Genome Variation Flashcards
1
Q
SNP
A
- Single nucleotide polymorphism
- 1% of population
- affect disease, chemical response, pathogen response, comparing populations with and without SNP/disease
2
Q
SNP location
A
- intergenic
- promoter or TF binding region
- exon: protein coding
- intron: regulatory/splicing region
3
Q
Disease SNPs
A
Monogenic - one nucleotide change leads to disease - simple traits Polygenic - multiple changes affect probability of disease - complex traits
4
Q
Coding SNPs
A
- potentially disease causing as they affect protein
Synonymous - silent mutation but may affect exon splicing enhancers and silencers
Non-synonymous - affected codon codes a different amino acid
- may be detrimental
5
Q
Transition
A
- purine to purine or pyrimidine to pyrimidine
- less common
6
Q
Transversion
A
- purine to pyrimidine or vice versa
7
Q
Ti/Tv ratio
A
- varies within genome (average 2)
- assesses GWAS quality
- in coding regions the ratio is higher as transversions in the third codon base more likely to change the encoded amino acid
8
Q
Sickle Cell Anemia
A
- inherited blood disorder due to mutations in beta globin HBB
- fragile sickle red blood cells that clump together
- mutation of amino acid 6 (GAG to GTG)
- glutamic acid to vline
- autosomal recessive
- monogenic SNP with transversion
9
Q
Alzheimers
A
- polygenic SNP
- apolipoprotein contains 2 SNPs with 3 possilbe alleles
- some alleles have increased or decreased chances of developing disease
- only an indication of likelihood, not absolute
10
Q
Non-Coding SNPs
A
- disease associate SNPs enriched in regulatory regions of DNA
- includes enhancers/silencers, promoters, etc
- difficult to work out effect of regulatory region SNP
- challenges in GWAS
- transcription regulation is complex and involves numerous non coding regions so SNPs in this region can affect transcription
- mapping and association is difficult
11
Q
Splice Site Disruption
A
- SNP can knock out splice site or introduce cryptic splice site
- 10% of all mutations causing human inherited diseases disrupt splice site consensus sequences
- causes loss of associated exon
12
Q
BRCA2 gene
A
- sequence within intron 12 of BRCA2 is exon like in nature
- lacks strong 5’ exon donor site to be included
- T to G transversion SNP generates strong donor site so exon is included
13
Q
OAS1 gene
A
- OAS1 gene associated with type 1 diabetes
- intron 6 AG - AA variant shifts 3’ splice site by 1 nucleotide
- changes reading frame of exon 7 causing a longer protein
14
Q
GWAS
A
- genome wide association study
- identifies genetic variations and SNPs between cohorts
- correlates phenotype to genotype
- difficult to accurately identify SNPs
- sequence multiple genomes from a population at low coverage from a population and pool data
- align to reference and identify variants
- most of genome will be identical and variants are shared
15
Q
100,000 genome project
A
- aims to identify SNPs associated with disease using GWAS as a resource of treatment and research
- aim to create new genomic medicine service for NHS
16
Q
Challenges of GWAS
A
- non coding elements disrupting regulatory elements are significantly less clear
- regulation dependent on many factors like tissue, cell type, temporal patterns, etc
- only identifies candidate SNPs
17
Q
Linkage Disequilibrium
A
- association of alleles at two or more loci within a population
- haplotypes don’t occur at expected frequencies
- non random
- improves genetic association studies like cancer
- important for GWAS as it can identify genetic markers for associated disease
18
Q
Expression Quantitative Trait Loci (eQTL)
A
- mapping variants altering gene expression by testing genotype association with quantitative RNA levels
- measures difference in RNA levels with and without variant
- disease associated SNP also a significant eQTL is expected to confer risk of disease via expression effec
- enables identification of regulated genes via an SNP even if they are not close
- association between GWAS and eQTL identified SNPs can lead to identification of disease causing genes
- eQTL: link SNP to gene
- GWAS: link disease to SNP
19
Q
SNP Genotyping
A
- microarrays to identify presence of SNPs
- probes for known SNPs and normal sequence
- variant will be detected
20
Q
Heterplasmy
A
- bottleneck effect of mitochondrial division can cause mutant accumulation in oocytes
- this leads to offspring with differing levels of mitochondria
- need accurate mapping
