Genetics Flashcards
what are the 4 major categories of genetically determined diseases
- Single gene disorders
- Chromosomal disorders
- Multifactorial genetic disorders
- Somatic cell disorders
Define
mutation
Polymorphism
Mutation
* Any permanent heritable change in the sequence of genomic DNA
* Any change in DNA from its natural state: may be disease-causing or a benign normal variant
Polymorphism
* The occurrence together in a population of two or more alternative genotypes, each at a frequency greater than that which could be maintained
by recurrent mutation alone
Types of mutations and brief description
- Silent
- Single base change that does not result in an amino acid change (triplet code degeneracy) - Missense
- Single base change that does result in an amino acid change (may not cause abnormal phenotype) - Nonsense
- Single base change that changes an amino acid to a STOP codon - Frameshift
- Insertion or deletion of bases in anything other than multiple of 3 - Splice donor / acceptor
- Alteration of sequences for accurate splicing of introns - InDel
- An Insertion or Deletion of one or more bases
- If it does not involve a multiple of 3 bases, it will shift the reading frame
Sickle cell anaemia type of mutation
Missense mutation in HBB gene
- Wild type: CTC (DNA) = GAG (RNA) = Glutamic acid
-Missense: CAC (DNA) = GUG (RNA) = Valine
Somatic vs germline mutation
If a new mutation occurs in non-gamete-forming cells (somatic cells), the consequences of the changes are limited to the person in whom the changes occurred.
If the new mutation occurs in cells that ultimately form the gametes (germline cells), the change may be transmitted to (and inherited by) subsequent generations.
wildtype means?
Normal
Phenotypic consequences of Mutations
- Gain-of-function mutations
* Produce either an increased amount or increased activity of the encoded protein (= gene product) - Loss-of-function mutations
* Produce either a reduced amount or a reduced activity of the encoded protein
* Usually have minimal effect on phenotype unless both alleles affected
* If no functional protein results from an allele, known as NULL ALLELE
- Some heterozygous loss-of-function mutations produce a DOMINANT NEGATIVE
effect (the abnormal protein interferes with the protein encoded by the remaining wild type allele)
pedigree symbols
square
circle
diamond
coloured circle
circle with line through
line connecting two shapes
diazygotic twins and monozygotic twins
Lecture Slide
square = male
circle = female
diamond = unknown gender
coloured circle/sqaure = affected
circle with line through = deceased
line connecting two shapes = married
diazygotic twins and monozygotic twins= top of triangle, full triangle
Single Gene Disorders
-result from?
- Result from mutations in one (dominant) or both (recessive) of a pair of genes
- Putting this another way - a trait is dominant if it is manifest in a heterozygote and recessive if it is not
Patterns of inheritance
- Autosomal dominant
- Autosomal recessive
- X-linked recessive
- X-linked dominant
- Y-linked (holandric)
Auto dom inhertiance example
- symptoms
-where is mutation
Example: Achondroplasia
* Autosomal dominant
* Clinical features include shortening of proximal limbs,
prominent forehead, depressed nasal bridge, otitis media
* The most common type of short-limbed dwarfism
* Achondroplasia means “without cartilage formation” - actually the pathology is altered ossification of cartilage into bone
* Mutation in fibroblast growth factor receptor 3 (FGFR3) gene
* The remaining wild type allele cannot compensate for / reduce
the mutant alleles activity
Even though achondroplasia is auto dom, why do only 20% get the mutation?
- When inherited from an affected parent(s), achondroplasia follows an autosomal dominant inheritance pattern (20% cases)
- However, ~80% of people with Achondroplasia have parents of normal size - for these people, a spontaneous (de novo) mutation has occurred in the father’s germ cells
Autosomal recessive
- who does it affect
-what sex
-% of being affected from carrier parents
-example
- affected people usually born to unaffected parents
- affects either sex
- increased incidence of parental consanguinity
- after birth of affected child, each subsequent child has 25% chance of being affected (assuming both parents phenotypically normal
carriers)
Haemochromatosis
Hereditary Haemochromatosis
-inhertiance type
- what is it
Autosomal recessive disorder of iron metabolism
* Iron overload over time causes organ and tissue damage
* Multi-organ dysfunction due to iron deposition
From:
* Increased iron absorption
* Excess iron accumulation
Haemochromatosis: Clinical Features
- lethargy
As disease progresses, organ damage from iron overload:
* hepatomegaly and cirrhosis
* diabetes
* arthritis
* cardiomyopathy
* hypogonadism, hypothyroidism
* skin pigmentation
* hepatic cirrhosis and increased risk of hepatocellular carcinoma
* Phenotype varies
* Venesection to deplete iron stores
Locus heterogeneity
in Hereditary Haemochromatosis
- Type 1 - HFE gene mutations (C282Y) or (H63D) (95% of HC) (AR)
- Type 2 - juvenile hemochromatosis resulting from mutations in
hemojuvelin (HJV) and hepcidin (HAMP) (AR) - Type 3 - resulting from mutations in the transferrin receptor
protein 2 (TFR2) (AR) - Type 4—non-classical resulting from mutations in the iron
exporter, ferroportin (SLC40A1 gene) (AD)
Sex-linked inheritance
- what is it
-who does it affect
- affects mainly males
- affected males usually born to unaffected parents
(mother asymptomatic carrier and may have affected male relatives) - no male to male transmission
- all daughters of affected males are obligate carriers
X-linked dominant inheritance
- who does it affect
- affects either sex, but more females than males
- females often more mildly and variably affected than males
(because of Lyonisation - random inactivation of parts of one X chromosome in female somatic cells) - child of an affected female, regardless of sex, has 50% chance of
being affected - for an affected male, all his daughters but none of his sons are affected
(distinguishes from autosomal dominant)
Y-linked inheritance
- who does it affect
- affects only males
- affected males always have an affected father (unless it is a new mutation)
- all sons of an affected man are affected
Complications to basic Mendelian pedigree patterns
- Variable penetrance: failure of dominant condition to manifest
(penetrance is simply whether or not a trait ‘manifests’ = ‘is expressed’) - Variable expressivity (including anticipation)
(variable expressivity is when the clinical phenotype varies between
two individuals with the same genotype)
Genetic heterogeneity
- 2 types and examples of each
Allelic heterogeneity = different mutations at the same locus (same gene)
- cystic fibrosis: >1000 mutations in the CFTR gene
- Locus heterogeneity = mutations at different loci - retinitis pigmentosa
Chromosomal disorders
- EXAMPLE
-cause
Down syndrome (trisomy 21)
-translocation mechanism
Multi-factorial genetic disorders
- result from?
- examples
Result from interaction of many genes, some have major effect and some minor effect
eg diabetes mellitus
hypertension
cleft lip
Somatic Cell Genetic Disorders
-occurs in what cells
-inhertied?
- example
Arise in a single somatic cell then propagates
Not transmitted in generations
Eg cancer
compound heterozygote
Definition: A compound heterozygote refers to an individual who has two different mutated alleles at a specific gene locus, one on each chromosome. Each allele may carry a different mutation, but together, they result in a loss of function or disease phenotype.
