Pedigrees + inheritance (just key stuff) Flashcards
What is autosomal linkage?
When it is located on an autosome (chromosome 1-22)
What it X-linked/Y-linked?
Gene located on the X or Y chromosome
What is a locus?
The position/site on a chromosome where a gene is located
What is an allele?
Alternate forms of a gene
What is a heterozygote?
Different alleles at the same locus
What is a homozygote?
Identical alleles at the same locus
What is a genotype?
An individual’s genetic constitution
What is a phenotype?
Observed effect of the action of a gene or genes
What is a propositus vs a proposita?
Propositus = A male index case
Proposita = A female index case
What are the 5 patterns of inheritance that we cover?
- Autosomal Dominant
- Autosomal Recessive
- X-linked Recessive
- X-linked dominant
- Maternal (mitochondrial)
What are the characteristics of autosomal dominant inheritance?
- Found in heterozygous stae
- Transmitted from one generation to next
- Can arise thru new mutation
- Can be followed in family tree
- Usually affects males & females equally
- Have a 1 in 2 chance of inheriting from the affected parent
Give examples of Autosomal Dominant diseases:
- Myotonic Dystrophy
- Huntington’s disease
What are the characteristics of Autosomal Recessive inheritance?
- Heterozygotes are healthy –> carriers
- Mutation present in homozygous (double dose of mutation)
- Often cannot be followed in family tree
- Affects males & females equally
- If parents heterozygous for same autosomal recessive condition = offspring 1 in 4 chance of inheriting
- For rare autosomal recessive alleles –> parents of a homozygous may be consanguineous
- Affected person usually born to unaffected parents (parents usually asymptomatic carriers)
What does consanguineous mean?
Mating between 2 closely related relatives
Give an example of an Autosomal Recessive mutation:
Cystic Fibrosis
What happens is a homozygote & a heterozygote for an Autosomal recessive condition mate?
The condition may appear as dominant as children will either be affected or carriers
(in reality the condition is recessive but high chance of inheriting in this fmaily)
What are the 3 ways heterogeneity can occur?
- Locus
- Allelic
- Clinical
What is clinical Genetic Heterogeneity?
Mutations in the same gene that leads to 2 or more different genetic conditions
What is allelic Genetic Heterogeneity?
Differnt mutations within a given gene give rise to the same condition
(Mutation at point 1 or 2 on the gene but both = same condition phenotypically
What is locus Genetic Heterogeneity?
Same clinical phenotype reuslts from mutations at any one of several different loci
When can double heterozgyotes arise?
Double heterozygous parents can lead to a homozygous individual w a mutant allele but at a different locus
e.g. there are at least 16 loci that cause sensorineural deafness
What is a compound heterozygote?
Where there are 2 different mutations at the same locus
What are X-linked recessive mutations determined by?
Determined by a gene on the X-chromsome
What are the characteristics of an X-linked recessive inheritance?
- Traits usually only show in males (as males have 1 X chromosome)
- Male w a mutant X is hemizygous
- X-linked disorder is transmitted by heterozygous female carries to affected males
- 1 in 2 males from carrier females affected
- Affected males may transmit to carrier daughters but NOT sons (sons inherit Y from father = no transmission)
- Pedigrees can show ‘diagonal’ or ‘knights’ move transmission
- Mother is typically aymptomatic carrier
Can male-to-male tranmission occur in X-linked recessive disorders?
No male to male transmission
Bc son will inherit Y from dad so cannot physically pass on the disorder
Give examples of X-linked recessive disorders:
- Duchenne muscular dystrophy
- Fragile X syndrome
- Haemophillia
How can females be affected by X-linked recessive disorders?
If the father is affected & the mother is a carrier
Or
Nonrandom X-inactivation
Read thru other possibilities for X-linked recessive disorders
Bottom of page 10 notes
What are the characteristics of a X-linked Dominant inheritance?
- Males & females may be affected –> demales more common (bc 2 copies of X chromosome)
- Females usually less severely affected than males
- Affected females transmit to BOTH sons & daughters
- Affected males transmit to all daughter but NOT SONS (give sons Y chromosome)
- Child of an affecte female, regardless of its sex, had 50% chance of being affected
Give an example of X-linked Dominant Inheritance:
Vitamin D Resistance Rickets
What are the characteristica of maternal (mitochondrial) inheritance?
- Mithcochondrial inheritance –> expected to be inhertied from mum as all mitochondria inherited from motehr
- Maternally inherited so will affect BOTH males & females
- Note–> incomplete penetrance of phenotype in some examples (due to multiple type of mitochondria (multiple types inherited) - due to different levels of mutations, some individuals might recieve more mutant copies than others)
What are the 4 other considerations we must make in pedigrees?
- Pleiotrophy
- Variable expressivity
- Penetrance
- Reduced/incomplete penetrance
What is Pleiotrophy?
When a single gene affects multiple traits or charateristics in an organism
What is Variable Expressivity?
Means that the same gene mutation can show up differently in person to person
(Variation in phenotype)
What is Pentrance?
How likely a gene mutation is to show up in someone
(The proportion of heterozygotes for a dominant gene who express a trait, even if mildly)
What is reduced/incomplete penetrance?
Means even with a gene mutation, some ppl may not show the expected traits
(A condition where some heterozygotes with a mutation cannot be detected clinically. An individual who is heterozygous for a dominant mutation but shows no symptoms represents non-penetrance)
What are the 3 main mutation classes?
- Deletions
- Insertions
- Single base substitutions
What are the 5 types of singe base substitutions?
- Missense mutations
- Nonsense mutations
- Splice site mutations
- Frameshift mutations
- Dynamic mutations
What are missense mutations?
Replace one amino acid with another in the gene product
What are nonsense mutations?
Replaces an amino acid with another in the gene product
What is a splice site mutation?
Creaste or destroy signals for exon-intron splicing
What is a frameshift mutation?
Can be produced by deletions, insertions or splicing errors
What is a dynamic mutation?
Tandem repeats that often change size on transmission to children
What are the 4 mutation functional types?
- Gain-of- function
- Dominant-Negative
- Loss-of-function
- Haploinsufficiency
What is a gain of function mutation type?
A mutation which produces a NEW FUNCTION in the resulting gene product
What is a dominant negative mutation type?
A mutation (which in the heterozygous state) results in the LOSS OF FUNCTION/ ACTIVITY of the mutant gene product
This interferes w the function of the gene product from the normal allele (mutant gene distrupts function of the normal gene)
What is a loss of function mutation type?
Mutation which causes absent or REDUCED activity of the gene product
What is a haploinsufficiency mutation type?
Mutations in which the heterozygote state produce HALF THE NORMAL LEVELS of a gene product
Results = ina mutant phenotype i.e. dosage sensitivity
How is linkage analysis used?
No longer used in human genome mapping
Some utility in rare disease gene recovery & risk assessment
Still useful in finding genes in non-human organisms
What does linkage describe?
(Linkage analysis)
It describes the cosegregaation of genetic variants htat are close to each other
Where will linked markers be found?
(Linkage analysis)
Linked markers will be on the same chromosome & close together
What would stop linked markers from cosegregating?
(Linkage analysis)
Linked markers will cosegregate unless a recombination separates them
Tighter linkage = ?
The tighter linkage = the less recombination there is between them
