203 L4 Flashcards
Mutations and disease
A mutation is a change in the ——- sequence of ———
This is reflected in the —- and then the —- that we see
Can expect that a change in the ——- sequence of a gene will cause a change in the ——– coded by that gene
New mutations arise in ——– cells and accumulate as we —— or in the ——- when the mutations can be transmitted to the ———-.
If a ——— mutation does not seriously impair an individual’s ability to have ——– it can spread
De novo mutations - variations in DNA sequences result in new mutations. This is rare because most mutations are ————.
If someone has a mutation that neither the mother or father have then it is a — —- mutation.
Use agarose —— ———- to determine if the mutation has been ———- by either parent or occurs in any siblings.
Most disease associated mutations are ————-
Mutations can be positive (selective advantage e.g. 32bp deletion in the human chemokine receptor that confers HIV resistance), neutral, damaging or lethal
A mutation is a change in the base sequence of DNA
This is reflected in the mRNA and then the protein that we see
Can expect that a change in the base sequence of a gene will cause a change in the product coded by that gene (protein)
New mutations arise in somatic cells and accumulate as we age or in the germline when the mutations can be transmitted to the offspring.
If a germline mutation does not seriously impair an individual’s ability to have children it can spread
De novo mutations - variations in DNA sequences result in new mutations. This is rare because most mutations are inherited.
If someone has a mutation that neither the mother or father have then it is a de novo mutation.
Use agarose gel electrophoresis to determine if the mutation has been inherited by either parent or occurs in any siblings.
Most disease associated mutations are inherited
Mutations can be positive (selective advantage e.g. 32bp deletion in the human chemokine receptor that confers HIV resistance), neutral, damaging or lethal
Origins of new mutations
Endogenous mutations
Due to ———– errors in DNA ———– and ———-. The ————- mechanism of the cell picks up on these ———–
There is 1 nucleotide change per cell division
Mutagens - the environment
The occurrence of mutations can be ———– by treatment with certain compounds called ———– - physical or chemical (e.g. UV light, smoking)
Most mutagens act directly by virtue of an ability either to damage a particular nucleotide or to become incorporated into the nucleic acid
Due to spontaneous errors in DNA replication and repair. The Proofreading mechanism of the cell picks up on these mutations. There is 1 nucleotide change per cell division
Mutagens - the environment
The occurrence of mutations can be increased by treatment with certain compounds called mutagens - physical or chemical (e.g. UV light, smoking)
Most mutagens act directly by virtue of an ability either to damage a particular nucleotide or to become incorporated into the nucleic acid
Chromosome disorders
Have quite pronounced effects
Due to an excess of deficiency of the genes contained in whole chromosomes or chromosome segments = many genes
Due to a change in the number of chromosome
Often occur during the formation of the zygote, often occur within the egg (when we age)
- Translocations
- Delections (e.g. cri, du chat syndrome)
- Duplications
- Inversions
- Chromosome loss (e.g. XO = Turner syndrome)
- Chromosome duplications (e.g. trisomy 21 = down syndrome)
Are rare in live born infants, but occurs about 50% in all spontaneous 1st trimester miscarriages (tested by CGH)
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Trisomy 13 - Patau syndrome
Due to the error in the cell —— of the —— - non ———–
Results in the ——- having an increased number of ——— - chromosome —– has 3 copies instead of 2
Increasing risk with ———- age (exponential rise after 30 years old)
In 95% of cases of Patau syndrome a ————- is initiated, live births rarely survive beyond 1 year, disruption of ——- and ——- development
Features include - Holoprosencephaly (failure of the ——– to divide properly), ——— defects, dysmorphology, seizures, severe mental retardation
Due to the error in the cell division of the egg - non disjunction
Results in the egg having an increased number of chromosomes - chromosome 13 has 3 copies instead of 2
Increasing risk with maternal age (exponential rise after 30 years old)
In 95% of cases of Patau syndrome a miscarriage is initiated, live births rarely survive beyond 1 year, disruption of kidney and heart development
Features include - Holoprosencephaly (failure of the forebrain to divide properly), Heart defects, dysmorphology, seizures, severe mental retardation
Monosomy - 45 XO Turner’s syndrome
Complete or partial —- chromosome monosomy (chromosome lacks its homologous partner)
Lymphedema - swelling of the hands and feet
Gonadal dysfunction - no menstruation
Complete or partial X chromosome monosomy (chromosome lacks its homologous partner)
Cri du chat syndrome or 5p monosomy
——- deletion of chromosome ——
90% of cases are not inherited, 10% are balanced translocation
Individuals are fertile and are able to reproduce
Partial deletion of chromosome m5p
Single gene (monogenic) disorders
Caused by individual mutant genes
May be recessive or dominant
May be contained in the mitochondrial or nuclear genomes
Usually exhibit obvious pedigree patterns (inheritance through a family)
Individually rare, but are responsible for a significant portion of disease and death
Affects 2% of the population
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Substitution mutations
Silent mutations
Often occurs in the —– base position. There is —– change in the —- —–. you would only notice this mutation if the gene was —–.
Nonsense mutation Replacement of —— ——- with a ——– codon dramatically causing a reduction in gene ———. Leads to protein ———-.
Missense mutations
Replacement of ——- —– with different —– ——
Conservative: replacement amino acid is ——- = —— effect on function
Non-conservative: replacement amino acid is ———- = more ——– effect on function
Silent mutations
Often occurs in the 3rd base position. There is no change in the amino acid. You would only notice this mutation if the gene was sequenced.
Nonsense mutation Replacement of amino acid with a stop codon dramatically causing a reduction in gene function. Leads to protein truncation.
Missense mutations
Replacement of amino acid with different amino acid
Conservative: replacement amino acid is similar = minimal effect on function
Non-conservative: replacement amino acid is dissimilar = more serious effect on function
Molecular pathology
Mutation = Altered ——- = abnormal —- = disease
There is a clear correlation between ——- and phenotype
Sometimes you can use the —– to predict the ——-.
Mutation = Altered protein = abnormal function = disease
There is a clear correlation between genotype and phenotype
Sometimes you can use the genotype to predict the phenotype.
Pathogenic mutations occur in:
———- ———- regions (—–)
Majority of recorded pathogenic mutations
Includes non-synonymous mutations
Mutations disrupting —– stability or —– splicing
Mutations in the ——- sequences
10% of total mutations
——— have to be spliced out from the ——- in order to get the correct —— formed, so when things go wrong in that process it can result in ——-.
Mutations affecting —– regulation or dosage
Promotor/enhancer region mutations
1% of total mutations
Gene regulation or dosage - e.g. abnormal amounts of the protein being expressed, protein being expressed in the wrong place
protein coding regions (exons)
Majority of recorded pathogenic mutations
Includes non-synonymous mutations
Mutations disrupting RNA stability or RNA splicing
Mutations in the intronic sequences
10% of total mutations
Introns have to be spliced out from the mRNA in order to get the correct protein formed, so when things go wrong in that process it can result in disease.
Mutations affecting gene regulation or dosage
Promotor/enhancer region mutations
1% of total mutations
Gene regulation or dosage - e.g. abnormal amounts of the protein being expressed, protein being expressed in the wrong place
What is a frameshift mutation?
Insertion or deletion of a base or bases.
Frameshift mutations
Results in a different sequence of ——- —– from the point of ——- or ——-, usually ending in a premature ——- of the ——.
Usually when they occur in a multiple of ——– they are —– severe, as they don’t change the ———- frame
Usually associated with severe ———.
Results in a different sequence of amino acids from the point of deletion or insertion, usually ending in a premature truncation of the protein.
Usually when they occur in a multiple of 3 they are less severe, as they don’t change the reading frame
Usually associated with severe phenotypes.
The effect of the premature protein truncation (smaller protein) will depend on:
The ——— of the ———– product
The extent of the ——–
The ———- importance of the missing ——- ——-.
The stability of the polypeptide product
The extent of the truncation
The functional importance of the missing amino acids
Autosomal recessive inheritance
Appears mainly in the ——- of the proband, not in the —–, —— or other relatives
Males and females are —– affected
Parents of the affected child are ———— carriers of the —— allele so are unaffected.
The risk for each sibling of the proband is — in —-.
Not many people are ——– because you need —– copies of the gene to have the condition.
Name an disease that results from autosomal recessive.
Appears mainly in the siblings of the proband, not in the parents, offspring or other relatives
Males and females are equally affected
Parents of the affected child are heterozygous carriers of the mutant allele so are unaffected.
The risk for each sibling of the proband is 1 in 4.
Not many people are affected because you need 2 copies of the gene to have the condition.
Name an disease that results from autosomal recessive
Cystic fibrosis
Rare
Carriers are not clinically recognisable
Common in caucasian children
In heterozygotes the normal copy of the gene creates enough good protein to compensate.
Autosomal dominant inheritance
The ——- usually appears in every generation, each affected person has an affected ——–.
Any child of affected parent has —–% risk of inheriting the trait
————- normal family members do not transmit the ——— to their children.
Males and females are —– affected.
Autosomal dominant disease:
myotonic dystrophy
Severity of phenotype increases with each ——–.
The phenotype usually appears in every generation, each affected person has an affected parent.
Any child of affected parent has 50% risk of inheriting the trait
phenotypically normal family members do not transmit the phenotype to their children.
Males and females are equally affected.
Autosomal dominant disease:
myotonic dystrophy
Severity of phenotype increases with each generation.
X-linked recessive inheritance
Males have a single — chromosome
Females have two —, one of which is ————.
The incidence is much higher in ——- than in ———-.
Heterozygous ——- are usually ———-/mildly ——- due to random —- ———–.
An affected —— will pass on the gene to all of the daughters, who will be ——-.
The gene is normally never transmitted directly from the —– to the —— because they inherit the —–.
The gene may be transmitted through a series of carrier —-.
e.g. Androgen insensitivity syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Hamophilia.
Males have a single X chromosome
Females have two X’s, one of which is inactivated.
The incidence is much higher in males than in females.
Heterozygous females are usually unaffected/mildly affected due to random X inactivation.
An affected male will pass on the gene to all of the daughters, who will be carriers.
The gene is normally never transmitted directly from the father to the son because they inherit the Y.
The gene may be transmitted through a series of carrier females.
e.g. Androgen insensitivity syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Hamophilia.
Random X-inactivation
Within each cell you can get the random ———– of — of the two —- chromosomes
This means that you can get enough of the —— product to not see the phenotype. As a result the disease is ——- in ———- females.
Within each cell you can get the random inactivation of 1 of the two X chromosomes
This means that you can get enough of the good product to not see the phenotype. As a result the disease is milder in heterozygous females.
X-linked dominant
Affected males with normal mates have no affected —- and no normal ——–.
Male and female offspring of ——- carriers have a —% risk of inheriting the phenotype.
Affected ——- are about twice as common as affected ——, but the affected ——– usually have a milder disease.
E.g Retinitis pigmentosa, Rett syndrome and vitamin D resistant rickets, congenital generalized hypertrichosis.
-linked dominant
Affected males with normal mates have no affected sons and no normal daughters.
Male and female offspring of female carriers have a 50% risk of inheriting the phenotype.
Affected females are about twice as common as affected males, but the affected female usually have a milder disease.
E.g Retinitis pigmentosa, Rett syndrome and vitamin D resistant rickets, congenital generalized hypertrichosis
Y-linked dominant
Affects only males
Affected males always have an affected father (unless there is a sporadic mutation
All sons of an affected man are affected
Example - non obstructive spermatogenic failure due to mutations in USP9Y
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