Topic 4: Multifactorial inheritance Flashcards
What is Familial Hypercholesterolemia and how does it affect patients?
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.
How does genetic variation affect individuals?
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.
What are the characteristics of rare genetic variants?
Age: Recent variants
Ancestry: Personal/family
Allele frequency: Rare
Effect size: Strong
Disease alleles: Many
What are the characteristics of common genetic variants?
Age: Ancient
Ancestry: Shared by population
Allele frequency: Common
Effect size: Weak
Disease alleles: Few
How do common diseases and traits arise according to polygenic interactions?
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.
What leads to familial clustering of common diseases and traits?
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.
What are continuous and discrete traits in genetics?
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.
What is a normal distribution and where is it seen?
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.
What does the liability-threshold model (L-T model) explain?
The L-T model explains how polygenic inheritance can cause common diseases.
What factors are grouped as liability in the development of a disease according to the L-T model?
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).
When is the abnormal (disease) phenotype expressed in the L-T model?
The abnormal (disease) phenotype is expressed when liability exceeds a specific threshold.
What is a major problem with measuring liability in the L-T model?
Liability cannot be measured directly.
How do complex diseases often involve interaction between genes and the environment?
Some complex diseases may arise after a lifetime of excess or exposure, while others may result from a trigger that may be poorly defined
What does the L-T model propose about the expression of the disease phenotype?
The L-T model proposes that the abnormal (disease) phenotype is expressed when liability exceeds a specific threshold.
How is causation described in the L-T model?
Causation is multifactorial, and the phenotype is dichotomous (affected or unaffected).
How do related individuals compare to the general population in terms of risk alleles?
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
How is the assessment of genetic contribution to disease risk performed in family history case-control studies?
By comparing the fraction of probands whose family members have the same disease to a matched sample of healthy subjects from the general population
How is heritability of disease estimated?
Heritability of disease is estimated by comparing concordance rates in monozygotic (MZ) and dizygotic (DZ) twins.
how is the assessment of genetic contribution to disease risk performed in a correlation analysis?
perform regression analysis of phenotypic trait values for related subjects (correlation co-efficient indicates positive or negative genetic effect)
how is the assessment of genetic contribution to disease risk performed in an adoption study?
examine disease risk for unrelated children adopted into or out of a shared environment with high disease prevalence
what are ways to asses genetic contribution of disease?
- family history case-control studies
- correlation analysis
- heritability of quantitative traits
- heritability of disease
- adoption studies
What principle do twin studies rely on?
MZ twins provide an extreme example of genetic relatedness and can be used to separate environmental and genetic effects on disease.
What is the most common study design in twin studies?
The most common study design compares disease risk ratios in MZ and DZ twins.
How much of their alleles do MZ and DZ twins share?
MZ twins share 100% of their alleles, while DZ twins share approximately 50% of their alleles
What type of studies may be used for diseases with strong environmental influences?
Studies of twins reared apart may be used for diseases with strong environmental influences (e.g., neuropsychiatric disorders and other behavioral traits).
How is trait correlation measured in twin studies?
Trait correlation is measured by comparing rMZ and rDZ, using Falconer’s formula: H2= 2 ×(rMZ− rDZ).
What are some issues with twin studies?
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.
Why are complex diseases considered complex?
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
What is the challenge of the Human Genome Project?
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).
What are the two processes that change our human genome sequences?
Reduced fidelity of genome replication and recombination/gametogenesis.
How does reduced fidelity of genome replication affect offspring’s genome?
Offspring’s genome will contain new mutations that form by chance during gametogenesis and development.
How does recombination/gametogenesis affect offspring’s genome?
Offspring’s genome will contain a mixture of genes/alleles that their parents inherited from the offspring’s grandmother and grandfather.
How many SNPs does your genome have compared to your parents?
Your genome has approximately 150 SNPs compared to your parents.
Are most SNPs harmful or helpful?
Most SNPs are neither harmful nor helpful, but other types of mutations can occur (e.g., deletions, insertions, indels, chromosome modifications).
What are de novo mutations?
De novo mutations are germline mutations often caused by fidelity issues, and certain somatic mutation signatures are associated with certain diseases.
How do germline mutations arise and what can be their effects?
Certain polymorphisms will arise at different times and can be passed on. Most will not have any effect, but sometimes they do cause disease.
What does genetic drift involve and what are its effects?
what makes it mroe severe?
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.
What assumptions are made in genetic drift studies?
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.
What is the chance that a mutation disappears after one generation in genetic drift?
The chance of fixation is 50%
What is positive/adaptive selection?
Positive/adaptive selection involves advantageous genetic variations being preserved and spreading throughout a population over time.
What are the assumptions of Hardy-Weinberg Equilibrium?
Hardy-Weinberg Equilibrium assumes that alleles a and A have population frequencies p and q, with no selection, no migration, and no mutation
Under Hardy-Weinberg Equilibrium, how can a given population’s equilibrium for an allele be predicted?
It can be predicted using the frequencies of each aa, Aa, and AA.
What is the principle of genetic recombination and linkage analysis?
Crossing over (recombination) of chromosomal DNA during meiosis leads to new combinations of genes and genetic markers.
What is required for genetic recombination and linkage analysis?
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.
How do you measure recombination fraction (θ) in genetic recombination and linkage analysis?
The recombination fraction (θ) is measured between disease and markers.
What is an example of genetic recombination affecting populations?
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.
What are recombination rules of thumb in a single family?
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).
What are recombination rules of thumb in a population?
Recombination often occurs in the same small region of the genome (“hotspots”), resulting from chromatin structure and specific “fragile” DNA sequences (trinucleotide repeats).
How can you use the HeatMap to find haplotype blocks?
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.
What is the rationale for using SNPs in genetic studies?
SNPs may be genetically indistinguishable or “linked” to each other as a result of biological processes, and statistical tests detect association (not causation).
What are the sequencing approaches for genetic diseases?
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.
How do these sequencing approaches go beyond classical family studies?
They look at not only inherited mutations but also de novo dominant mutations and mosaic mutations.
What do CFTR variants mainly alter?
CFTR variants mainly alter protein coding sequences to change the amount or activity of CFTR protein.
What causes the heterogeneity of symptoms in CFTR-related diseases?
“Modifier” genes in conjunction with the main CFTR mutation and other environmental factors cause the heterogeneity of symptoms.
What does the MBL2 gene encode, and how does it affect CF lung disease outcomes?
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).
What does the TGFB1 gene encode, and how does it affect CF lung disease outcomes?
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).
What do family studies show about genetic risk factors in Coronary Artery Disease (CAD)?
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.
What factors increase the risk of Coronary Artery Disease (CAD)?
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.
What gene products and pathways have been implicated in the pathogenesis of CAD?
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.
How do many variants affect gene transcription in CAD?
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).
