Mendelian Inheritance Flashcards
Mendelian inheritance
Think “single gene inheritance”
Monogenic: single-gene
Law of segregation:
either tall OR dwarf
Law of independent assortment:
wrinkled/tall VS wrinkled/dwarf
One particular trait wasn’t dependent upon another
Chromosome 1 is not dependent on chromosome 4 etc in division
Dystrophin and Duchenne MD
Loss of function
Oncogene and cancer
Gain of function
β-globin and sickle cell anemia
Protein alteration
Genotype
An individual’s genetic makeup
Gene: A, a etc
Genotype: AA or Aa
Phenotype:
What is actually observed
Individuals w/ distinct genotypes can have a single phenotype
Ex. Cystic Fibrosis
“Allelic heterogeneity” -can affect the expressivity of the disease
Gene can be mutated in several ways leading to various outcomes
(Just know general overview of classes)
Class 1 defect: don’t get a protein even though you have the gene (most severe)
Class 2: gets made and gets outside but is desposed of because cell thinks it’s garbage
Class 3: Makes way to cell surface but isn’t regulated, doesn’t bind well to membrane or other proteins
Class 4: Makes way to membrane but doesn’t transport chloride as it should
Class 5: Underproduction: you get the protein but you just don’t have enough of it (not as serious)
Class 6: recognized as not doing well and gets disposed of
PKU
People w/ PKU have a defective PAH enzyme so phenylalanine builds up. Normally the PAH enzyme breaks down phenylalanine. Affects person’s IQ
*Individuals with the same genotype can have multiple phenotypes
Locus
Site on chromosome: where gene is. 2 alleles at locus
Pedigrees: proband (propositus)
The 1st diagnosed person in pedigree
Arrow –> donotes the proband
Autosomal Dominant Inheritance
Ex. Postaxial Polydactyly
**Only 1 allele of a gene is needed for expression, 1 copy
(Aa)
Autosomal: all chromosomes except x/y, so there are 22 out of the 23
Affected offspring has one affected parent
Both males and females can transmit trait to both males and females-autosomal
Trait is expected in EVERY generation (i.e. vertical transmission)
Recurrent risk for having affected children of proband is 50%
(chance of infected person giving it to their kids-infected father+not infected mother) Aa x aa
Affected offspring have one affected parent
Autosomal Recessive
2 copies of a gene is needed to influence phenotype
Ex. Tyrosinase (converts tyrosine to precursor for melanin)-albinism. If enzyme is defective, you get albinism
Autosomal Dominant vs Recessive
Dominant needs 1 copy and recessive needs 2 copies
Punnet Square for Autosomal Recesive Inheritance
AaxAa
25% chance of getting disease (need aa)
Autosomal Recessive: Pedigree
Affected individuals have normal parents
Recurrent risk for heterozygote parents is 25%
Both males and females may be affected
Affected individuals who mate with normal individuals tend to have normal children
Occurrence is more likely among individuals who share genes, as with consanguinity (first cousin mating)
Autosomal dominant vs Autosomal Recessive inheritance
Autosomal dominant: disease expected in every generation
What does consanguinity (first cousin mating) look like on pedigree chart?
Double line connecting sexual partners
XX
Female
X-linked Recessive
Males only have 1 X chromosome and females have 2
Unaffected males do not transmit the trait (no carriers)
All daughters of affected males are heterozygous carriers
Ex. Duchenne Muscular Dystrophy
Allele on X-chromosome in males is termed _______
Hemizygous
X-linked recessive for women
Females can be heterozygous or homozygous
Females passing on X-linked Recessive trait to children
Female carriers transmit the affected allele to 50% of sons and 50% of daughters
X-linked dominant
Ex. Hypophosphatemia (defect in the reabsorption of phosphate in kidney).
Very rare
No carriers
Males transmit the trait to only females; 100% of females (men give their Y to the son and not their X, unlike females getting both X’s from parents)
Females transmit the trait to males and females; transmit to 50% of offspring (Xx x Xy)
Both males and females affected
Hypophosphatemia
Abnormally low levels of phosphorus in blood due to defective reabsorption of phosphate in kidney
Deficient reabsorption of Ca in intestines causes softening of bones (RIckets)
Vitamin D metabolism abnormal
Short stature: abnormally short limbs with onset
Reduced Penetrance
We would expect that 100% of people inheriting the genetic defect to have the problem (phenotype) but it’s more like 90%
Ex. Retinoblastoma
Autosomal dominant inheritance
Phenotype occurs in 90% of individuals inheriting gene defect so 90% penetrance
Variable Expressivity
Describes the range of phenotypes that vary between individuals with a specific genotype
Ex. Neurofibromatosis
- Develop tumor-like growths called neurofibromas
- Patients have cafe-au-lait spots; pigmented areas the color of coffee with cream (spots differ in number, shape, size and position)
Locus Heterogeneity
Single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci
Also in PKU?
Ex. Osteogenesis Imperfecta
- Brittle-bone disease
- Mutations in collagen genes (2 loci; chromosome 7 and 17), either mutation exhibits the same phenotype
Pleiotropy
Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits.
If same disease has many tissues/organ involve it is example of pleiotropy
Literally means”many turnings” -a given phenotype is carefully observed at different levels or as you said a mutation that affects multiple organs.
In assessing a patient with osteogenesis imperfecta, blue sclera and bone fractures were noted.these findings are example of which of the following?
1) allele hetergeity
2) locus heterogeniety
3) pleiotropy
4) multiple mutations
5) gain of functions
3)pleiotropy
De novo mutation
Sporadic mutation- no other affected family members
Pedigree: Autosomal Dominant
- Affected offspring have 1 affected parent
- Unaffected individuals do not transmit
- Trait is expected in every generation
e.g. Marfan syndrome
Huntington’s disease
Retinoblastoma
Pedigree: Autosomal Recessive
- Affected individuals have normal parents (not infected)
- Affected individuals who mate with normal individuals tend to have normal children
- Occurence is more likely among individuals who share genes, as with consanguinity (1st cousin mating)
e.g. Cystic fibrosis Hartnup disease Nieman pick disease Sickle cell disease Werner syndrome Xeroderma pigmentosa
Barr body
The X chromosome is bigger than the Y, and to keep the gene dosage equal between the sexes, X-inactivation occurs.
One X chromosome in each cell is inactivated, condensed and is known as a Barr body
Metacentric
Centromere in middle of chromosome
(Middle to far end)
M–>S–>A–>T
Metacentric, Submetacentric, Acrocentric, Telocentric
Submetacentric
centromere between the middle of the chromosome and the tip of the chromosome
(Middle to far end)
M–>S–>A–>T
Metacentric, Submetacentric, Acrocentric, Telocentric
Acrocentric
centromere almost at the tip of the chromosome
(Middle to far end)
M–>S–>A–>T
Metacentric, Submetacentric, Acrocentric, Telocentric
Telocentric
centromere at the tip of the chromosome
(Middle to far end)
M–>S–>A–>T
Metacentric, Submetacentric, Acrocentric, Telocentric
Short arm of chromosome
p
Long arm of chromosome
q
What does 14q32 refer to on chromosome?
14q32
Second band in the third region of the long arm of chromosome 14
Aneuploid
Refers to conditions when the total chromosome number is not a multiple of 23
Can arise via nondisjunction
Hardy-Weinberg explained
Consider two alleles, A and a, at a particular locus; aa represents a disease phenotype for an autosomal recessive disorder
a. Let p=frequency of allele A in the population
b. Let q=frequency of allele a in the population
c. p+q=1
d. If one squares p+q=1, the Hardy-Weinberg equation is realized p² + 2pq + q² = 1
(1) p² represents the frequency of AA homozygotes in the population (wild type)
(2) q² represents the frequency of aa homozygotes in the population (those with the autosomal recessive disease)
(3) 2pq represents the frequency of carriers (heterozygotes) in the population
Prader Willi syndrom
Inherit mutated allele from the father while the allele inherited from the mother is naturally silenced
When the paternal chromosome is deleted
Symptoms:
- Developmental delay/Mental retardation
- Hyperphagia
- Hypotonia
- Initial failure to thrive
- Distinctive facial features
- Hypogonadism
- Eating disorder
Angelman syndrome
Inherit mutated allele from the mother while the allele inherited from the father is naturally silenced
When the maternal chromosome is deleted
Symptoms: -Unprovoked smiling/laughter -Severe developmental delay/mental retardation -Hypotonia -Seizures -Jerky, uncoordinated movements -Lack of speech
Imprinting
Refers to a modification of a gene’s ability to be expressed via a means other than changing the base sequence of the DNA
The expression of the gene will be determined by the sex of the parent
Maternal imprinting: alleles that females modify during gamete formation
Paternal imprinting: alleles that males modify
Maternal imprinting is being interpreted to mean that alleles that are inactivated by the mother, whereas paternal imprinting is the inactivation of alleles by the father
**methylation of bases which leads to genes not being expressed
Genomic Imprinting
Imprinted genes=methylation=down regulated
Epigenetics
Study of heritable changes that do not affect the DNA sequence
Genetic changes
Things that can be inherited through changing DNA sequence
Genetics vs Epigenetics
Genetics determines WHAT is transcribed and Epigenetics determines HOW MUCH is transcribed
Histones and DNA
Negatively charged DNA is wrapped around positive histones
Epigenetics: determines how tight DNA is wrapped around histones
Mnemonic for heterochromatin and euchromatin
People from E.U tend to be more relaxed and less up-tight
Histone acetylation
Removes positive charge (neutralizes) –> decreases attraction to DNA
Methylating DNA
It’s hydrophobic, so DNA will clump up
Mnemonic for Acetylation and Methylation
Acetylation–> Active transcription
Methylation–> genes are Missing (turn genes off)
Imprinting
One allele is naturally inactivated/silenced by epigenetic changes and only 1 allele is expressed
e.g. Allele from mother expressed and allele from dad silenced or vice versa
Reason it’s important: if you are automatically silence one gene then that means that only one genetic defect can give you at disease (normally you have two functioning alleles but now you only have one, and no ‘backup’)
Mnemonic for Angelman Syndrome
Angels are Mother-like and Happy
Angelman syndrome leads to happiness and excessive laughter, and due to maternal mutation
Mnemonic for Prader-Willi
Willi is like a man’s name and men usually eat more then women (hyperphagia=increased appetite)
Disease due to paternal/father’s mutation
