Genetic basis of disease Flashcards
(32 cards)
How many chromosomes (pairs) do adult males and females have?
Females = 22 pairs of autosomes + XX
Males = 22 pairs of autosomes + XY
What is an allele?
Individual version of a gene/DNA sequence at a locus on a single chromosome
What do homozygous dominant , heterozygous, and homozygous recessive genotypes look like?
Dominant = AA
Heterozygous = Aa
Homozygous = aa
What is an autosomal dominant disease, how does this affect the heritance of the disease?
What is an example of an autosomal dominant disease and what is the mutation which causes it + what does this lead to?
Aa and AA are affected, aa is unaffected (Only need one mutant copy (A) of the gene to cause disease)
Will be an affected individual in every generation
Achondroplasia - caused by mutation of the gene FGFR3. FGFR3 has a negative regulatory affect on bone growth. The mutated form is constantly active, and so is constantly inhibiting bone growth, leading to shortened limbs
(Example of a gain of function mutation)
What is an autosomal recessive disease, how does this affect the heritance of the disease?
What is an example of an autosomal recessive disease, what mutation causes it and what can this lead to?
Only aa is affected (need 2 copies of the mutant gene to cause the disease)
The disease can skip generations (Not every generation will contain an affected individual)
PKU - mutation in both copies of the gene coding for the enzyme phenylalanine hydroxylase, which is an enzyme that catalyses the conversion of phenylalanine to tyrosine. Can lead to impaired cognitive development due to neurotoxic effects of accumulation of phenylalanine
What is sex-linked inheritance and how does this affect the inheritance of the disease?
Females have 2 of the related genes (one on each X), whereas Males only have 1 (One on the X and none on the Y)
Since sex-linked diseases are usually recessive, males are more likely to be affected than females, as they only have one x chromosome, so only need one mutant version of the gene to be affected
Daughters of affected males and unaffected females will always be carriers
What is an example of a sex-linked disease and how does it work? (how are males more likely to be affected than females?)
Red-green colour blindness
In normal recombination of opsin genes of non-sister chromatids, the red opsin swaps with the other red opsin and the green opsin swaps with the other green opsin. (R+G+)
In red-green colour blindness there is a mutation where there is unequal crossing over of the genes leading to one X chromosome containing 2 green opsins and 1 red opsin (R+G+G+), and the other X chromosome containing only a red opsin (R+G-)
A male only needs to inherit one mutated R+G- chromosome from their mother/father to lack green opsin and be red-green colourblind, whereas females need inherit 2 R+G- chromosomes, one from each parent, to be affected
This means that red-green colour-blindness is a lot more common in males than females
What is sickle cell disorder caused by (in basic terms) and what gene therapy steps involved in treating it?
Point mutation in the gene beta globin, causing deoxyhaemoglobin molecules to stick together and form sickle shaped RBCs
Gene therapy steps:
- Stem cells extracted (from bone marrow)
- Stem cells genetically modified
- Engineered stem cells making healthy haemoglobin and normal red blood cells are injected back into the patient
What is spinal muscular atrophy (SMA), what mutation is it caused by and what does this do?
What gene therapy can be used to treat it?
Severe neuromuscular disorder, causes death of motor neurons
Caused by mutation of the SMN1 gene
Exon 7 is required in the SMN1 mRNA to form normal SMN protein levels
SMN2 frequently skips exon 7, causing lower SMN protein levels (Normal for SMN2)
Gene therapy = Nushersen, blocks the exon 7 skipping in SMN2, to form more SMN proteins to make up for the loss of SMN proteins from the SMN1 mutation
What is penetrance?
The frequency with which a genotype manifests itself in a given phenotype (frequency at which the genotype causes the disease)
e.g. Aa genotype has 100% penetrance in a dominant mutation
What is a gene?
A section of DNA that codes for proteins and is a factor that controls phenotype
What is a locus?
Unique chromosomal location defining the position of an individual gene or DNA sequence
What is the risk ratio (λ), what does it mean when λ = 1, and what does it mean when λ is greater than 1?
How can this help us tell if a disease is genetically caused?
λ = risk for a particular group of people compared to the risk of the whole population
λ = 1 - there is no higher risk for the group compared to the risk for the whole population
If λ increases above 1, then there is a higher risk for the group than the whole population
Genetically caused, if λ increases, the more closely related the group is to the person with the disease e.g. if λ is higher for parents of the infected individual than the λ for cousins, then likely to be genetically based
What is Odd ratio (OR) in terms of genetic disease, and what does it mean when OR = 1, OR >1, and OR < 1
Statistic that quantifies the strength of association between the number of people with the allele and the number of people with the disease
OR = Number of people with allele and WITH disease/ Number of people with allele WITHOUT disease
OR > 1 - positive correlation, people with allele and with the disease is more likely than people with allele without the disease (allele and disease positively correlated)
OR = 1 - No correlation, number of people with allele and number of people with disease are independent of each other
OR < 1 - negative correlation, number of people with the allele without the disease is greater than the number of people with the allele and with the disease
What is a simple genetic disease and what is a complex genetic disease?
Simple = monogenic, caused by the mutation of a single gene with a high OR (allele extremely likely to associate with the disease, so is sufficient to cause the disease by itself). Simple genetic diseases are mostly rare.
Complex = Polygenic, caused by the mutation of multiple genes. The result of the interaction between alleles of several genes with modest ORs - each individual allele not sufficient to cause the condition by itself, but when all put together they cause the condition (accumulative effect).
They result from the interaction between the alleles of several genes, and between genotype and the environment.
What are 5 examples of simple genetic diseases?
Achondroplasia, PKA, CF, SMA, Sickle cell anaemia
What are 2 examples of genetic diseases that can be simple or complex?
Obesity and schizophrenia
What is Polyphagia and how is this linked to obesity?
How is obesity defined?
Polyphagia = abnormally strong sensation of hunger or desire to eat often leading to overeating, doesn’t go away after eating (never feeling full)
Can be caused by genetic factors of obesity, and is a symptom of obesity
Defined using BMI = weight/Height squared (kg/m squared)
BMI > 30 = obese
How is the risk associated with a particular allele quantified, and how is the overall risk calculated?
Effect of each allele = β
β > 0, indicates an increased risk associated with the allele
β = 0, indicates no risk
β < 0, indicates a reduced risk (protection)
Dosage = number of each allele the person has (0,1, or 2)
Risk contributed by each allele = β x dosage
Overall risk = allele1 (β x dosage) + allele2 (β x dosage) + …
What does GLP-1 do? What genetic disease is it linked to?
Helps to regulate blood sugar levels, which in turn talks to the brain to make you feel less hungry and prevent cravings.
Linked to obesity
What is polymorphism?
What is SNP, and how can it be used in GWAS + what is GWAS used for?
Polymorphism = existence of 2 or more variants in a population
SNP = Single nucleotide polymorphism - locus on a chromosome where different individuals have a different DNA base in their genomic sequence
GWAS - studies the SNPs of thousands of patients. Some SNPs are found more frequently in patients with a disease than the controls (OR>1), and therefore that loci can be considered a genetic risk factor for a disease. (GWAS identifies risk locus, rather than specific genes/alleles)
How does GWAS work in determining the risk of a loci in causing genetic disease (including what is an effect allele)?
Usually SNP loci are correlated with disease (not causation)
Effect allele = DNA sequence which causes the disease
As the distance between the SNP and effect allele decreases, the correlation is stronger and is more likely to remain linked through multiple generations
What is trio analysis and how is this different to GWAS?
GWAS = studies unrelated people
Trio analysis analyses DNA from an effected child and both of their parents
2 scenarios - child inherits a risk allele from one or both of their parents OR a mutation occurs producing a “de novo” risk allele (mutation that neither parent has)
Direct sequencing of the patient genome can reveal de novo mutations
What is the difference between somatic and germline mutations, and what type of mutation is cancer caused by?
Germline = mutations in germ cells (sex cells), and those that form gametes
Somatic = mutations in any cell in the body that isn’t part of the germline (isn’t involved in reproduction, so won’t be passed down to future generations)
Cancer is caused by somatic mutations
