Mendelian Genetics I and II & Hardy Weinberg_Foil_NOTES.pdf Flashcards
Gregor Mendel (1822‐1884) studied ____#____ of traits, they are ___________.
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
Color of a rose….
Parental generation (P): True Bred Red (RR) x True Bred White (rr) (homozygotes)
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)
Mendel’s First Law: Law of Segregation
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
Mendel’s Second Law:
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.)
Exception to 2nd Law
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.
Modern Mendelian Applications
“Mendelian” disorders=
___#____ genes across __#____ of chromosomes
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
Allele= One of two or more forms of a gene at a given locus (e.g. tall vs. short at height locus)
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 allelesphenotype
Mutation = change in the gene that results in abnormality (e.g. dwarf)
AKA “pathogenic varian
Mutation ***
- what would be the mutation for height?
- what do we call mutations todaY?
Mutation = change in the gene that results in abnormality (e.g. dwarf)
AKA “pathogenic variant
Combination of 2 alleles = genotype
Combination of 2 alleles = genotype
Expression of allelesphenotype
Expression of allelesphenotype
Expression of allelesphenotype
Chromosome to Gene to Protein
note
Mendelian Disorders
______diseases with Mendelian inheritance
_____% of childhood hospitalizations due to single gene disorders
____% of single gene disorders present in adolescence or adulthood
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
Mendelian Inheritance Patterns
- def: when to use?
- name them
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
Autosomal
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
Dominant or Recessive
Dominant or Recessive
Dominant: one mutation sufficient to cause condition; one
normal gene is not protective
Recessive: one normal gene is enough
Mendelian Applications
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
Pedigrees
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
Common pediggree symbols
- diamond
- how to show adopted?
- who is the patient
notes
Autosomal Dominant Inheritance
**be able to recognize this pedigree
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
Autosomal Dominant Inheritance
T/F the sons of females cannot be affected
what is the percent chance a normal parent will pass it on?
False
-the daughters of males and the sons of females can be affected
50%
Autosomal Dominant Example
Huntington disease
Affects ____ persons of European decent
problems?
Death usually occurs within _____ years after symptoms develop
Onset age?
penetrance?
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.]
Some other AD Conditions
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‐)
Autosomal Recessive Inheritance
-when both parents are carriers?
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
Autosomal Recessive Inheritance ● Parents ? ● Family history? ● sibs? ● Males vs females ● by ethnic group?
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
Autosomal Recessive
When disorder is quite rare, consider ____
● _____ increases risk for AR disorders
● Denoted by ____pedigree
When disorder is quite rare, consider consanguinity
[the fact of being descended from the same ancestor.]
● ConsanguinityincreasesriskforARdisorders
● Denoted by double line in pedigree
consanguinity
When disorder is quite rare, consider consanguinity
● ConsanguinityincreasesriskforARdisorders
● Denoted by double line in pedigree
Pseudo‐dominance:
● Pseudo‐dominance: when AR disease is seen in multiple generations
● Disorderiscommon,ormatingwithinat‐riskgroup
AR Examples
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)
Autosomal Recessive Example- Example of successful population carrier screening
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%
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
Autosomal Co‐Dominant
Two alleles equally affect the phenotype in heterozygotes ABO Blood Type ‐ 3 alleles
A & B are co‐dominant, O is recessive
Co‐Dominant
• Alpha‐1 antitrypsin deficiency: Single gene risk for lung & liver disease
explain
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”
• MMnormal AAT level, no increased risk
• MZ heterozygotemildly reduced AAT level, some increased
risks
• ZZSevere AAT deficiency, high risks
COPD Risk – burden due to Alpha-1 genotype
X-Linked Inheritance
*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)
Normal female:
Normal male:
*men are _____ for x genes
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
X‐linked Recessive Inheritance
- Unaffected males
- male to male transmission
- daughters of affected males
- Carrier women
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)
X‐linked Recessive Examples
X‐linked Recessive Examples Duchenne muscular dystrophy Becker muscular dystrophy X‐linked ichthyosis Hemophilia Most color blindness
Duchenne Muscular Dystrophy is an example of ?
fraction? Expect who to be affected? carriers? problems? Mutations in \_\_\_ gene \_\_\_\_ exons in gene *\_\_\_new mutations******
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)
Duchenne Muscular Dystrophy New Treatments
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
Duchenne Muscular Dystrophyfemale carriers
DMD female carriers
Will not meet diagnostic criteria
But have risk for cardiomyopathy and should be screened
X‐linked Dominant
• rate compared to other modes of inheritance?
r
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
4 Factors that Impact Pedigree Patterns *****
4 Factors that Impact Pedigree Patterns
- Pleiotropy
- Penetrance
- Variable Expressivity
- Heterogeneity
* Many Mendelian disorders exhibit several of these factors
Pleiotropy
•def
• AD Example:
- AR Example:
- X‐LR Example:
- 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
Penetrance
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
• Complete penetrance: **
• 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
• Reduced penetrance**
• 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
Some disorders have age‐related penetrance:
• Examples:
Some disorders have age‐related penetrance:
• Examples:
• HNPCC: 52‐82% lifetime risk for colorectal cancer • Huntingtondisease:100%penetrant
Variable Expressivity
- Example**
- Contrast with Penetrance
(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)
Heterogeneity
- 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 ]
Mendel’s Laws of Inheritance
Crosses showed that on average, traits occur in fixed & predictable proportions
prior to Mendel, what was the believed way traits were passed on
“blending”
F1 generation stands for
1dt offspring generation
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 ?
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)
karyotype def
def
explain Note: Role of de novo mutations in some dominant disorders
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‐)
in x-linked recessive inheritance : All daughters of affected males are ? explain
All daughters of affected males are “obligate” carriers
they have to get the X
