Genetics of Common Disorders with Complex Inheritance and Personalized Medicine

Question 1

What percent of the genome is identical between individuals?

Answer 1

99%

Question 2

1% of the DNA sequence between individuals is different. These DNA differences are called

Answer 2

Polymorphisms

Question 3

Can be small insertions/deletions, differences in the number of repeats, or single nucleotide differences (SNPs)

Answer 3

Polymorphisms

Question 4

Most polymorphisms are silent, meaning they exert no functional

Answer 4

Difference

Question 5

The entire genome is equivalent to a book, each chromosome is equivalent to a chapter, each gene is equivalent to a paragraph, and each nucleotide is equivalent to a

Answer 5

Letter

Question 6

A DNA change that severely alters the activity or expression of a gene

Answer 6

Mutation

Question 7

Silent change in the DNA that does not alter the

expression or activity of the gene.

Answer 7

Polymorphism

Question 8

Subtle changes that alter the levels or activity of a gene, but the gene is still in NORMAL range

Answer 8

Functional Polymorphism

Question 9

How do we find relative risk?

Answer 9

Prevalence in affected / prevalence in unaffected

Question 10

The variance within pairs of dizygotic (DZ) twins will be similar to that seen within monozygotic (MZ) twins, and heritability (h^2) will approach 0 if the variability of the trait is determined chiefly by the

Answer 10

Environment

Question 11

If the variability is determined chiefly by the environment, the heritability will approach

Answer 11

0

Question 12

If the variability is determined exclusively by genetic makeup, than the variance of MZ pairs is 0 and the heritability is

Answer 12

1

Question 13

A single gene disorder named after Gregor Mendel

Answer 13

Mendelian Disorder

Question 14

What are the three modes of inheritance for the Mendelian disorder?

Answer 14

1. ) Recessive
2. ) Dominant
3. ) semi-dominant

Question 15

To identify the causative gene, we want to sequence all the genes in the region and look for a mutation that segregates with disease in all

Answer 15

Pedigrees

Question 16

To find the causative gene, we want to look for the presence of different mutations in different

Answer 16

Families

Question 17

To identify the causative gene, we want to confirm that the mutation affects expression or activity of a

Answer 17

Gene

Question 18

Deep sequencing, the next generation of sequencing, allows for sequencing the entire genome in a cheap and relatively fast manner. We can sequence the

Answer 18

Genome, Exome, or Transcriptome

Question 19

Neural crest defect for cells that go on to form the enteric nervous system of the intestines

-leads to enlarged colon

Answer 19

Hirschsprung’s disease (HSCR)

Question 20

The frequency of HSCR is

Answer 20

1/5000

Question 21

Does not follow a simple recessive or dominant inheritance pattern

Answer 21

HSCR

Question 22

The relative risk for siblings to get HSCR is about

-Monozygotic twins do not show perfect concordance

Answer 22

200

Question 23

How much more likely are males within the family to get HSCR than females?

Answer 23

2x

Question 24

HSCR is caused by a mutation in the tyrosine kinase receptor needed for neural crest migration known as

Answer 24

RET

Question 25

Scanning of the genome for 67 siblings that both have HSCR showed that 55/67 siblings shared alleles at

Answer 25

10q11.2 (RET), 3p21, and 19q12

Question 26

Are major health concerns and therefore understanding the biological basis of these disorders so new treatments can be developed is necessary

Answer 26

Common diseases

Question 27

The phenotypic overlap of Multiple sclerosis (MS), type 1 diabetes, and survival bone marrow transplant is

Answer 27

Autoimmunity

Question 28

The phenotypic overlap of schizophrenia, bipolar disorder, and autism is

Answer 28

Neurodevelopmental disorder

Question 29

Refers to inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes, or interaction with the environment, or both

Answer 29

Multi-factorial inheritance

Question 30

A character determined by the combined action of a number of genetic loci

Answer 30

Polygenic

Question 31

Caused by mutations in single genes -ex: Cystic fibrosis and Duchene Muscular Dystrophy

Answer 31

Monogenic (Mendelian) disorders

Question 32

Do not follow simple recessive or dominant inheritance patterns

Answer 32

Multi-factorial diseases

Question 33

What are the risks for common diseases

Answer 33

1. ) Genetic 2. ) Epigenetic 3. ) Non-genetic environmental factors

Question 34

What are two types of genetic risks for common diseases?

Answer 34

Functional polymorphisms (common variants) and mutations (rare variants)

Question 35

Hormones, diet, or infections that alter cell biological pathways

Answer 35

Non-genetic environmental factors

Question 36

Common diseases occur frequently in the population; some of the genetic susceptibility alleles are then likely to be

Answer 36

Common (>5%)

Question 37

Are likely to have less of a phenotypic effect per individual but would affect more individuals within the population

Answer 37

Common variants (functional polymorphisms)

Question 38

Would have a significant phenotypic effect per | individual but contribute less to general population

Answer 38

Rare variants (mutations)

Question 39

If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the A polymorphism should be inherited more frequently in

Answer 39

Affected individuals

Question 40

If we have two polymorphisms, A and G, and the A polymorphism is co-inherited with a disease allele, then the G polymorphism should be inherited more frequently in

Answer 40

Unaffected individuals

Question 41

The previous polymorphism example was an example of an

Answer 41

Association study

Question 42

SNPs are co-inherited as blocks or bins. Panels are created with tagged SNPs for each bin. Thousands of people with the disease are recruited and their DNA is isolated and genotyped for their whole genome

Answer 42

Genome Wide Association Analysis (GWAS)

Question 43

Once the recruits have been genotypes, we then do statistical analysis to identify the

Answer 43

SNP alleles co-inherited with disease

Question 44

What are some problems with GWAS?

Answer 44

Reproducibility and functionality

Question 45

49% of variants in individuals affected with ASD are

Answer 45

Common inherited (A)

Question 46

Seeks to identify all functional elements in the human genome

Answer 46

ENCODE

Question 47

Identified protein coding regions contained in approximately 20,000 genes -discovered that protein coding regions made up only 1% of genomeq

Answer 47

Human genome project

Question 48

Aims to characterize other functional DNA elements

Answer 48

ENCODE

Question 49

ENCODE discovered that what percent of the genome is involved in at least one biochemical event?

Answer 49

>80%

Question 50

ENCODE discovered that 95% of the genome is within 8kb of a

Answer 50

DNA protein interaction

Question 51

What percent of the genome is within 1.7kb of an ENCODE identified event?

Answer 51

99%

Question 52

A substantial proportion of variants are annotated as having predicted functional effects in the

Answer 52

Non-coding category

Question 53

Affects the epigenome, transcriptome, proteome, and metabolome

Answer 53

Environment

Question 54

Says that risks of commmon diseases are due to epimutations

Answer 54

Epigenetic hypothesis

Question 55

Changes in the epigenetic signature -affects gene regulation

Answer 55

Epimutation

Question 56

Contribute to non-genetic components of diseases

Answer 56

Epimutations

Question 57

Epimutations provide an interface between environmental factors and

Answer 57

Gene expression

Question 58

For many common diseases cause by epimutations, phenotypes are very

Answer 58

Heterogeneous

Question 59

The metabolic state of a cell is not invariant and is directly linked to

Answer 59

Cellular function

Question 60

The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.

Answer 60

Warburg effect

Question 61

What most human diseases are, where if you get one allele, you have a certain clinical phenotype, but if you get two mutant alleles, you have a much worse phenotype

Answer 61

Semi-dominant

Question 62

Looks like AD, but may appear to skip a generation

Answer 62

Incomplete penetrence

Question 63

Identifying pieces of DNA that are co-inherited with the mutation

Answer 63

Genetic linkage

Question 64

A handful of mutations cause these diseases as opposed to just one -Ex: HSCR

Answer 64

Simple complex disorders

Question 65

Pose less individual risk, but more population risk

Answer 65

Common varaints

Question 66

Tell us how the cell is functioning

Answer 66

Metabolites