GENETICS OF COMPLEX DISEASES Flashcards
how common are single gene mutations in disease?
rare
what are single gene mutations in disease?
Mutations in a gene Dominant/recessive pedigree patterns
Structural proteins, enzymes, receptors, TF
how common are Multifactorial/Complex?
common
how many genes are affected in Multifactorial/Complex?
> 1 gene affected, gene variants
how common are Chromosomal changes?
common
how many genes are affected Chromosomal changes?
100’s of genes affected, e.g. gain/loss of chromosome
how common do Environmental factors affect disease?
very common
give examples of environmental factors that effect disease?
Includes viral/bacterial infections, affect disease penetrance
what is multifactorial inheritance?
The inheritance and expression of a phenotype being determined by the cumulative action of multiple genes at multiple loci.
what effect do the genes have in multifactorial inheritance?
Each gene contributes a small amount to a final phenotype that is also significantly influenced by environmental factors.
what is the effect of each gene contributing to the phenotype in multifactorial inheritance?
As a result these multiple genes are not viewed as being dominant or recessive to each other.
how are the genes arranged in multifactorial inheritance?
These multiple genes do segregate in a Mendelian manner, but the phenotype does not.
what are monogenic diseases?
Have a single strong highly penetrant phenotype
how common are monogenic diseases?
very rare
what are modifiers?
Other genes that affect phenotype severity (e.g. regulate expression of the disease allele) but the primary gene dominates
how common are polygenic diseases?
very common
what are polygenic diseases?
Have lower penetrant phenotypes
Not dominated by one gene though a genetic locus could have a predominant effect (e.g. BRCA1/2 genes in breast/ovarian cancers)
what effect does environmental contribution have on polygenic diseases?
reduces penetrance
what are pedigrees?
more complex
what is penetrance?
the fraction of cases carrying a given gene that manifests in a specified phenotype
what are the 2 factors that cause any trait?
genetics
environment
give examples of polygenic complex diseases?
Obesity, Schizophrenia, Alzheimer’s, Asthma, Multiple sclerosis, Autism, Cancer
Why study genetics of multifactorial disease?
Identify individuals with an increased risk of disease
Understanding may identify targets for better therapy
Untangle complexity of gene-environment interactions
why is complex inheritance the underlying factor for most common human diseases?
Multifaceted interactions of genotypes at multiple loci
Environmental factors that trigger, accelerate or worsen disease development
what is polygenic inheritance?
Traits are usually quantified by measurement
>= 2 genes contribute to the phenotype
does phenotypic variation in polygenic inheritance vary?
yes across a wide range
how is polygenic inheritance best analysed?
in populations rather than individuals
what does the interaction of genes with the environment produce?
a wide range of phenotypes
give an example of polygenic inheritance
adult male height
what are the 2 methods to study multifactorial traits?
Threshold model
Recurrence risk
what is the threshold model?
Frequency of disorder among relatives is compared with the frequency of the disorder in the general population
what is the recurrence risk?
Estimates the risk that the disease will recur
what is the liability threshold?
Measure of the disease state of an individual
When alleles push the distribution towards the liability threshold they are termed ‘risk alleles’ or susceptibility alleles
are all alleles additive?
not all of them
some are dominant, epistatic (=modifier genes), protective
what is heritability?
the proportion of disease variation due to genetic variation
what is monozygotic twins?
Single fertilization
Genetically identical
what is dizygotic twins?
Independent fertilization events
Share approximately half their genes
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 do you estimate heritability?
Difference between the % concordance in dizygotic twins versus monozygotic twins
how do you estimate the genetic, shared environment and non-shared environment contributions?
By looking at the concordance and discordance between mono- and dizygotic twins
how is familial breast cancer caused?
Known genes (e.g. BRCA1&2) involved in familial breast cancer account for <30% of the familial risk
what is autism?
characterized by great difficulty in communicating, forming relationships and in using language and abstract concepts
Known to be strongly influenced by genetics
what is an allele?
one of a number of alternative forms of the same gene
how are disorders inherited?
Studies have shown that an individuals risk of inheriting certain disorders correlates to the relatedness of affected family members (e.g. schizophrenia)
what are Single Nucleotide Polymorphisms
(SNPs)?
DNA sequence variations that occur when a single nucleotide in the genome sequence is altered at the same genetic location between different chromosomes
how are variations considered a SNP?
variation must occur in >= 1% of the population
what do SNPs act as?
While most have no effect on protein function, it is believed they can act as biological markers, helping us identify genes associated with disease
what do SNPs help to understand?
widely differing susceptibilities to complex yet common diseases
what are SNPs used as?
to map haplotypes
what are haplocytes?
disease-linked genomic loci that are physically linked on a chromosome and segregate together
what are GWAS?
genome-wide association study
how many genes are involved in chromosomal disorders?
thousands
what is aneuploidy?
presence of an abnormal number of chromosomes in a cell
Humans should have 46 chromosomes
give examples of aneuploidy affecting sex chromosomes?
Triple-X syndrome (47,XXX) Klinefelter syndrome (47,XXY) XYY syndrome (47,XYY) Turner syndrome (45,X0)
why is aneuploidy nearly always deleterious?
because of genetic imbalance
give examples of autosomal chromosomes?
Trisomy 21, Down syndrome
Trisomy 18, Edward syndrome
Trisomy 13, Patau syndrome
what is DiGeorge Syndrome?
Deletion of band 11.2 on long arm of chr 22
what are the symptoms of DiGeorge Syndrome?
Congenital cardiac defects, facial dysmorphia, thymic aplasia, cleft palate, hypocalcemia, learning disabilities, T-cell immunodeficiency
what causes down’s syndrome?
Meiotic non-disjunction
what is non-disjunction?
failure of chromatids to separate into 2 chromosomes
what effect does non-disjunction have on age?
increases with maternal age
