Genetics Flashcards
Consanguinity
When relatives who are second cousin/ closer, have children.
- Child is inbred due to sharing common ancestor
- Increases the likelihood of child inheriting recessive conditions
Due to genetic similarity being greater, the parents are more likely to have same copies of mutated genes
- More likely for child to inherit two copies of the same mutated gene shared by parents.
Probability of offspring inheriting 2 copies of ancestral allele is 0.0156 or higher (F inbred coefficient)
Relatedness of parents and inbreeding coefficient
The more related a parent is, the higher the inbreeding coefficient
- More likely to share identical genes
This increases poor outcomes of health as homozygous mutations are more likely to be shared.
Genomic imprinting
Process that causes genes on homologous chromosome to be expressed in a parent-of-origin/ parent-specific manner.
- Modification= some of genes in the allele from one parent is turned off
Causes of this is hypothesised in ‘parental conflict hypothesis’
- Imprinting occurs due to differing interest of each parent for evolutionary fitness
- I.e. growth promotion more expressed for father
Example - IGF2 is only expressed from allele inherited from father.
Imprinting centres
Areas of the genes that control genomic imprinting.
Methylation of the gene switches it off.
Prader willi syndrome
Disease caused by mutation of epigenetic genes - genomic imprinted genes
Paternal copies of the active gene is deleted whilst maternal copies are silent gene on chromosome 15.
- Located on long arm (15q11-13)
- Protein is unable to be produced
Phenotype
- Mental retardation
- Life expectancy around 30
- Hypotonia
- Obesity
- Male hypogenitalism
Angelman syndrome
Imprinting genetic condition caused by deletion of maternally expressed genes on chromosome 15
- Deletion on long arm (15q11-13)
- Paternal gene is silent.
Phenotype
- Mental and growth retardation retardation
- Lack of speech
- Hyperactivity
- Inappropriate laughter
Autosomal dominant disorders
Disorders where mutations causes modification of the gene’s function/ expression.
- Inheriting the mutation means that the disorder is inherited.
Examples
- Huntington’s chorea
- Acondroplasia
Autosomal recessive disorders
Disorders where the mutation causes a loss of function for a gene product.
- Due to insertions/ deletions/ premature stop codons/ frameshift mutation.
Examples
- SCD
- CF
- Phenylketonuria
Achondroplasia
- Description
- Mutation
Disorder that causes abnormality of cartilage formation.
- Due to mutation in fibroblast growth receptor 3 (FGR3)
Autosomal dominant disorder
- Although, most of the cases are ne novo mutations (7/8)
Retinoblastoma
- Description
- Inheritance
Tumour of the retina that arises due to mutation of Rb gene
- Inherited in autosomal dominant fashion
Has 90% pentrance
- 10% with the mutation are obligate carriers
Obligate carriers
Someone who carries a mutation for a disorder but does not express the mutation
- Therefore does not show phenotype for disorder.
The greater the proportion of obligate carriers for a condition, the less the penetrance is for the disorder.
Huntington’s disease
- Description
- Genetics
Progressive neurodegenerative disease caused by expansion of CAG repeats in the huntington gene, chromosome 4.
- Polyglutamine disorder= excess glutamine production
- Unstable repeat number= 36+
- Repeat numbers increases with age.
Characterised by
- Dementia
- Severe depression
- Chorea
Autosomal dominant disorder
- Age dependent penetrance: age of onset is lower +/ severity is worse in successive generations (anticipation)
Anticipation
A genetic disorder in which the symptoms become more apparent with each successive generation it’s passed on to.
- Can also show an increase in severity of symptoms
- Common in trinucleotide repeat disorders
Example: Huntington’s, myotonic dystrophy
Age dependent penetrance
Genetic mutation that only develops depending on the age.
Example:
- Huntington’s onset is younger that more the CAG repeats increase
- Male pattern baldness is X-linked and develops in later years.
Variable expression
The degree in which a genotype is phenotypically expressed.
- Multiple people with the same disease can have the same genotype but one may express more severe symptoms, while the other may appear normal.
Example
- Neurofibromatosis
- Marfan’s
Neurofibromatosis
- Description
- Mutation
- Types
- Genetics
Autosomal Dominant conditions that causes tumours of the nervous system.
- NF1 mutation on chromosome 17, a tumour suppressor gene
Types
- Type 1, 2 and schwannomatosis
- The severity of the parent’s disease does not affect how severe the condition will be in the child= variable expression.
- Causes spots (cafe au lait) on skin, freckles and scoliosis.
X-linked disorders
Mutations carried on the X-chromosome
- Which contains a lot more genes than Y.
Condition mainly affects males and is inherited from the mother
Examples
- Haemophilia
- Fragile X
Haemophilia
X-linked, recessive disorder characterised by a lack of clotting factors.
- Leading to the tendency to bleed.
- Most common in males. If female requires homozygous inheritance of mutation, which is very unlikely.
Haemophilia A
- Lack of factor 8
Haemophilia B
- Lack of factor 9
Fragile X
X-linked disorder characterised by CGG expansion in FMR1 gene
- Most common single-gene cause of autism/ inherited mental retardation
Normal range of repeats =<54
Premutation= 55-200
- Reduced penetrance
Fragile X allele= 200-1300 repeats
Repeats increases as it is passed through the female line, in which the severity increases with each inheritance.
Lyonization
X-chromosome inactivation
- Occurs early in embryogenesis in females to avoid overexpression of X genes
X chromosome from mother/father is randomly selected and condensed to be inactive= bar body
This can lead to a female inheriting a condition and not expressing it, but showing reduced penetrance.
Germiline mosaic
Where during embryogenesis, mutation occurs in the germline cells.
- This leads to the parent not having the condition, but can pass on the mutation to their offspring.
Example
- 15% of Duchenne muscular dystrophy occurs from germline mosaics
Mitochondrial inheritance
Mutation occurs in mitochondrial and is almost exclusively pass on from the mother
- As the sperm loses mitochondria during fertilization
Genetic tests
- Samples
- Types
Done through blood/ saliva/skin sample.
Prenatal= amniocentesis/ chorionic villus sampling
Types
- Diagnostic tests= identifies/ exclude specific genetic conditions.
- Carrier tests= sees if individual carries mutations
- Predictive/ presymptomatic test= family history of serious, later onset genetic condition (i.e Huntington’s disease)
- Exome tests= looks at expression of all genes, looking for the genetic change causing the disorder
- Whole genome test- Looks at entire genome, including non-coding regions
- New born blood spot screening tests= screens for multiple conditions (i.e. SCD, CAH, MCAD)
Locus heterozygeneity
Mutation that occurs at different genetic loci but cause the same/ similar phenotype.
Example
- Haemophilia A/B
-
Alleic heterogeneity
Where a single phenotype can be produced by multiple mutations on the same locus of a chromosome
Examples
- Beta-thalassemia
- Phenylketonuria
- Achondroplasia
Promotor nucleotide sequence
TATA
Start codon
ATG
Splice site nucelotide sequence
GT
AG
Stop codons (3)
TAG
TAA
TGA
Classes of mutation (5)
Deletions
Insertions
Single base substitution
- Missense: substitution of amino acid
- Nonsense: insertion of premature stop codon.
- Splice site; formation of splice site (GT, AG)
Frameshift
Dynamic mutations
Cystic fibrosis
- Most common mutation
- Location and inheritance of mutation
Delta-F508 mutation (most common mutation in whites)
- Deletion of phenylalanine oat 508th amino acid
- CTT deletion
- Loss of function for CFTR
Location on Chromosome 7
- Inherited in autosomal recessive fashion
Phenylketonuria
- Features
- Mutation/ defect
- Inheritance
Features
- Severe learning difficulties
- Fair skin
- Eczema
- Epilepsy
Enzyme affected
- Phenylalanine hydroxylase
Autosomal recessive
Phenylketonuria mutations
- Most common
Exon 7
- 143-410 catalytic domain
Compound heterozygotes
Having two or more different recessive alleles at the same gene locus.
Seen in Phenylketonuria, CF
- Tend to have a less severe form of the condition
Inbreeding coefficient of child for: - Siblings - Half-siblings - Uncle/niece - First cousins - Second cousins
Siblings
- 1/4
Half-siblings
- 1/8
Uncle/niece
- 1/8
First cousins
- 1/16
Second cousins
- 1/32
Chromosome 15 genomic imprinting
In a bialleic gene
- maternal expressed gene is active on the maternal chromosome, while the paternally expressed gene is silent
- Paternally expressed gene is active on the paternal chromosome, whilst the maternally expressed gene is silent.
Huntington’s disease CAG repeats
- Chromosome location
- Stable repeats
- Unstable repeats
Located on chromosome 4
Stable repeats
- 6-35
Unstable
- 36+
36-39 repeats= uninformative test result, reduced penetrance range.
40+ is positive test result.
