L1+2 (intro)

Question 1

Why is it said diseases are not inherited but have genetic components

Answer 1

Because there are other factors which affect likeliness like epi genetics and environment

Question 2

What are complex diseases

Answer 2

Where more than 1 alleles/variations/mutations work alone or together to cause a risk of disease
(POLYGENIC)

Question 3

What are the 3 models of a genetic disorder

Answer 3

Chromosomal - structural or number changes (less than 1%)

Mendelian - 1-4% monogenic mutations

Complex - polygenic (70-95%)

Question 4

Give some Mendelian mutations types and a disease example of each

Answer 4

Point mutation/substitution (in sickle cell Hbb gene glycine to valine)

Deletion (f508 in cf)

Insertion (Huntington has CAG repeats)

Question 5

What 3 Mendelian inheritance patterns do these diseases follow

Answer 5

Recessive , dominant or sex linked

Eg cf is autosomal recessive so needs both copies

Question 6

When does a Mendelian disorder have 100% penetrance

Answer 6

If it is a dominant disease

Question 7

Why does environment have weak/no impact on if you get the disease (still affects progress and outcome)

Answer 7

Dominant allele = always have phenotype

Question 8

What is Mendels law of segregation

Answer 8

During gamete formation, 2 alleles from each parent segregate into each gamete (get 2 copies m and f)

Question 9

What is independent assortment whcih was discredited due to linkage (where genes on same chr inherited together)

Answer 9

Alleles for different traits segregate indep from eachother

Question 10

What is the difference between somatic cell mutation and gamete mutations

Answer 10

Gamete are passed onto progeny whereas somatic aren’t but can cause some malignancy or congenital diseases

Question 11

What is the difference between de novo and mosaic somatic mutations (not Mendelian as not passed on from parent)

Answer 11

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

Question 12

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

Answer 12

It isn’t Mendelian as it is not a disease present in parents eg trisomy Down syndrome. But is also present in life

Question 13

What is an example in cf Mendelian where another gene modifier exist other than the CFTR gene = Mendelian vs complex overlap

Answer 13

A tgfb1 variant which has been associated to affect severity of the lung disease

Question 14

Do complex/multi factorial diseases follow Mendelian inheritance patterns

Answer 14

No because there are many susceptibility loci/snps and depends more on environment interaction too

Question 15

How can penetrance vary in complex disease

Answer 15

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

Question 16

Which illness has 80% penetrance (AKA REDUCED PENEtrance)

Answer 16

Familial breast cancer if you have the germ line mutation in brca genes

Question 17

Do common variants in popn usually cause penenteance

Answer 17

No it is a combination with some rare low freq variations which can increase risk/ penentrance

Question 18

Give the example of how environment ca n still impact Mendelian diseases

Answer 18

P.aeruginosa exposure more in hot climates which exacerbates Cf

Manganese can interact with Huntingtin mutant gene and reduce the phenotype

Question 19

What makes up most of genetic variation (90%)

Answer 19

SNPs which can then cause disease susceptibility and impact treatment options

Question 20

What do studies on SNPs and disease not take into account

Answer 20

Structural genetic variations like copy number variants which impact the gene dosage causing disease

And other issues like deletions, inversions and translocations

Question 21

Why are SNPs evolutionary

Answer 21

Happened mutations due to selective pressures. Those advantageous SNPs were passed on

Question 22

How many SNPs exist

Answer 22

85 million

Question 23

What is the difference between a mutation and snp

Answer 23

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)

Question 24

Give some examples of how SNPs can be functional (alter genes)

Answer 24

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

Question 25

Are most SNPs non functional

Answer 25

Yes. For example in an intron or don’t change the amino acid sequence

Question 26

What happens in prophase 1 which allows unique homologs one each to 1 gamete

Answer 26

Homologous recombination (alleles/snps not linked)

Question 27

What causes linkage disequilibrium

Answer 27

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

Question 28

What are alleles for diff traits at diff loci on chr inherited together through linkage called

Answer 28

Haplotype

Question 29

What is genotype

Answer 29

A dna sequence at a given locus expressed as AA etc because 2 allelic copies

It determines phenotype

Question 30

What can affect interpretation of findings in case control studies

Answer 30

Confounding factors like age size smoking etc which affect disease risk

Question 31

What is epigentics

Answer 31

modifications that affect gene exp without changing sequence. Heritable but reversible

Question 32

What does hyper acetylation of histone tails do

Answer 32

Repels dna and allows access for gene exp

Question 33

What does hypermethylation on either cpg islands on dna or histone tails do

Answer 33

Makes dna inaccessible for tf etc and forms heterochromatin

Question 34

What other epigentic modification is there other than histone and cpg methylation

Answer 34

Mirna (see further reading)

Question 35

What can change epigenetic patterns eg to have pro or anti cancer effects

Answer 35

Diet, nutrition, ageing, chemical exposure and drugs eg smoking

Question 36

Give example of nutrition having a positive epigenetic effect

Answer 36

Methyl groups can increase activity of certain mirna important to reduce cancerous protein exp

Question 37

Which study design is usually done to study which snps/alleles are significant

Answer 37

Case control through looking at allele frequency in case vs control

Question 38

What does the candidate approach use

Answer 38

Looks at genes who are known to be associated and snps with known functionality ie changing aa sequence or gene exp on that gene.

Question 39

What is the major advantage of candidate approach

Answer 39

Small sample up to 100 people meaning it’s cheap and can easily match case v controls

Question 40

What is the major disadvantage in all of the study designs

Answer 40

Replicabilitt as ofher cultures have diff diet, genetics eg LD frequency and allele frequency.

Question 41

What is the flaw with candidate approaches

Answer 41

Can miss important genes not discovered yet / snps in other disease pathway genes

Question 42

How is the pathway approach different

Answer 42

It still focuses on genes known to be linked to the disease but looks at all the snps even if their functionality is unknown

Question 43

What is the statistical issue with pathway approaches

Answer 43

Many snps analysed so need many stats tests and therefore to increase statistical power need a larger popn and reduced snp number

Question 44

How would you reduce the snp number

Answer 44

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

Question 45

What is some advs of pathway approach

Answer 45

There are some functionality snps there so credible and also can still match controls and cases bc only around 1000 popn size

Question 46

What is the issue with pathway alongside the representation and reliability

Answer 46

Need prior knowledge of all of the disease pathways and the genes involved

Question 47

Which approach is hypothesis free and needs a really large sample

Answer 47

Gwas

Question 48

Why is it hypothesis free

Answer 48

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

Question 49

What I’d the big advantage of gwas

Answer 49

Can identify new pathways / genes and snps not previously known eg the autophagy genes linked to crohns were found by gwas

Question 50

What do you need to do after gwas

Answer 50

Functionality tests to figure out the impact of the genes/snps

Question 51

What cannot be controlled for in gwas

Answer 51

Perfect matches with case and controls causing false positives

Question 52

Which genetic variant is involved in diseases like Alzheimer’s, schizophrenia and crohns which can’t be tested via gwas

Answer 52

Cnvs

Question 53

What else do gwas not study the impact of aswell as the other methods

Answer 53

Epi genetics , microbiome , LD patterns in other countries and their allele frequencies