17/ human genetics 4

Question 1

3 different possible architectures of complex disease

Answer 1

• small number of dominant alleles confer large increase in risk
• common variant model - many alleles confer a small increase in risk
• intermediate - one major allele exerts major effect, plus many other lower risk alleles

Question 2

how many common SNPs (single nucleotide polymorphisms) are there

Answer 2

11 - 15 million

Question 3

what is a common SNP

Answer 3

the Minor Allele Frequency is greater than 5%

Question 4

where can SNPs occur

Answer 4

• coding regions: synonymous (no amino acid change) or non-synonymous (missense or nonsense mutation)
• non coding regions: affect gene expression

Question 5

what do WES and WGS stand for

Answer 5

whole exome sequencing, whole genome sequencing

Question 6

what is the gnomAD database

Answer 6

• exome and genomes from unrelated individuals sequenced
• for disease specific and population genetic studies
• records frequency of alleles in a pop
• documents rare mutations

Question 7

how do you carry out a genome wide association study GWAS

Answer 7

• examine a panel of SNPs in the genome for association w disease phenotype
• search for alleles that occur more frequently in disease cases than unmatched controls
• need huge number of participants to get results

Question 8

explain the missing heritability problem in GWAS

Answer 8

• many risk loci not yet identied

Question 9

linkage equilibrium

Answer 9

• method by which a SNP correlates w a risk allele
• non-random association of alleles at different genomic sites
• depends on: distance between alleles, recombination rate

Question 10

what are haplotype blocks

Answer 10

• summarises patterns of LD in the human genome
• regions of high LD separated from other haplotype blocks by many historical recombination events

Question 11

what happens in haplotype mapping

Answer 11

• single SNP can identify a cluster of alleles, since groups of alleles are clustered
• Tag SNP

Question 12

are SNPs associated with a disease risk alleles?

Answer 12

• they can be but not always
• need further studies to determine causation

Question 13

how do you measure the likelihood of a SNP being associated w a disease

Answer 13

• odds ratio - or
• or = 1 : events are independent
• or > 1 : events are positively correlated
• or< 1 : events are negatively correlated

Question 14

what is the common disease common variant CDCV

Answer 14

• theory that multiple alleles increase risk of a disease
• multiple alleles w or<1.2 showing weak association w disease phenotype

Question 15

what is the p value for genome wide significance, what does this mean about false negatives/positives

Answer 15

• p< 5 x 10 ^-8
• false negatives very likely

Question 16

3 alleles that confer risk for type ii diabetes

Answer 16

• TCF7L2: greatest risk, intronic variant, TF required for pancreas development
• FTO: intronic variant, body weight regulation
• CDKN2A/B: non coding regulatory variant

Question 17

lifetime risk for breast cancer in females

Answer 17

8-12%, risk increases if 1st degree relatives have it

Question 18

2 risk alleles for breast cancer, what % of breast cancer cases have these risk alleles

Answer 18

• BRCA1, BRCA2 - autosomal dominant
• 5%

Question 19

heritability definition

Answer 19

proportion of variance in a particular phenotype in a pop that is due to genetic variation

Question 20

what can missing risk be caused by/ what genetic factors that increase a disease risk cant be identified in GWAS

Answer 20

• false negatives in GWAS
• rare variant alleles w MAF 1-5%
• structural alteration of genome
• epigenetics
• 3d genome organisation