Genetic Basis of Disease

Question 1

Definition single nucleotide variant

Answer 1

Difference in a single nucleotide (SNV)

Question 2

Definition of copy number variant

Answer 2

Inversion, insertion, deletion and duplications of greater than 1000 nucleotides

Question 3

Definition of short tandem repeats

Answer 3

Repetitive elements comprised of recurring DNA motifs of 2-6 bases
Highly prone to variation

Question 4

Definition of indels

Answer 4

Insertion or deletion polymorphism which a sequence of nucleotides are added or deleted

Question 5

Definition of common variants

Answer 5

Minor allele frequency >1% in population

SNP

Question 6

Definition of rare variant

Answer 6

Minor allele frequency <1%

When pathogenic = mutation

Question 7

Definition of epigenetics

Answer 7

Study of heritable changes in gene expression that do not involve changes to the underlying DNA sequences

Question 8

Definition of genome wide association studies

Answer 8

Analysis of genome wide set of genetic variants in different individuals to see if any variant is statistically associated with a trait

Question 9

Definition of genetics

Answer 9

Study of inherited variations

Question 10

Definition of genomics

Answer 10

Study of genomes

Question 11

Definition of functional genomics

Answer 11

Attaching information about function to knowledge of DNA sequence
Includes systematic analysis of mRNA and protein expression, explanation of gene product interactions and influence on different phenotypical traits to define gene functions

Question 12

Definition of transcriptomics

Answer 12

Study of mRNA sequences and expression level

Question 13

Definition of proteomics

Answer 13

Study of protein sequences

Question 14

Definition of epigenomics

Answer 14

Study of histone modification and DNA methylation

Question 15

Definition of cistronics

Answer 15

Study of the genetic repertoire of the binding sequences of a transcriptome factor

Question 16

Definition of bioinformatics and biostatistics

Answer 16

Organisation, visualisation, analysis and interpretation of biological data

Question 17

Definition of biological databases

Answer 17

Libraries of biological information, collected from scientific high-thorough experiments, published literature, computational analysis

Question 18

Definition of stratified/personalised/precision medicine

Answer 18

Medical decisions, practises and treatments tailored to individual patient based on genomic, environmental and lifestyle information

Question 19

Definition of conventional medicine

Answer 19

Uses same drug at same dose for all patients w the same disease

Question 20

Definition of biomarker

Answer 20

Characteristic that is objectively measured, evaluated as an indicator of a normal biological process, pathogenic processes, pharmacogenic response to therapeutic intervention

Question 21

Definition of pharmacogenics

Answer 21

Identify responders and non responders to medication, avoiding adverse events and optimizing drug dose

Question 22

Common vs rare

Answer 22

Refers to the frequency of the minor allele in the human population

Common, minor allele frequency >1% in population, OKA SNP

Rare, minor allele frequency <1% in population
When pathogenic = mutation

Question 23

What is neutrality

Answer 23

Vast majority of genetic variants, no contribution to phenotypic variation

Question 24

What is epigenetics

Answer 24

Study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence
Affects DNA methylation (cytosine), histone methylation/acetylation
Modulate DAN accessibility, regulate gene transcription

Question 25

What are the genetic disease types

Answer 25

Single gene, mutation of 1 gene (Mendelian disease) Multifactorial, combination of environment and mutations in multiple genes (complex disease) Chromosomal, abnormalities in chromosome structure Mitochondrial, mutation in non chromosomal DNA of mitochondria

Question 26

Characteristics of Mendelian disease

Answer 26

``` Single gene Rare High penetrance Autosomal dominant, recessive, X linked Minimal to mild environmental influences Often gross perturbation in gene/protein function ```

Question 27

Characteristics of complex diseases

Answer 27

``` Polygenic Common Variable penetrance Variable, unclear modes of inheritance Gene environment interactions Minor common variations, regulatory and modifying changes ```

Question 28

What is cystic fibrosis and what can it lead to

Answer 28

Abnormal levels of thickened mucus to gather in the lungs and Gi tract Leads to breathing problems, resp infections, permanent damage (fibrosis) Can lead to malnutrition, diabetes, osteoporosis etc

Question 29

Inheritance of CF

Answer 29

Autosomal recessive | 25% chance of inheriting from 2 carrier parents

Question 30

How does CF arise

Answer 30

CFTR on chromosome 7 encodes for Cl- channel q31.2 locus ∆F508, deletion of phenylalanine Reduces ion channel functioning, disrupting epithelial fluid transport => abnormal levels of thick mucus

Question 31

What is Hungtingtons and what can it lead to

Answer 31

Progressive neurodegenerative disorder | Leads to personality changes, chorea, dystonia, tremor, cognitive decline, depression, irritability

Question 32

Inheritance of HD

Answer 32

Autosomal dominant | Only 1 copy needed to be expressed

Question 33

How does HD arise

Answer 33

Chromosome 4, >35 CAG stutters | Inverse correlation between repeat size and age of onset

Question 34

What is genome wide association studies

Answer 34

Analysis of the genome wide set of genetic variants in different individuals to see if any variant is statistically associated with a trait Uses micro assays and Manhattan plots

Question 35

What is psoriasis

Answer 35

Immune mediated, chronic inflammatory skin disease | Characterized by red, inflammed scaly plaques from excessive keratinocyte proliferation and immune cell activation

Question 36

Comorbidities associated with psoriasis

Answer 36

Psoriatic arthritis | obesity, CVD, IBD, depression

Question 37

How does psoriasis arise and treated

Answer 37

Interaction between genetic susceptibility, environmental triggers, immune system activation Treated w topical/systemic immunomodulatoty drugs

Question 38

Genetics of psoriasis, pre GWAS Population and family studies Twin studies

Answer 38

Higher incidence in relatives vs general population and matched control subjects High concordance rates in MZT than DZT, 66% heritability

Question 39

Genetics of psoriasis

Answer 39

Each locus contributes in small part to susceptibility | Odd ratio caries from 1:1 => 4:3 with HLA-C gene involved in immune system activation, conferring highest risk

Question 40

What has GWAS told us about psoriasis

Answer 40

Highlighted the importance of immunobiological processes involved in immune system activation (antigen presentation) IL17 leads to production of a molecule that causes skin inflammation New drugs target IL-17 or other proteins that favor its production

Question 41

Types of genetic analysis

Answer 41

``` Genomics Transcriptomics Proteomics Epigenomics Cistronics ```

Question 42

What is genomics

Answer 42

Genomic DNA sequencing Annotations Study of gene sequences

Question 43

What is transcriptomics

Answer 43

Microarray hybridization RNA sequencing mRNA sequences and expression level

Question 44

What is proteomics

Answer 44

Liquid chromatography Mass spectrometry Protein sequences

Question 45

What is epigenomics

Answer 45

ChIP sequencing Bisulfite sequencing Histone modification DNA methylation

Question 46

What is cistronics

Answer 46

ChIP sequencing Genomic repertoire of binding sequences of a transcriptome factor

Question 47

Stratified/personalised/precision medicine

Answer 47

Medical decisions, practises, treatments tailored to individual patient based on genomic, environmental, lifestyle into Otherwise drugs have a 24% of being unaffective Requires identification of predictive biomarkers, stratify patients according to their theranostic biomarkers

Question 48

100000 genomes project

Answer 48

25000 cancer patients can contribute 2 genomes (own and tumor) 17000 w rare diseases + 2 blood relatives add 50000 more genomes Sequence patients w severe infections All genomes sequenced

Question 49

Pharmacogenics

Answer 49

Identify responders and non responders to drugs, avoiding adverse events, optimizing drug dose