Topic 4: Multifactorial inheritance

Question 1

What is Familial Hypercholesterolemia and how does it affect patients?

Answer 1

Familial Hypercholesterolemia is an autosomal dominant disease. Patients often develop Achilles tendon xanthoma at a young age and may die young. There are differences in the impact of the disease between males and females.

Question 2

How does genetic variation affect individuals?

Answer 2

Genetic variation can lead to differences in risk of developing disease (susceptibility), disease features, severity or outcome, response to environmental factors, and response to medical treatment.

Question 3

What are the characteristics of rare genetic variants?

Answer 3

Age: Recent variants

Ancestry: Personal/family

Allele frequency: Rare

Effect size: Strong

Disease alleles: Many

Question 4

What are the characteristics of common genetic variants?

Answer 4

Age: Ancient

Ancestry: Shared by population

Allele frequency: Common

Effect size: Weak

Disease alleles: Few

Question 5

How do common diseases and traits arise according to polygenic interactions?

Answer 5

Common diseases and traits result from complex interactions among many genetic variants that increase or decrease disease susceptibility, specific environmental exposures that promote or prevent disease, and chance events that may trigger the disease.

Question 6

What leads to familial clustering of common diseases and traits?

Answer 6

Familial clustering of common diseases and traits results from a complex pattern of inheritance that reflects polygenic interactions among genetic risk loci. Environmental exposures and other non-genetic factors are also involved, making these diseases and traits multifactorial in origin.

Question 7

What are continuous and discrete traits in genetics?

Answer 7

Continuous quantitative traits include traits like height and the risk of developing a disease. Discrete qualitative traits include traits like eye color and the state of having a disease.

Question 8

What is a normal distribution and where is it seen?

Answer 8

A normal distribution is seen for many physiological traits in a population such as height, weight, blood pressure, biochemical tests (cholesterol, glucose), and behavioral/performance tests. Some diseases will have an age-related distribution, such as blood pressure, which will have different mean values, width, and shape of distribution.

Question 9

What does the liability-threshold model (L-T model) explain?

Answer 9

The L-T model explains how polygenic inheritance can cause common diseases.

Question 10

What factors are grouped as liability in the development of a disease according to the L-T model?

Answer 10

All factors contributing to the development of a disease are grouped as liability, which includes genetic and non-genetic risk factors (e.g., “bad” genes and exposure to environmental risks).

Question 11

When is the abnormal (disease) phenotype expressed in the L-T model?

Answer 11

The abnormal (disease) phenotype is expressed when liability exceeds a specific threshold.

Question 12

What is a major problem with measuring liability in the L-T model?

Answer 12

Liability cannot be measured directly.

Question 13

How do complex diseases often involve interaction between genes and the environment?

Answer 13

Some complex diseases may arise after a lifetime of excess or exposure, while others may result from a trigger that may be poorly defined

Question 14

What does the L-T model propose about the expression of the disease phenotype?

Answer 14

The L-T model proposes that the abnormal (disease) phenotype is expressed when liability exceeds a specific threshold.

Question 15

How is causation described in the L-T model?

Answer 15

Causation is multifactorial, and the phenotype is dichotomous (affected or unaffected).

Question 16

How do related individuals compare to the general population in terms of risk alleles?

Answer 16

Related individuals share a greater number of risk alleles than the general population:
- distantly related individuals will have fewer alleles in common (i.e., less “allele sharing”)
- measured by the relative (sibling) risk ratio:
- reflects degree of family clustering

Question 17

How is the assessment of genetic contribution to disease risk performed in family history case-control studies?

Answer 17

By comparing the fraction of probands whose family members have the same disease to a matched sample of healthy subjects from the general population

Question 18

How is heritability of disease estimated?

Answer 18

Heritability of disease is estimated by comparing concordance rates in monozygotic (MZ) and dizygotic (DZ) twins.

Question 19

how is the assessment of genetic contribution to disease risk performed in a correlation analysis?

Answer 19

perform regression analysis of phenotypic trait values for related subjects (correlation co-efficient indicates positive or negative genetic effect)

Question 20

how is the assessment of genetic contribution to disease risk performed in an adoption study?

Answer 20

examine disease risk for unrelated children adopted into or out of a shared environment with high disease prevalence

Question 21

what are ways to asses genetic contribution of disease?

Answer 21

• family history case-control studies
• correlation analysis
• heritability of quantitative traits
• heritability of disease
• adoption studies

Question 22

What principle do twin studies rely on?

Answer 22

MZ twins provide an extreme example of genetic relatedness and can be used to separate environmental and genetic effects on disease.

Question 23

What is the most common study design in twin studies?

Answer 23

The most common study design compares disease risk ratios in MZ and DZ twins.

Question 24

How much of their alleles do MZ and DZ twins share?

Answer 24

MZ twins share 100% of their alleles, while DZ twins share approximately 50% of their alleles

Question 25

What type of studies may be used for diseases with strong environmental influences?

Answer 25

Studies of twins reared apart may be used for diseases with strong environmental influences (e.g., neuropsychiatric disorders and other behavioral traits).

Question 26

How is trait correlation measured in twin studies?

Answer 26

Trait correlation is measured by comparing rMZ and rDZ, using Falconer’s formula: H2= 2 ×(rMZ− rDZ).

Question 27

What are some issues with twin studies?

Answer 27

Issues include: - ascertainment bias, - different environmental exposures for MZ and DZ twins during adolescence or later life, - somatic rearrangement or mutations, - epigenetic imprinting, - difficulty accounting for interactions between loci, - large heritability not meaning genes with large effects are involved in the etiology.

Question 28

Why are complex diseases considered complex?

Answer 28

Due to various biological and environmental factors. biological: - pathogenesis often involves serval tissues - metabolic and signaling pathways have may members - effects of genetic changes may be buffered - effect of a gene/protein interaction may be hard to predict environmental: - many known and unknown influences - exposure hard to measure - duration of exposure can be hard to measure

Question 29

What is the challenge of the Human Genome Project?

Answer 29

The challenge is to find which variant causes or increases the risk of a specific disease within our genome's 3 billion bases (20,000 coding genes).

Question 30

What are the two processes that change our human genome sequences?

Answer 30

Reduced fidelity of genome replication and recombination/gametogenesis.

Question 31

How does reduced fidelity of genome replication affect offspring's genome?

Answer 31

Offspring's genome will contain new mutations that form by chance during gametogenesis and development.

Question 32

How does recombination/gametogenesis affect offspring's genome?

Answer 32

Offspring's genome will contain a mixture of genes/alleles that their parents inherited from the offspring's grandmother and grandfather.

Question 33

How many SNPs does your genome have compared to your parents?

Answer 33

Your genome has approximately 150 SNPs compared to your parents.

Question 34

Are most SNPs harmful or helpful?

Answer 34

Most SNPs are neither harmful nor helpful, but other types of mutations can occur (e.g., deletions, insertions, indels, chromosome modifications).

Question 35

What are de novo mutations?

Answer 35

De novo mutations are germline mutations often caused by fidelity issues, and certain somatic mutation signatures are associated with certain diseases.

Question 36

How do germline mutations arise and what can be their effects?

Answer 36

Certain polymorphisms will arise at different times and can be passed on. Most will not have any effect, but sometimes they do cause disease.

Question 37

What does genetic drift involve and what are its effects? | what makes it mroe severe?

Answer 37

Genetic drift occurs due to random sampling of gametes and has more severe effects in small populations, with a founder effect, and following a bottleneck. In the long term, it leads to loss of diversity in populations.

Question 38

What assumptions are made in genetic drift studies?

Answer 38

Assumptions include a single individual, one chromosome with a mutation, a large number of gametes, mating by selfing, and subsequent generations consisting of single individuals.

Question 39

What is the chance that a mutation disappears after one generation in genetic drift?

Answer 39

The chance of fixation is 50%

Question 40

What is positive/adaptive selection?

Answer 40

Positive/adaptive selection involves advantageous genetic variations being preserved and spreading throughout a population over time.

Question 41

What are the assumptions of Hardy-Weinberg Equilibrium?

Answer 41

Hardy-Weinberg Equilibrium assumes that alleles a and A have population frequencies p and q, with no selection, no migration, and no mutation

Question 42

Under Hardy-Weinberg Equilibrium, how can a given population's equilibrium for an allele be predicted?

Answer 42

It can be predicted using the frequencies of each aa, Aa, and AA.

Question 43

What is the principle of genetic recombination and linkage analysis?

Answer 43

Crossing over (recombination) of chromosomal DNA during meiosis leads to new combinations of genes and genetic markers.

Question 44

What is required for genetic recombination and linkage analysis?

Answer 44

It requires families with a disease or phenotype of interest, a collection of genetic polymorphisms (markers) spread across the genome, and a map of distances between genetic markers.

Question 45

How do you measure recombination fraction (θ) in genetic recombination and linkage analysis?

Answer 45

The recombination fraction (θ) is measured between disease and markers.

Question 46

What is an example of genetic recombination affecting populations?

Answer 46

An example is the long haplotype surrounding the lactase persistence allele, leading to different populations with different mutations, and some populations without the adaptive or persistent mutations.

Question 47

What are recombination rules of thumb in a single family?

Answer 47

Typically, one recombination event occurs in each chromosome arm per generation. Distances between loci can be measured by physical units (number of base pairs) or genetic units (chance of recombination event). Two loci that are 1 centimorgan (cM) apart have a 1% chance of being separated by recombination in a single generation (1 cM is about 1 million bases).

Question 48

What are recombination rules of thumb in a population?

Answer 48

Recombination often occurs in the same small region of the genome ("hotspots"), resulting from chromatin structure and specific "fragile" DNA sequences (trinucleotide repeats).

Question 49

How can you use the HeatMap to find haplotype blocks?

Answer 49

By finding where there are just a couple of SNPs that vary, and by using these common associations, you can make a mosaic chromosome seen in a certain population. Then, using this information, you can test just a couple of SNPs to figure out the probability of getting a specific haplotype.

Question 50

What is the rationale for using SNPs in genetic studies?

Answer 50

SNPs may be genetically indistinguishable or "linked" to each other as a result of biological processes, and statistical tests detect association (not causation).

Question 51

What are the sequencing approaches for genetic diseases?

Answer 51

Take unrelated patients with the same disease. Utilize disease-linked regions from both families with multiple affected members and consanguineous families. Take affected sibling pairs.

Question 52

How do these sequencing approaches go beyond classical family studies?

Answer 52

They look at not only inherited mutations but also de novo dominant mutations and mosaic mutations.

Question 53

What do CFTR variants mainly alter?

Answer 53

CFTR variants mainly alter protein coding sequences to change the amount or activity of CFTR protein.

Question 54

What causes the heterogeneity of symptoms in CFTR-related diseases?

Answer 54

"Modifier" genes in conjunction with the main CFTR mutation and other environmental factors cause the heterogeneity of symptoms.

Question 55

What does the MBL2 gene encode, and how does it affect CF lung disease outcomes?

Answer 55

MBL2 encodes a serum protein called mannose-binding lectin. Common alleles in Europeans alter blood levels of MBL2, and lower MBL2 levels are associated with worse outcomes for CF lung disease, possibly due to difficulties with combatting respiratory pathogens (Pseudomonas).

Question 56

What does the TGFB1 gene encode, and how does it affect CF lung disease outcomes?

Answer 56

TGFB1 encodes the cytokine transforming growth factor B (TGFβ). Common alleles that increase TGFβ production lead to worse outcomes, possibly due to its effects on pulmonary inflammation (TGFβ promotes lung scarring and fibrosis).

Question 57

What do family studies show about genetic risk factors in Coronary Artery Disease (CAD)?

Answer 57

Family studies show that genetic risk factors play an important role in CAD, particularly for women and younger men, with a 6-8x increased risk in MZ twins and a 3-4x increased risk in DZ twins.

Question 58

What factors increase the risk of Coronary Artery Disease (CAD)?

Answer 58

Environmental, lifestyle, and medical factors increase the risk, including tobacco use, physical inactivity, poor diet quality, overweight and obesity, raised blood glucose (diabetes), increased blood pressure (hypertension), and elevated cholesterol/lipids.

Question 59

What gene products and pathways have been implicated in the pathogenesis of CAD?

Answer 59

Gene products and pathways implicated in CAD pathogenesis include serum lipid transport and metabolism, vasoactivity and arterial wall components, blood coagulation, platelet function, and inflammatory and immune pathways.

Question 60

How do many variants affect gene transcription in CAD?

Answer 60

Many variants affect gene transcription to change the amount of mRNA and protein produced at baseline or in response to specific stresses (e.g., inflammation).