mendelian/ non-mendelian/ complex inheritance Flashcards
sickle cell anaemia:
autosomal recessive inherited diseases
caused by a single-point mutation on the HB gene.
Adenine to Thymine substitution leads to → encoding changes from Glutamate to Valine
Characterized by:
→ sickle-shaped erythrocytes
→ pain & tissue damage & infection
→ widespread in Africa, Middle-East, India
sickle cell anaemia and cf:
Sickle cell disorders (SCD) & Cystic fibrosis are autosomal recessive traits
Requires two allele mutations to be affected
Homozygote (AA) → normal
Homozygote (aa) → affected
(nonfunctional protein)
Heterozygote (Aa) → carrier
(reduced protein function)
cystic fibrosis:
an autosomal recessive inherited disease
characterized by the buildup of thick mucus in the airways causing bacterial infection.
punnet square:
a square diagram that is used to predict the genotypes of a particular cross or breeding experiment
achondroplasia and Huntington:
Achondroplasia & Huntington’s disease
- autosomal dominant traits
Requires one allele mutation to be affected
Homozygote (aa) → normal
Homozygote (AA) → affected
(nonfunctional protein)
Heterozygote (Aa) → affected
(nonfunctional protein)
Features of Autosomal Dominant Inheritance:
- Each child has a 50% chance of inheriting the mutation
- No “skipped generations”
- Equally transmitted by men and women
- Male-to-male transmission
Huntington’s disease:
is an autosomal dominant inheritance that is progressively neuro-degenerative.
achondroplasia:
Dominant inheritance disease-associated Mutations Alter Protein Function:
1- non-functional/missing protein
2- {{c1::gain of function}} alteration
e.g. (achondroplasia) → slows down growth of bone
Glycine → Arginine
Duchenne muscular dystrophy:
an x-linked disease that causes muscle weakness
due to a mutation in the dystrophin gene.
→ fatal in early adult life & prenatal diagnosis done to check for risk
Haemophilia - an x-linked disease that is a bleeding disorder.
x linked disease inheritance:
If the father has it, and the mother is unaffected
None of the sons will have it, all the daughters will carry it.
If the mother has it, and the father is unaffected
50% chance that a son will have it
50% chance that a daughter will carry it.
x linked/ sex-linked inheritance features:
Only males affected classically
Can skip generations (through unaffected women)
Unaffected women and affected men can transmit the condition
- No male-to-male transmission
→ only inherits Y chromosome from father
mendelian disease:
Multiple Genes in the same Molecular Pathway can cause the same Mendelian Disease
→ each gene has a strong effect
e.g. Long QT, ARVC & Cardiomyopathy
Mode of inheritance can differ:
– Autosomal Dominant
– Autosomal Recessive
– XL variants in >1 gene
mendelian/non-mendelian inheritance laws:
Mendelian Inheritance:
- The Law of Dominance
- The Law of Segregation
- The Law of Independent Assortment
non-Mendelian Inheritance: does not fit in with Mendelian’s Law
e.g. Several variants in several genes acting together.
The contributions of genetic and environmental factors to human diseases:
Rare disorders:
Genetics simple
Uni-factorial
High recurrence rate in following generations
Common disorders:
Genetics complex
Multi-factorial
Low recurrence rate in following generations
Inheritance Patterns & Mechanisms of Non-Mendelian Inheritance:
[1] Incomplete Penetrance
Environmental factors
Genetic Modifiers
[2] Genomic Imprinting
Variants from parents
[3] Extranuclear Inheritance
e.g. Mitochondria mutations
[4] Anticipation
e.g. Triplet repeat expansion
→ bigger and more severe as generations continue
[5] Complex
Multi-genic risk
Different levels of genetic penetrance:
e.g. Cystic fibrosis - mutations in CFTR gene
→ 100% penetrance
→ mild mutations only have congenital absence of vas deferens (infertility)
with no chest mucus build-up
penetrance
the frequency with which a trait is manifested by individuals carrying the gene.
Personalised / Precision Medicine, BRCA1 mutation:
BRCA1 mutation → targeted chemotherapy with olaparib (if metastatic)
A mastectomy is an operation to remove the breast
An oophorectomy is a surgical procedure to remove one or both of your ovaries
genetic modifiers and environmental factors:
CFTR mutation alone does not explain the severity of CF in organs and variation within families.
We have to take into account:
[1] Genetic modifiers
Genes that have small quantitative effects on the level of expression of another gene.
May involve polymorphism, maybe intra- or extra-genic
[2] Environmental factors
Lifestyle, Diet, Smoke, Alcohol, Drug,
Stress, Air pollution, Chemicals,
Infection, etc.
genomic imprinting:
an epigenetic phenomenon that causes genes
to be expressed in a parent-of-origin-specific manner.
Some regions of the genome are imprinted, where only one of the two copies of the gene is active
and the other is switched off through methylation.
Maternally Expressed Gene (MEG)
Paternally Expressed Gene (PEG)
Epigenetic modifications:
heritable changes in gene function not explained by changes in DNA sequences
→ mediated by DNA methylation → gene isn’t available to be copied
Methylcytosine (mC) induces the structural adaptation of chromosomal regions to perpetuate altered activity states
- stops it being available for translation
Genetic mechanisms of imprinting disorders:
Deletions
Point mutations
Imprinting errors
Uniparental disomy
uniparental diomy:
inheritance of a chromosome pair from one parental origin
refers to the situation where a child has inherited both copies of a chromosome from just one parent
[1] Trisomy
[2] Monosomy
[3] Mitotic Error
uniparental diploidy:
when a cell line has all 46 chromosomes derived from one parent.
Gynogenic
- 2 maternal genomes
- Mass of embryo
- Ovarian teratoma
Androgenic
- 2 paternal genomes
- Mass of placenta
- Hydatidiform mole (molar pregnancy)
why is mitochondria a mutation hotspot?
High mutation rate: 100-fold higher than the nuclear genome.
→ Lack of efficient DNA repair system.
→ Lack of protective proteins, such as histones.
→ Damaged by reactive oxygen species (ROS), such as free radicals.
Mitochondria-associated disease mutations:
always inherited maternally
→ Affect tissues with high metabolic demand.
3 major myopathies:
- Myoclonic epilepsy with ragged red fibres (MERRF)
- Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)
- Chronic progressive external ophthalmoplegia (CPEO)
Leber’s hereditary optic neuropathy (LHON)
- loss of central vision
Leigh’s syndrome - encephalopathy
Diabetes mellitus and deafness (DAD)
anticipation:
a phenomenon whereby as a genetic disorder is passed on to the next generation,
the symptoms of the genetic disorder become apparent at an earlier age with each generation.
In most cases, an increase in the severity of symptoms is also noted.
Triplet repeat diseases - mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable.
e.g. Triplet repeat diseases
- Huntington’s disease
- Myotonic dystrophy (DM1)
- Fragile X syndrome
multigenic/ complex inheritance:
when genes interact additively to influence a phenotypic trait.
Features:
- Often seen in common conditions
e.g.
– Heart disease
– Breast cancer
– Autism - Multiple low penetrance variants
– Breast cancer e.g. CHK2, ATM, polygenic risk scores becoming tested in clinical practice
– Heart disease - genome-wide polygenic risk score under evaluation
– Often extra-genic affecting expression rather than DNA code - Rare high penetrance variants in many genes causing the same phenotype
– schizophrenia
