’s Laws of Inheritance

A

 Crosses showed that on average, traits occur in fixed & predictable proportions

49
Q

prior to Mendel, what was the believed way traits were passed on

A

“blending”

50
Q

F1 generation stands for

A

1dt offspring generation

51
Q

Mendel’s First Law: Law of Segregation:

Hereditary traits are determined by discrete factors that occur in pairs and segregate (separate) during transmission to offspring

-what do we call these discrete factors today ?

A

Mendel’s First Law:
 Law of Segregation:
 Hereditary traits are determined by discrete factors (genes) that occur in pairs and segregate (separate) during transmission to offspring

(genes)

52
Q

karyotype def

A

def

53
Q

explain Note: Role of de novo mutations in some dominant disorders

A

Note: Role of de novo mutations in some dominant disorders

-the person is severly affected- will not reproduce- new mutations are more common

—-e.g. Cornelia de Lange
 Note: Chromosomal microduplication/deletion syndromes follow AD pattern of inheritance
—e.g. DiGeorge, VCF (22q‐)

54
Q

in x-linked recessive inheritance : All daughters of affected males are ? explain

A

All daughters of affected males are “obligate” carriers

they have to get the X

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