Genetics Flashcards
What are the 4 major groups that genetic diseases can be classified into?
Single-gene (Mendelian): mutation of a single gene, e.g. cystic fibrosis.
Chromosome: where entire chromosomes are altered, i.e. they are missing, duplicated or altered in other ways.
Mitochondrial: Alteration in a small cytoplasmic mitochondrial chromosome.
Multifactors: a combination of multiple genetic and environmental causes.
How can mendelian diseases be classified?
Autosomal: diseased gene is on autosomes (our chromosomes with the exception of sexualk chromosomes).
X/Y linked: diseased gene is on sexual chromosomes.
Dominant: expressed in heterozygous individuals.
Recessive: expressed in individuals homozygous for the recessive allele.
Mutation: DNA sequence changes that cause genetic disease and are consequently relatively rare in the general population.
Polymorphism: common variation in population with an estimated frequency >1%. This is important as it drives evolution.
What is polymorphism?
Common variation in population with an estimated frequency >1%. This is important as it drives evolution.
Describe germline vs somatic mutations.
Somatic: occurs in a single body cell and can’t be inherited.
Germline: occurs in gametes and can be passed down to offsprings.
What is a splice site mutation?
Occurs in an intron-exon boundary altering the splicing signal that is necessary for the proper excision of an intron.
The exon can be skipped, so the mRNA lacks this exon. Sometimes there can be the inclusion of the intron region.
What does a promoter mutation result in?
A promoter mutation alters the affinity of RNA polymerase for a promoter site resulting in the alteration of the transcription level of the gene.
Describe a static mutation.
Mutation that is stably transmitted towards somatic cells in the next generation.
Each somatic cell has a copy of the mutation in its genome. E.g. sickle cell.
Describe a dynamic mutation.
Associated with TNR - arise from mutations during replication, repair or recombination.
Highly unstable leading to somatic and germline instability.
Describe static mutation.
Mutation in the germline that is stably transmitted towards somatic cells in the next generation.
Each somatic cell has a copy of the mutation in its genome. E.g. sickle cell.
Describe dynamic mutation.
Associated with TNR (tricleotide repeat expansion) - arise from mutations during replication, repair or recombination. They are caused by an increase in TNRs.
Highly unstable leading to somatic and germline instability.
What is somatic mosaicism?
2 genetically different cell lines in the same person.
What is germline mosaicism?
2 genetically different cells in the reproductive cells (or precursors) of each person. This is transmitted to offspring.
Describe the diseases associated with dynamic mutations.
Identified as the cause of more than 50 genetic diseases, mostly neurological.
They mutate between different tissues and across generations.
The longer the tract lengths of TNR, the more likely the repeat will continue to mutate.
Disease is more severe in successive generations.
Genetic anticipation - each generation the disorder becomes worse.
Describe a hypothesis to explain the instability caused by too much TNRs.
Gives DNA a different non-canonical form.
Due to the repetitive nature of dynamic mutation, a single-stranded loop is formed by the TNRs.
In the next round of replication, DNA polymerase has difficulting replicating it, causing an increased number of repetition.
Describe a hypothesis to explain the instability caused by too much TNRs.
Gives DNA a different non-canonical form.
Due to the repetitive nature of dynamic mutation, a single-stranded loop is formed by the TNRs.
In the next round of replication, DNA polymerase has difficulting replicating it, causing an increased number of repetitions.
What happens if expansions in dynamic mutations occur in a coding region?
If expansion occurs in the coding region, the result usually involves a protein containing a stretch of amino acids with an altered function.
This is usually toxic for the cells. An example is Huntington diseases, which is caused by a dynamic mutation. CAG repetition.
What happens if expansions in dynamic mutations occur in a coding region?
If expansion occurs in the coding region, the result usually involves a protein containing a stretch of amino acids with an altered function.
This is usually toxic for the cells. An example is Huntington diseases, which is caused by a dynamic mutation. CAG repetition, causing a strong of glutamines in the protein huntington.
Describe fragile X syndrome as a dynamic mutation.
Repetition is CGG and localised in the regulatory 5’ region.
This means that there can be a hypermethylation of the promoter of a gene, causing gene silencing and thus loss of protein function.
Describe the condition albinism.
Caused by a mutation in the gene encoding for tyrosinase, a tyrosine-metabolizing enzyme. This tyrosinase deficiency leads to a block in the metabolic pathways resulting in the synthesis of melanin.
Consequently a lack of melanin causes the affected person to have little pigment in their skin, eyes and hair.
As melanin is also involved in the development of optic fiber in the eyes, albinosm can cause nystagmus, strabismus and reduced eye activity.
Describe the condition cystic fibrosis.
The most common genetic mutation in infancy.
Caused by a mutation in a gene that codes for the cystic fibrosis conductance receptor (CFTR).
Describe the location and structure of the CFTR gene.
Locus: the ctrf gene is located on the long arm of human chromosome 7.
Gene structure: abount 250,000 bp long.
Describe the deltaf508 mutation.
Most common in patients with cf, present in approx 50% of patients.
Caused by deletion of a single amino acid at position 508. Located in the STP-binding domain of protein.
What symptoms chracterize cystic fibrosis?
Chronic bacterial infection of the airways and sinuses.
Fat maldigestion due to pancreatic exocrin inefficiency.
Infertility in males due to obstructive azoospermia.
Elevated concentrations of chlorine in sweat.
What is allelic heterogeneity?
Describes conditions with different diseases-causing alleles within the same gene.
What is recurrence?
Probability that an individual offspring will be affected by the disease in question.
Describe chracteristics of autosomal dominant traits.
No healthy carriers.
Females and males exhibit approx equal proportions.
No generations are skipped.
If neither of the parents has the disease, none of the children will have it.
Father to son transmission may be absent (If X-linked).
Describe chracteristics of autosomal recessive traits.
Homozygosity is needed.
The parents are usually both heterozygous carriers.
25% recurrence risk from heterozygous parents.
Consanguinty increases recurrence risk.
What reasons are there for an irregularity in transmission?
New mutation Germline mosaicism Delayed age of onset Reduced penetrance Variable expression Pleiotropy
Describe how new mutations can explain an irregularity in transmission.
The gene transmitted by one of the parents undergo an alteration either in germline or somatic tissues, resulting in change from normal alleles.
Can arise after the formation of a zygote.
This is a frequent cause of appearance of genetic disease in individuals with no prior family history of disorder. The recurrence risk for individual’s sibling is very low but can be 50% in the case of the individual’s offspring with germline mosaicism.
Describe how new mutations can explain an irregularity in transmission.
The gene transmitted by one of the parents undergo an alteration either in germline or somatic tissues, resulting in change from normal alleles.
Can arise after the formation of a zygote.
This is a frequent cause of appearance of genetic disease in individuals with no prior family history of disorder. The recurrence risk for individual’s sibling is very low but can be 50% in the case of the individual’s offspring with germline mosaicism.
Describe how germline mosaicism can explain an irregularity in transmission.
Mosaicism: the existence of 2 more genetically different cell lines derived from the same zygote.
Somatic cells are not affected by the mutation. The recurrence risk can be elevated for future offsprings.
This situation can be suspected when 2 or more offspring will present with an AD (Alzheimer’s) disease when there is no family history.
Describe how delayed age of onset can explain an irregularity in transmission.
Can cause difficulty in deducing mode of inheritance.
It’s not possible until later in life to determine whether an individual carries a mutation, therefore many individuals have children before they develop the disease.
Describe how reduced penetrance can explain an irregularity in transmission.
An individual with the genotype for the disease might not manifest the disease at all, even though they can transmit this to the next generation.
What is penetrance?
Penetrace is a numerical value given by number of affected individuals/number of heterozygotes.
If 10% of obligated carriers of disease causing allele do not have the disease, the penetrance of disease causing genotype is 90%.
Describe how variable expression can explain an irregularity in transmission.
This refers to the severity of the expression of the disease phenotype, which can vary greatly, e.g. Cystic fibrosis.
Consequently parents with mild expressions can transmit to children with severe expressions without realizing so.
