L26 Genetics of Complex Diseases Flashcards
What is a polygenetic disease?
A disease caused by two or more genes
What is a multifactorial disease?
A disease caused by genetics and environmental factors
What is being defined here: ‘The inheritance and expression of a phenotype being determined by the cumulative action of multiple genes at multiple loci.’
A polygenetic disease.
I thought this was multifactorial disease…?
True or false: Genes involved with multifactorial disease are viewed as being dominant or recessive to each other.
False.
Because each involved gene contributes to the final phenotype and environmental factors also play a role, the multiple genes in multifactorial disease are not viewed as being dominant or recessive to each other.
True or false: Genes that contribute to multifactorial diseases segregate in a Mandelian manner, but the phenotype they produce does not.
True
Monogenetic or polygenetic:
Has a single strong, highly penetrant phenotype.
Monogenetic
Monogenetic or polygenetic:
Very common.
Polygenetic
Monogenetic or polygenetic:
Has less penetrant phenotypes
Polygenetic
Monogenetic or polygenetic:
Not dominated by one gene, though a gene could increase susceptibility.
Polygenetic
Monogenetic or polygenetic:
Dominated by one gene, but expression of this gene is regulated by modifier genes that affect the severity of the phenotype.
Monogenetic
What is ‘penetrance’, with relation to genetics?
Penetrance is the fraction of cases carrying a given gene that manifests in a specified phenotype
Single gene disorders are fully penetrant; multifactorial disorders have a low penetrance.
Monogenetic or polygenetic:
Hypertension, obesity, schizophrenia, Alzheimer’s , asthma, diabetes mellitus, MS, coronary artery disease, Crohn’s disease, autism, cancer, migraine, arthritis
Polygenetic
Why is it important to study the genetics of multifactorial disease?
- Identify individuals with an increased risk of disease
- Identify targets for better therapy
- Untangle complexity of gene-environment interactions
- Multifactorial disease affects 60% of the population
What is ‘liability threshold’ when referring to genetic disease?
Some diseases seem to be polygenic, but do not show the typical bell-shaped distribution with its associated severity of disease. Instead, disease symptoms seem to be related to a liability threshold within a distribution that must be passed before the disease is expressed.
How is heritability quantified?
A number between 0 and 1.
0 = no genetic influence
1 = high genetic influence
High heritability does not mean the phenotype is solely determined by genetics - environment may still have an effect.
True or false: Dizygotic twins are genetically identical.
False. Dizygotic twins share roughly 50% of their genes.
Monozygotic twins are genetically identical.
Twins are often studied as part of concordance studies. What is concordance?
Probability (%) that twins (identical or non-identical) will both have the disease, given that one of the pair has the disease.
How are concordance studies used to estimate the heritability of a disease?
Difference between the % concordance in dizygotic twins versus monozygotic twins = estimate of heritability
Define ‘allele’.
One of a number of alternative forms of the same gene.
What are SNPs?
Single nucleotide polymorphisms
DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered at the same genetic location between different chromosomes (either within an individual or between individuals)
To be considered a SNP, the variation must occur in what percent of the population?
More than 1%
SNPs are responsible for what percentage of human genetic variation?
~90%
True or false: Most SNPs have no effect on protein function.
True.
Why are SNPs useful in genetic research?
SNPs can act as biological markers that help us identify genes associated with disease.
They can be used to map haplotypes.
Define ‘haplotypes’.
Disease-linked genomic loci that are physically linked on a chromosome and segregate together.
What is GWAS?
Genome-wide association study.
Compare patient DNA to non-patient DNA to identify disease-specific SNPs.
True or false: Chromosomal disorders are usually de novo, but can be inherited.
True
Trisomies, deletions, duplications, translocations are all types of what kind of disorder?
Chromosomal disorders
What term is being defined:
‘presence of an abnormal number of chromosomes in a cell’
Aneuploidy
Humans should have 46 chromosomes
Triple X syndrome is an example of chromosome aneuploidy. What is it?
Additional sex chromosome
47 chromosomes
XXX
Affects 1 in 1000
Klinefelter syndrome is an example of chromosome aneuploidy. What is it?
Additional sex chromosome
47 chromosomes
XXY
Affects 1 in 1000
XYY syndrome is an example of chromosome aneuploidy. What is it?
Additional sex chromosome
47 chromosomes
XYY
Affects 1 in 1000
Turner syndrome is an example of chromosome aneuploidy. What is it?
Missing sex chromosome
45 chromosomes
Xo
Affects 1 in 2000-5000
Why is chromosome aneuploidy almost always deleterious (harmful)?
Because it results in genetic imbalance, interfering with normal genome function.
What are autosomal chromosomes?
Non-sex chromosomes
22 pairs of autosomal chromosomes
What is trisomy-21?
Down’s syndrome
Affects 1 in 800-1000
What is trisomy-18?
Edward syndrome
Affects 1 in 6000
What is trisomy-13?
Patau syndrome
Affects 1 in 10,000
What is DiGeorge syndrome?
Chromosome deletion.
Deletion of band 11.2 on long arm of chr 22.
~3 Mb deleted, containing ~45 genes
Prevalence: 1:4000
Risk: 0.025% in population
Cardiac defects, facial dysmorphia, thymic aplasia, cleft palate, hypocalcaemia, learning difficulties, T-cell immunodeficiency
What is meiotic nondisjunction?
During gamete formation the chromosomes should split and give a chromatid to each daughter.
nondisjunction is failure of chromatids to separate during meiotic division. Results in a gamete with 2 chromatids and a gamete with none. Leads to trisomy and monosomy diseases, such as Down’s syndrome (trisomy-21)
