Exam 2 Review Flashcards
1
Q
What are the 6 violations of normal segregation behavior?
A
- Allele frequencies in populations (common recessive)
- Penetrance and expressivity in pedigrees
- Imprinting (Maternal or Paternal Effect)
- Segregation Distortion due to lethality
- Inbreeding effects: “male to male” X transfer
- New mutations
2
Q
Can you define the inheritance pattern of a syndrome by looking at one pedigree?
A
No. Many pedigrees are required in order to define a syndrome.
3
Q
What is unique about a common recessive allele and what is an example?
A
The recessive trait appears dominant in a pedigree because the allele is so common in a population
Example: O in ABO blood types
4
Q
What type of inheritance is seen in this pedigree?
A
Common Recessive=Dominant
5
Q
In a situation with incomplete penetrance, what is ambiguous about individuals appearing to be unaffected?
A
Unaffected individuals may still be heterozygotes even though they do not show the characteristic phenotype
On a pedigree: the trait will skip generations, even though it is dominant
6
Q
What type of inheritance is seen in this pedigree?
A
Incomplete Penetrance
7
Q
Describe variable expressivity
A
Multiple traits can be associated with a disease/syndrome. Different affected individuals can show different combinations of these traits, even though they all have the same genotype
8
Q
What type of inheritance is seen in the pedigree?
A
Variable Expressivity
9
Q
What is imprinting?
A
Certain genes are expressed in a parent-of-origin manner, meaning that the gene is only expressed if it comes from the father (in paternal imprinting) or mother (in maternal imprinting).
10
Q
What type of inheritance is seen in the pedigree?
A
Paternal Imprinted Autos Dominant
11
Q
What type of inheritance is seen in the pedigree?
A
Maternal Imprinted Auto Dominant
12
Q
What type of inheritance is seen in the pedigree?
A
X Linked, Dom Hemis Abort
13
Q
Explain why a pedigree could appear as though there is male-male passing of X chromosomes
A
In inbred populations, it may appear that an X-linked trait gets passed from a father to a son. In this situation, the mother must have been a carrier for the trait, and passed it on to her son.
14
Q
What type of inheritance is seen in the pedigree?
A
X Linked Inbred “M to M”
15
Q
What type of inheritance is seen in the pedigree?
A
Novel Mutation
16
Q
What are the steps for characterizing genetic syndromes?
A
- Characterize propositus
- Identify affecteds
- Chard the pedigree and assess the phenotypic extent
- analyze segregation, assess expressivity/penetrance
- aggregate families and commence genome-wide association study, mapping
17
Q
What is a propositus?
A
The person initially being studied, also referred to as the proband.
Labelled on pedigrees with a diagonal arrow pointing to the subject.
18
Q
What does WGA stand for? Is it different than a GWA?
A
WGA=whole genome association study
GWA = genome wide association study
These mean the same thing: examining many common genetic variants to see if any variant is associated with a specific trait.
19
Q
What is the Westermarck Effect?
A
People who live in close proximity during the first few years of their lives become desensitized to later sexual attraction
Protection against close mating
20
Q
Do first and second cousins experience the Westermarck effect?
A
They tend not to. In present U.S. society, cousins tend not to be raised in close proximity
21
Q
What is the evidence that humans may be sexually attracted to genetically similar people?
A
Women tend to prefer males with 2-7 alleles in common to their father’s Leukocyte Antigen/MHC. They do not prefer perfect mathches or 0 mathches.
22
Q
What is the inbreeding coefficient?
A
A measure of the level of consanguinity between two given individuals. This value approches 1 (100%) for individuals coming from a completely inbred population.
23
Q
How is the inbreeding coefficient calculated?
A
Take consanguinous parents, and trace each individual path through their ancestors that connects them. Count the number of individuals involved in each path.
For each path: probability = (1/2)^(number of individuals in path)
Add up the probabilities for each path to get the coefficient of inbreeding.
24
Q
Explain polygenic/complex inheritance
A
Alleles of different genes can impact the same phenotypic trait. This means that different genotypes can produce the same phenotype.
Example: Obesity is caused by many different genotypes, all leading to the same phenotype.
25
What is a quntitative trait?
A measurable physiological or biological quantity that shows continuous variation throughout a population.
Example: Height
26
What is a qualitative trait?
Traits that are either present or absent. Sometimes called 'discrete traits'
27
Can a qualitative trait be polygenic?
Yes. Many genes can all contribute to the presence/absence of a trait.
28
What is a normal distribution?
Also called a Gaussian curve or Bell curve. This is a curve that is defined by the mean and the standard deviation of a population.
Example: If number of dominant alleles present in a poulation dictates the phenotype, then most individuals will have half dominant and half recessive, whereas very few will have all recessive or all dominant
29
What is an example of a qualitative trait that can be analyzed with quantitative genetics?
The color of rice hulls from a triple heterozygote X triple heterozygote cross.
The individual alleles determine red or white (qualitative) but the overall color is determined by the combination of the 3 alleles (quantitative).
30
What percentage of a population will have a quantitative trait that is greater than 2 standard deviations above or below the mean of the population?
5% will be outside of 2SD of the mean for a normally distributed trait
31
# Define Variance in words (as opposed to the equation)
The aggregate difference between each individual and the mean value for a given trait
32
Why is standard deviation a more useful statistic than variance for looking at population distributions?
Standard deviation has the same units as the mean, whereas variance has units that are squared
33
In a trait that has little/no environmental effect, describe the overlap in phenotypes between individuals with different genotypes.
Low environmental effect: small phenotypic overlap between individuals with different genotypes
34
As the environmental impact on phenotypic expression increases, what happens to the variance?
Variance increases with environmental impact. The effect of the environment further spreads out the variations due to genetics.
35
What is the equation for Variance?
Vx = Σ(X-M)2 /N-1
X=each measurement
M= mean
N= number of observations
36
What is heritability?
the amount of phenotypic variance in a quantitative trait that is caused by genotypic rather than environmental influences
The fraction of the total phenotypic variance that is caused by genes
H= VG/VT
VG= variation of genotypes
VT= total variation
37
Does selection act at the genotypic or phenotypic level?
Selection ALWAYS acts at the level of the phenotype
38
Describe the distribution of a trait that has a high heritability compared to one that has a low heritability
A trait with a higher heritability will have a taller narrower gaussian curve (i.e. lower variance)
39
What is the Falconer's threshold hypothesis?
Falconer postulated that everybody has a certain susceptibility (liability) for a disease. A threshold exists and people beyond that threshold will be affected.
40
Explain how the distribution of liability for a disease shifts for siblings of affected people
The curve is shifted to the right, so more people fall above the threshold, higher risk for having disease.
41
How can you estimate heritability from the liability distribution curves (based on Falconer)?
You compare the number of people (area under curve) that lie to the right of the threshold between the two groups: general population and sibs of affecteds.
42
What are the three corners of the triangle showing the causes for human disease?
Environment, single gene, and polygenic
43
What are the assumptions for the Hardy-Weinberg equation?
1. No mate choice
2. Two high frequency alleles
3. No selection or genetifc drift
44
What are the two major flaws of the Hardy-Weinberg equation for humans?
Humans do not usually follow free breeding behavior (violates assumption of no mate choice)
There are favored phenotypes in humans (violates assumption of no selection/genetic drift)
45
What is the definition of a population?
A group of individuals from the same species that can interbreed
46
What is a subpopulation?
a local population that may enjoy/suffer partial mating isolation in relation to the total population
47
What does the Hardy Weinberg equation model?
It models the number of alleles that are available in a population to contribute to any genotype
48
What do P, H and Q represent in the Hardy Weinberg eqation?
They are the genotypic frequencies of homozygotes and heterozygotes
P = %AA
H = %Aa
Q = %aa
49
What are the equations associated with the HW equation?
P + H + Q = 1
p + q = 1
(p + q)2 = 1
p2 +2pq + q2 = 1
50
What do p and q represent in the HW equation?
p is the %A alleles
q is the %a alleles
51
What does p equal in terms of P, H and Q in the HW equation?
p = P + 1/2H
because p is the %A, all of P are A's and half of H are A's
52
What does q equal in terms of P, H and Q?
q = Q + 1/2H
53
List the steps that are taken in order to calculate allelic frequencies with the HW equation
1) Population description: #homozygotes, #heterozygotes
2) Calculate P, H and Q from population description
3) calculate p and q from P, H and Q
4) verify that p + q = 1
54
How does the relative frequency of heterozygotes in a population change as p and q change?
As p and q approach 0.5, heterozygotes become the most frequently appearing genotype
55
Which violations of the HW assumptions do not change the values of p and q?
A population that does not freely breed (assumption #1) does not have altered p and q values
56
What violations of HW expectations cause changes in p and q?
1. Mutation: can cause new A or a alleles
2. Small population size can cause genetic drift
3. Migration in or out of the population
4. Natural selection
5. Neutral evolution
57
What is neutral evolution?
Theory that the majority of evolutionary changes are caused by random drift or selectively neutral mutants. These mutations do not affect the fitness of the species.
58
Do new mutations have a large effect on p and q?
No, they have a vanishingly small effect on p and q
59
What is the equation for how q and p change with the occurrence of a mutation?
Δq = *u*p
where u is the mutation rate
if q increases, than p must decrease by the same amount in order to keep p + q = 1
60
Do genetic drift and natural selection have a large or small effect on p and q?
Genetic drift and natural selection cause large changes in p and q.
61
What type of population is most affected by genetic drift?
Small populations where chance events will have a much greater effect on allelic frequencies
62
What is the difference between selection and genetic drift?
Both occur via random effects, but in genetic drift, the random effects occur for reasons unrelated to carrying the mutant allele. If an allele causes the effect, then it is selection, not drift.
63
What is fixation?
Genetic drift often leads to a situation where 2 alleles exist, but over time one takes over and the other is eliminated
64
Does population genetics help us study patterns of inheritance and epistasis?
No. It does not answer pedigree questions. It only shows us information about the genetic structure of populations over time.
65
What are Mendel's laws?
1) Segregation: The two parental alleles of a single locus segregate away from each other into gametes
2) Independent assortment: alleles of genes that are not linked together on a chromosome segregate into gametes independently of each other
66
What is recombination?
The exchange of genetic material by homologous chromosomes during prophase of meiosis I
67
Describe the cis-trans nomenclature
cis: share the same chromosome
trans: on opposite homologous chromosome
68
Describe the cis- trans orientation of A,B,a and b in this image:
A is in cis to B and in trans to a and b
69
What are coupling orientations? What are repulsion orientations?
Coupling is the same as cis
Repulsion is the same as trans
70
What is a chiasma?
The point of crossing over between two chromosomes during recombination
71
How many chiasma occur on average in a human meiosis in each chromosome pair?
2-3 chiasma on average
72
What is a parental chromosome?
A chromosome with the exact same genetic information as one of the parents. These chromosomes are not affected by recombination events.
73
What is a recombinant chromosome?
A chromosome with different genetic information than either of the parents. This is the outcome of a recombination event
74
How does recombination affect the cis-trans orientation of chromosomes?
If recombination occurs between two alleles, then the cis-trans orientation will be reversed
75
What is a haplotype (in the context of recombination)?
a block of closely spaced loci and alleles
76
If there is no linkage, what is the %recombination ?
50%
77
Is sister-sister recombination detectable?
No because sister chromatids have exactly the same genetic information, so a recombination event swaps two identical segments
78
How do the phenotypic ratios differ between a cross between 2 unlinked genes and a cross with linked genes?
Alleles of 2 unlinked genes will have a ratio of 9:3:3:1 and alleles of linked genes will have a ratio approaching 3:1
79
If the recombination fraction (theta) is 50%, then what is thr frequency of gametic recombination (r)?
If theta = 50%, then r = 0.5
80
What can you infer about distance between loci from the frequency of recombination?
Loci that are farther apart have higher frequencies of recombination because there is a greater probability of recombination between the two
81
Is the fusion of two gametes statistically independent or mutually exclusive?
Statistically independent
82
Is the pattern of fusion statistically independent or mutually exclusive?
Mutually exclusive
83
What is the probability that a gamete is parental in terms of r?
p(Parental) = 1/2(1-r)
84
What is the probability that a gamete is recombinant?
1/2 r
85
What does phase mean?
Phase refers to the cis-trans orientation of the gene. If you don't know the phase, it is more complicated because you have to consider all of the alternatives.
86
Why is human gene mapping much more of a challenge then mapping the genome of another species like Drosophilia?
Humans have "small brood sizes"
Fewer progeny makes it much harder to do linkage analysis.
87
What is a LOD score?
Log of the Odds Ratio: a statistical test to determine the likelihood of linkage
88
What LOD score is the cutoff between ambiguity and high likelihood of linkage?
high likelihood of linkage if LOD \>3
89
What does a negative LOD score suggest?
A negative LOD score suggests a high likelihood of independent assortment
90
What is the equation for calculating the LOD score?
91
Which individual in this pedigree suggests that a recombination event has occured?
Individual III-6 is an affected, but does not have the A1 allele that all of the other affecteds have.
This means that a recombination event must have occured moving the A2 or A3 allele in cis with the disease allele.
92
Mutation Can Alter/Cause?
1. Cis Regulatory Sequences (Promoters or Enhancers)
2. Single Nucleotides (SNPs)
3. Deletions/Insertions
4. Inversions/Translocations
5. Changes in Gene Dosage/Copy Number Variation/Duplication
6. All Possible Alleomorphic Functional Allele Types
93
What are an Amorphic Alleles?
1. Produce No or Very Little Normal Protein. Usually Recessive.
2. No protein produced unless Heterozygous and can produce enough protein to retain function.
3. Caused by SNP resulting in premature stop codon.
94
What are Hypomorphic Alleles?
1. Produce Reduced Level or Activity of Otherwise Normal Protein. Usually Recessive.
2. Decrease activity and function (but not a complete loss)= recessive
3. Caused by a SNP/point mutation that does NOT a induce premature stop codon, but instead results in a damaged protein that retains some WT functions
95
What are Hypermorphic Alleles?
1. Produce Higher Level or Activity of Otherwise Normal Protein. Usually Dominant.
2. Increase acitivity and product, thus increasing function but not altering what is done.
3. Caused by duplication of a gene or enhancer, both resulting in increased output of the protein product
96
What are Antimorphic Alleles?
1. Produce Proteins That Reduce the Level or Activity of Protein Made by Wild-type Allele. Usually Dominant in Presence of Wild-type Allele. Extremely Rare “Dominant/Negative” Human Alleles.
2. Dominant negative: protein works to decrease function of wild type
3. "Cellular poision"
4. Require the presence of a WT allele for strongest mutant effect of pheotype
97
What are Spatiotemporal Alleles?
1. Heterochronic (Difference in Timing of Expression) or Ectopic (Difference in Location of Expression) Alleles Could be Hypo/Hyper/Amo
2. Wrong time, right place
3. Right time, wrong place
98
What are Neomorphic Alleles?
1. Produce Protein That No Longer Perform the Wild-type Gene Function, but Instead Have a New Function. Jokers Wild, Shows No, Co, or Complete Dominance.
2. Cuased by a frameshift due to an insertion/deletion, resulting in the destrution of the current gene and the creation of a new gene/protein product.
99
What are the various points a mutation can affect the flow of genetic information?
1. Transcriptional: Regulation
of Transcription Initiation (loss of promoter or enhancer).
2. Post-transcriptional:
Regulation of RNA Degradation (no Poly-A tail or 5' cap) and Alternative Splicing (incorrect gene splicing)
3. Translational and
Post-translational: Modification
of the Polypeptide Product, Folding
And Conformation, Adding
Sugars, Phosphates etc.
4. Formation of Multimeric Structures:
Subcellular Localization, mutation may affect subunit interaction, etc.
100
If the LOD score from a pedigree is less than 3, what can you do to prove linkage?
You can add additional pedigrees to your analysis and then sum the individual LOD scores
101
From a LOD score plot, what can you infer about the recombination distance?
The x-axis is recombination rate (%). The peak of the curve, if over Z=3, represents probable linkage.
The peak location corresponds with the maximum distance of recombination in map units.
Peak at 20% --\> recombination at 20 map units
102
# Define the following for Hemoglobin:
1. What cell is it found in?
2. What does it carry? Where does it carry it from? Where does it carry it to?
3. What are the subunits of the most common type of Human Hb?
4. What does each subunit have?
5. What molecule can bind to the amino acid sequence of Hb?
1. Red blood cells
2. Oxygen; From lungs to tissues
3. 2 alpha subunits and 2 Beta subunits
4. Each subunit has a globin chain and a prosthetic group (Heme)
5. Carbon dioxide
103
Characterics of the Heme group in Hb:
1. What does Heme primarily bind? What does this group bind?
2. What can the Heme group also bind? Does this have a higher or lower affinity for Heme compared to the primary molecule?
1. Heme binds Iron which in turn binds Oxygen
2. Heme can also bind Carbon Monoxide (CO) which has an affinity 250X more compared to Oxygen
104
What are the various hemoglobin subunit types? What time in development are they most prominant?
1. Alpha: fetal into adult
2. Beta: begins to form at low levels around 6-12 weeks postconception, increases post birth, reaches normals levels 12+ after birth
3. Gamma: highest levels 6-30 weeks post conception, begin to fall after birth, low levels at 12+ weeks post birth moving to 0
4. Delta: levels begin to rise 12-18 weeks post-birth
5. Epsilon: highest levels immediately post-conception in yolk sac; falls to zero 6 weeks post-conception
6. Zeta: highest levels immediately post-conception in yolk sac; falls to zero 6 weeks post-conception
7. Mu: functions in erythrocyte differentiation
8. Psi: psuedogene
105
What is different about the equation for calculating LOD scores when the phase is unknown?
You have to consider both hypotheses (each individual is either recombinant or non-recombinant), then you multiply the LOD scores from each scenario by 1/2 and add them up
106
Why can it be dangerous to add LOD scores across pedigrees?
Locus heterogeneity can confound mapping efforts
Genetic and environmental effects different in different families
Even large well documented pedigrees sometimes don't produce Z \> 3
107
Is recombination uniformly distributed along a chromosome?
No. There are recombination hotspots where there is a high frequency of recombination.
108
A muation to which Hb subunit is most detremential? Why is one worse than the other?
A mutation to the Alpha subunit will be seen much earlier in fetal development becuase it becomes prominant immediately post-yolk sac. Thus, deletions to Alpha will decreases the fetus' ability to extract blood and will be spontaneously aborted early in development.
Beta mutations have no pre-natal consequences since episilon and gamma are the normal pre-natal "Beta derived" globins. Mutations in Beta will be seen once the child is born when beta levels rise and gamma levels fall.
109
What are the hallmarks of quantitative traits?
1. Continuous distribution of phenotypic characteristics in the population
2. Tend not to show simple Mendelian segregation patterns
3. Many genes contribute to the phenotype and polymorphism at these loci contributes variance along the distribution.
110
What are 3 Hemoglobinopathies discussed in class?
1. Structural Variants: Proteins Altered in Primary, Secondary or Tertiary Conformation Due to AA Changes, BUT Transcription/Translation Not Impacted
2. Thalassemias: Reduction in Amount of Globin Protein Due to Reduced Rate of Production, Deletion, or Instability
3. Hereditary Persistence of Fetal Hemoglobin: HbF Always a Major Presence in Blood, Benign, but Impaired γ to β Switch.
111
What value do twin studies have for testing heritability?
Monozygotic twin studies suggest strong heritability of a complex trait such as Schizophrenia
112
What are the defining characteristics of Sickle cell anemia?
1. Recessive Allele, High Frequency in Populations Challenged with Malaria (Hets 8-10%)
2. Caused by a Glu6Val Mutation in β-chain, Decreases Solubility of Deoxygenated HbS
3. Normal Oxygen Affinity but In Low Oxygen
Environments (such as Capillary Beds) Conformation Changes Reveal Hydrophobic Residues and Val Interacts with Them. Reversible Intermolecular
Interaction, Two Hydrophobic Regions Interact
4. Double Strands are Formed by Nucleation, And Then Seven
Double Strands Dock Together to Form the Sickle Fiber.
113
What are the defining characteristics of Thalassemia?
1. Most Common Mendelian Disorder
2. Most Impact Mediterranean, Middle East, Africa, India, Asia
3. Mutations Delete Genes, or Cause Change in Transcription, Post-transcriptional, or Post-Translational Regulation of α- or β-globin chains
4. Imbalance in Ratio of α or β chains
5. Predominantly caused by point mutations
114
What are the two classes of Thalassemia? Define the characterisitcs of each.
Simple β-thalassemia:
1. great majority of patients
2. impaired production of β-globin alone
3. One Loss of Function Allele (Simple
Heterozygote),
4. Slight Anemia, Hypochromic,
Microcytic RBCs.
Complex β-thalassemia:
1. large deletions remove β-globin and one or more other genes in the β-globin cluster, or β-globin LCR
2. Two Loss of Function Severe β Alleles.
If Not a Complex Null, HbF May be Normal
115
What are the three type of Splicing Mutations? Describe the characteristics of each.
Group 1: splice junction mutations
* Mutation destroying a normal splice acceptor site and activating a cryptic site
Group 2: Intron Mutations
* Mutation creating a new splice acceptor site in an intron
Group 3: Coding And Splicing
* Mutation enhancing a cryptic splice donor site in an exon
116
What are the different variants that can affect allele frequency?
1. Single nucleotide variant
2. Insertion-deletion variant (indel)
3. Block substitution
4. Inversion variant
5. Copy number variant
117
How are common variants useful for gene sequencing and identifying the presence of disease alleles?
Common polymorphisms can be mapped, and may be linked to disease alleles.
Specific marker alleles and linked disease alleles should tend to be co-occuring in affecteds
118
What percentage of genetic variants are believed to be structural (based on the sequencing of Dr. Venters DNA)?
20% are structural, and 70% are associated with structural variants
119
How has the number of polymorphisms changed over human history?
When humans left Africa, they had maximal polymorphisms, but genetic drift and fixation have reduced our allelism over time
120
Is linkage disequilibrium easier or harder to detect in African populations?
Harder
121
What kinds of technologies exist for genome wide association tests?
SNPChips = genome wide arrays
PCR amplification
Hybridization
Light emission to identify A, T G or C
122
What are the problems with comparing cases and controls in GWA studies?
1. Loss of power due to misdiagnoses
2. Sample size must be in the 1000s to account for small effect sides
3. Latent population structure. Different populations have different marker linkage disequilibrium
123
Can BRCA1 and 2 be detected using GWAs?
No. They are not detectable in high frequency populations. More than 65,000 genotypes would be needed
124
What does a manhattan plot show?
They display the log10 of the probability of association (p-values) of an SNP with a quantitative trait
Values of 7 or more are seen to be true replicates
