L1+2 (intro) Flashcards
Why is it said diseases are not inherited but have genetic components
Because there are other factors which affect likeliness like epi genetics and environment
What are complex diseases
Where more than 1 alleles/variations/mutations work alone or together to cause a risk of disease
(POLYGENIC)
What are the 3 models of a genetic disorder
Chromosomal - structural or number changes (less than 1%)
Mendelian - 1-4% monogenic mutations
Complex - polygenic (70-95%)
Give some Mendelian mutations types and a disease example of each
Point mutation/substitution (in sickle cell Hbb gene glycine to valine)
Deletion (f508 in cf)
Insertion (Huntington has CAG repeats)
What 3 Mendelian inheritance patterns do these diseases follow
Recessive , dominant or sex linked
Eg cf is autosomal recessive so needs both copies
When does a Mendelian disorder have 100% penetrance
If it is a dominant disease
Why does environment have weak/no impact on if you get the disease (still affects progress and outcome)
Dominant allele = always have phenotype
What is Mendels law of segregation
During gamete formation, 2 alleles from each parent segregate into each gamete (get 2 copies m and f)
What is independent assortment whcih was discredited due to linkage (where genes on same chr inherited together)
Alleles for different traits segregate indep from eachother
What is the difference between somatic cell mutation and gamete mutations
Gamete are passed onto progeny whereas somatic aren’t but can cause some malignancy or congenital diseases
What is the difference between de novo and mosaic somatic mutations (not Mendelian as not passed on from parent)
De novo is usually mutation early prenatally so present in most cells and all of life
Mosaic happens later in life in some cells meaning some are wt some are mutant cells
Both are not passed on
You can get inherited mutations from both or 1 parent which is then in all cells and passed onto next gen. How is gamete mutations different if it’s still an ‘inherited’ mutatioj
It isn’t Mendelian as it is not a disease present in parents eg trisomy Down syndrome. But is also present in life
What is an example in cf Mendelian where another gene modifier exist other than the CFTR gene = Mendelian vs complex overlap
A tgfb1 variant which has been associated to affect severity of the lung disease
Do complex/multi factorial diseases follow Mendelian inheritance patterns
No because there are many susceptibility loci/snps and depends more on environment interaction too
How can penetrance vary in complex disease
Can be low penetrance if someone has minor alleles that rely on environmental interaction
Also can be reduced penetrance
Some do still have high penetrance if have major susceptibility alleles
Which illness has 80% penetrance (AKA REDUCED PENEtrance)
Familial breast cancer if you have the germ line mutation in brca genes
Do common variants in popn usually cause penenteance
No it is a combination with some rare low freq variations which can increase risk/ penentrance
Give the example of how environment ca n still impact Mendelian diseases
P.aeruginosa exposure more in hot climates which exacerbates Cf
Manganese can interact with Huntingtin mutant gene and reduce the phenotype
What makes up most of genetic variation (90%)
SNPs which can then cause disease susceptibility and impact treatment options
What do studies on SNPs and disease not take into account
Structural genetic variations like copy number variants which impact the gene dosage causing disease
And other issues like deletions, inversions and translocations
Why are SNPs evolutionary
Happened mutations due to selective pressures. Those advantageous SNPs were passed on
How many SNPs exist
85 million
What is the difference between a mutation and snp
For an allele to be an snp the minor allele frequency in the popn needs to be over 4% (how many people have the snp minor allele)
For a mutation the number is below 1% minor allele frequency (must be rare)
Give some examples of how SNPs can be functional (alter genes)
In promoter region- affect tf binding and gene exp levels
In intron- could affect splice site so mrna processing
In 3’5’ utr regions- affect mrna stability
In coding region - missense or nonsense
Intergenic regions - affect silencer or enhancers affecting gene exp
Are most SNPs non functional
Yes. For example in an intron or don’t change the amino acid sequence
What happens in prophase 1 which allows unique homologs one each to 1 gamete
Homologous recombination (alleles/snps not linked)
What causes linkage disequilibrium
When alleles/snps too close on 1 chr to recombine so they get inherited together as linked snps and no hr so it’s from 1 parent
What are alleles for diff traits at diff loci on chr inherited together through linkage called
Haplotype
What is genotype
A dna sequence at a given locus expressed as AA etc because 2 allelic copies
It determines phenotype
What can affect interpretation of findings in case control studies
Confounding factors like age size smoking etc which affect disease risk
What is epigentics
modifications that affect gene exp without changing sequence. Heritable but reversible
What does hyper acetylation of histone tails do
Repels dna and allows access for gene exp
What does hypermethylation on either cpg islands on dna or histone tails do
Makes dna inaccessible for tf etc and forms heterochromatin
What other epigentic modification is there other than histone and cpg methylation
Mirna (see further reading)
What can change epigenetic patterns eg to have pro or anti cancer effects
Diet, nutrition, ageing, chemical exposure and drugs eg smoking
Give example of nutrition having a positive epigenetic effect
Methyl groups can increase activity of certain mirna important to reduce cancerous protein exp
Which study design is usually done to study which snps/alleles are significant
Case control through looking at allele frequency in case vs control
What does the candidate approach use
Looks at genes who are known to be associated and snps with known functionality ie changing aa sequence or gene exp on that gene.
What is the major advantage of candidate approach
Small sample up to 100 people meaning it’s cheap and can easily match case v controls
What is the major disadvantage in all of the study designs
Replicabilitt as ofher cultures have diff diet, genetics eg LD frequency and allele frequency.
What is the flaw with candidate approaches
Can miss important genes not discovered yet / snps in other disease pathway genes
How is the pathway approach different
It still focuses on genes known to be linked to the disease but looks at all the snps even if their functionality is unknown
What is the statistical issue with pathway approaches
Many snps analysed so need many stats tests and therefore to increase statistical power need a larger popn and reduced snp number
How would you reduce the snp number
Tag Snps
These snps capture the genotypes of all snps because they are in a haplotype meaning if this tag snp is associated the other snps in the hapolotype must be disease associated too
What is some advs of pathway approach
There are some functionality snps there so credible and also can still match controls and cases bc only around 1000 popn size
What is the issue with pathway alongside the representation and reliability
Need prior knowledge of all of the disease pathways and the genes involved
Which approach is hypothesis free and needs a really large sample
Gwas
Why is it hypothesis free
Because you have no prior knowledge you simultaneously genotype all snps / tagsnps then do stats tests for all loci to determine if it’s associated
What I’d the big advantage of gwas
Can identify new pathways / genes and snps not previously known eg the autophagy genes linked to crohns were found by gwas
What do you need to do after gwas
Functionality tests to figure out the impact of the genes/snps
What cannot be controlled for in gwas
Perfect matches with case and controls causing false positives
Which genetic variant is involved in diseases like Alzheimer’s, schizophrenia and crohns which can’t be tested via gwas
Cnvs
What else do gwas not study the impact of aswell as the other methods
Epi genetics , microbiome , LD patterns in other countries and their allele frequencies
