Midterm 1 Flashcards
(289 cards)
1
Q
What were the two hypotheses to explain inheritance in 1837?
A
- one parent contributes more to an offspring’s inherited traits (eg Aristotle contended that it was the male and that a fully formed homunuculus was inside the sperm)
- blended inheritance - the traits of the parents are blended in their offspring (like blue and yellow to make green) - explained single offspring, but not siblings, or the next generation
2
Q
5 characteristics of a model organism:
A
- short generation time
- can be inbred (self-fertilise)
- simple reproductive biology
- small size
- large numbers of progeny for robust statistical analysis
3
Q
why was Pisum sativum a good choice for Mendel’s experiments?
A
- Well characterized, cultivated plant, grew well in Brno
- Could be self-fertilized (selfed) - pollen from the plant could be used to
pollinate its own flowers - allows inbreeding - Could obtain and maintain pure-breeding lines - these always bred
true producing the same trait generation upon generation - Could be readily cross-fertilized to create hybrids between pure-breeding
lines - could have carefully controlled matings and reciprocal crosses - to
rule out the effect of one parent versus the other - Could examine clear-cut (qualitative/discrete) traits where there were 2 forms of the trait- “either-or” choices - unambiguously distinguish forms of the trait
- Could have a large number of plants and progeny, so could subject the
data to statistical analysis - Mendel did quantitative analyses that produced
robust results and aided interpretation
4
Q
The August Krogh Principle
A
For many problems there is an animal on which it can be most conveniently studied
4
Q
A
5
Q
what is a reciprocal cross?
A
a breeding experiment where two different parental strains are crossed twice, with the sex of the parents switched in the second cross
6
Q
process of cross-pollination of pea plants
A
- pollen transferred from one pea plant to the stigma of recipient pea plant (with anthers previously removed) with brush
- seed forms and germinates
7
Q
process of selfing of a pea plant
A
transfer of pollen onto stigma of same plant
8
Q
examples of antagonistic pairs that Mendel investigated
A
- seed colour (yellow/green)
- seed shape (round/wrinkled)
- flower colour (purple/white)
- unripe pod colour (yellow/green)
- ripe pod shape (round/pinched)
- stem length (long/short)
- flower position (axial - along stem/terminal - at tip of stem)
9
Q
broad overview of process of Mendel’s investigation
A
- isolated pure forms of each trait
- crossed 2 pure breeding lines that differed at one trait only
- looked at progeny (F1 and F2)
10
Q
how did dominance manifest itself in Mendel’s experiments?
A
one of the two traits in an antagonistic pair was dominant and would always be manifested in the F1 hybrid
11
Q
dominant antagonistic traits in Mendel’s experiments
A
- yellow
- round
- purple
- green
- round
- long
- along stem - axial
12
Q
how did Mendel disprove the theory of uniparental inheritance and demonstrate that both contribute equally?
A
reciprocal crosses revealed that not only were traits dominant but also that this was independent of the parent
‘it is immaterial to the form of the hybrid which of the parental types are used in the cross’
13
Q
define a locus
A
a genetically defined location - strictly speaking, we don’t know if it is only one gene or not - but it behaves like a single gene
14
Q
define an allele
A
alternative form at a given locus
15
Q
define dominant
A
the allele that manifests itself regardless of the other allele that is present - indicated by an upper-case letter (e.g. A) - the trait that is manifest in a hybrid
16
Q
define recessive
A
an allele whose effect is “masked” when the dominant allele is present - all alleles at a locus must be recessive in order for the recessive allele to manifest itself - indicated by a lower-case letter (e.g. a)
17
Q
define homozygous
A
when both alleles at a given diploid locus
are the same – i.e. AA or aa
18
Q
define heterozygous
A
when there is one dominant and one
recessive allele present at a diploid locus– i.e. Aa
19
Q
define homozygote
A
an individual who is homozygous at the
locus in question
20
Q
define heterozygote
A
an individual who is heterozygous at the locus in question
21
Q
define hybrid
A
derived from two different parents
22
Q
define monohybrid
A
one hybrid locus
23
Q
define dihybrid
A
two hybrid loci
24
define true-breeding
homozygous at the loci/locus in question
25
define P
parental generation
26
define F1
first filial generation - the offspring derived from the parental generation
27
define F2
second filial generation - the offspring derived from the F1 generation
28
define self
an inbreeding cross that involves individuals that are genetically identical (eg a plant with itself, or between full siblings derived from true breeding plants)
29
Mendel's experiments - monohybrid cross
- green peas (yy) crossed with yellow peas (YY)
- F1 all yellow (Yy)
- self-fertilisation of F1
- F2 yellow:green = 3:1
- the reappearance of the recessive trait completely disproves 'blending' and uni parental inheritance
30
how did Mendel infer the law of segregation (Mendel's First Law)?
F3 - diagram on slide 26
31
define and explain the law of segregation (Mendel's First Law)
- two members of a gene pair segregate from each other into the gametes, so that one-half of the gametes carry one member of the pair and the other one-half of the gametes carry the other member of the pair
- the alleles unite at random, one from each parent, at fertilisation
32
Mendel's first law incorporates the fact that his results reflected
basic rules of probability
33
define genotype
pair of alleles present in an individual
34
define phenotype
observable characteristic of an organism
35
give an example of how genotype and phenotype differed in Mendel's experiments
F2 generation
phenotype ratio was 3:1 = yellow:green
genotype ratio was 1:2:1 = YY:Yy:yy
36
how can we discriminate between dominant homozygotes (eg YY) and heterozygotes (Yy)?
Test crosses reveal unknown genotypes:
unknown genotype x homozygous recessive
diagram on 34
37
Mendel's experiments: dihybrid crosses
- crossed YYRR (yellow and round) with yyrr (green and wrinkled)
- F1 were all identical (YyRr)
- in F2, there were 4 different phenotypic combinations, including ones that weren't originally present in the parents.
- 16 possible allelic combinations, 9 unique genotypes, 4 different phenotypes
- this suggested that there had been a shuffling of alleles, proposed in the law of independent assortment
38
Mendel's second law - Law of independent assortment
- during gamete formation, the segregation of alleles at one locus is independent of the segregation of alleles at another locus
- results in predictable ratios of phenotypes in the F2 generation as shown by a Punnett square
- follows basic laws of probability
39
how can we calculate the number of possible allele combinations in gametes?
2^n
n= number of gene loci where the organism has two different alleles
40
use of product rule
Product Rule – "AND" Situations
Use the product rule when you're calculating the probability of two or more independent events happening together.
41
use of sum rule
Sum Rule – "OR" Situations
Use the sum rule when calculating the probability of either of two mutually exclusive events occurring.
42
Law of probability for multiple genes
loci assort independently - so we look at each locus independently to get the answer (eg on slide 43)
43
summary of Mendel's 1865 paper
1. inheritance is particulate - not blending
2. there are two copies of each trait in a germ cell (before meiosis)
3. gametes contain one copy of the trait
4. alleles segregate randomly
5. alleles are dominant or recessive - thus the difference between genotype and phenotype
6. different traits assort independently
44
what is the main source of allelic variation?
mutations
45
define mutation
the process by which genes change from one allelic form to another. the creation of entirely new alleles can occur.
46
describe how mutations arise
- genes mutate randomly, at any time and in any cell of an organism
- mutations can arise spontaneously during normal replication or can be induced by a mutagen
47
how are mutations transmitted to progeny?
- only mutations in gremlin cells can be transmitted to progeny
- somatic mutations cannot be transmitted
48
how do inherited mutations appear in populations of individuals?
as alleles
49
draw a flowchart describing the inheritance of mutations
slide 6
50
define allele frequency
the percentage of the total number of gene copies represented in one allele
51
how can allele frequency be calculated?
by dividing the number of times the allele of interest is observed in a population by the total number of copies of all the alleles at that particular genetic locus in the population
52
wild-type allele
allele whose frequency is greater than or equal to 1%
53
mutant allele
allele whose frequency is less than 1%
54
monomorphic gene
a gene with only one wild-type allele
55
polymorphic gene
a gene with more than one wild-type allele
56
forward mutation
changes wild-type allele to a different allele
57
reverse mutation
causes novel mutation to revert back to wild-type allele (reversion)
58
define a mutagen
a mutation inducer, eg UV light, certain chemicals, etc.
59
mutations affecting phenotype occur
very rarely
60
do all genes mutate at the same rate?
no; different genes mutate at different rates.
- mutation rate varies from 1 in 1000 to 1 in 1,000,000,000 per gene per gamete
61
which rate is higher; rate of forward or rate of reverse mutation?
rate of forward mutation is almost always higher than rate of reverse mutation
62
6 types of mutations (classified by effect on DNA molecule)
- substitution
- deletion
- insertion
- inversion
- reciprocal translocation
- chromosomal rearrangements
63
substitution
base is replaced by one of the three other bases
64
a substitution is a type of
point mutation
65
point mutation
changes in a single nucleotide base within a DNA sequence
66
deletion
block of one or more DNA pairs is lost
67
insertion
block of one or more DNA pairs is added
68
inversion
rotation of piece of DNA
69
reciprocal translocation
parts of non homologous chromosomes change places
70
chromosomal rearrangements
a change in the structure of a chromosome, often involving deletions, duplications, inversions, or translocations; affect many genes at one time
71
single nucleotide polymorphism (SNP)
a variation in a single base pair in a DNA sequence.
72
SNPs are
alleles
73
define a polymorphism
- detectable change (difference) in a given locus/gene
- this is what makes an allele an allele
74
how are Mendel's traits encoded?
in DNA: allelic differences at the DNA level can influence mRNA expression and/or protein function, and thus the phenotype
DNA -> mRNA -> protein -> organismal traits
75
two ways in which mutations may impact gene expression
1. mutation in exon -> altered transcription -> altered translation -> different amino acid -> folded protein with altered function
2. mutation in promoter sequence -> no transcription -> no RNA -> no function
76
null mutation
completely abolishes the function of a gene
77
leaky/hypomorphic mutation
mutated gene product retains some, but not all, of its normal function
78
silent/synonymous mutation
doesn't alter the amino acid sequence of the protein it encodes
79
give an example of how different types of mutations may result in the same phenotypic consequences
Coding DNA Sequence (CDS) region mutation -> RNA -> protein -> no function
Promoter mutant allele -> no RNA -> no protein -> no function
80
is there dominance/recessiveness at the DNA level? why/why not?
- there is no dominance and recessiveness at the DNA level, since it is the underlying genotypic basis of inheritance (codominance).
- dominance/recessiveness can only be assessed at the phenotypic level
81
describe the gene basis behind Mendel's pea shape
Starch branching enzyme 1
R: Sbe1
r: no Sbe1
Case 1: RR, Rr -> Sbe1 produced
- this causes amylose to be converted into amylopectin, which is a branched starch required to give the round pea shape
Case 2: rr -> no Sbe1 produced
- amylose is not converted into amylopectin, thus giving a wrinkled pea shape
82
describe the gene basis behind Mendel's stem length
GA = gibberellin acid plant growth hormone
gibberellin (GA) 3β-hydroxylase is an enzyme required for the conversion of GA20 (inactive form) into GA1 (bioactive form)
Case 1: dominant allele LE -> GA 3β-hydroxylase produced and there is rapid conversion of GA20 into GA1, leading to long stems
Case 2: recessive allele le -> GA 3β-hydroxylase produced and there is very low conversion of GA20 into GA1, leading to short stems
this is an example of how a SNP change in one amino acid disrupts the activity of enzymes
83
describe PKU
- normally, phenylalanine (found in food) is usually converted into tyrosine by the enzyme phenylalanine hydroxylase (PAH)
- in people with PKU, mutations in both exons and introns for the PAH gene can inactivate the gene
- this causes inability to convert phenylalanine into tyrosine, instead converting it into phenylpyruvic acid
- build-up of phenylpyruvic acid can interfere with nervous system development, so must be caught early in order to change diet accordingly
84
BRCA1
- a tumour-suppressor gene involved in repairing DNA damage
- mutations in this gene interfere with DNA repair, leading to cancer risk (breast + ovarian in women, breast + prostate in men)
- hundreds of mutations in BRCA1 have been found that increase the risk of breast cancer
- there is a 12% risk in the general public, 60% risk in those with harmful BRCA1 mutations
85
draw a table for pea genotype and amount of functional, starch-producing protein
25
86
is haplosufficiency or haploinsufficiency more common?
for many genes, 50% of the protein product is sufficient to give a wild-type phenotype (haplosufficient)
87
haplosufficiency
- A single copy of a functional allele (wild-type) (=50% of the protein product) is sufficient to produce a normal phenotype.
- If one wild-type allele is present, the individual will typically have a normal phenotype, even if the other allele is a mutant.
88
haploinsufficiency
- A single copy of a functional allele (wild-type) is not sufficient to produce a normal phenotype.
- Individuals with one wild-type and one mutant allele may show a mutant phenotype because the remaining functional allele cannot compensate for the loss of the other.
89
what is the similarity between haploinsufficiency and dominant negative situations?
Haploinsufficiency and dominant negative effects are two different ways in which a single mutated gene can cause a dominant phenotype.
90
describe the difference between haploinsufficiency and dominant negative situations
1. Haploinsufficiency
- When a single functional copy of a gene is not enough to produce a normal phenotype.
- Mechanism: One allele is inactivated or deleted → 50% of normal gene product → insufficient for normal function.
2. Dominant negative
- A mutated gene product interferes with the function of the normal (wild-type) protein.
- Mechanism: Mutant protein binds or competes with the normal protein → disrupts function of the protein complex.
91
how can we distinguish haploinsufficiency with dominant negative using protein levels?
Haploinsufficiency: ~50%
- One functional allele → reduced dosage
Dominant Negative: 0–50%
- Mutant protein disrupts normal protein
92
how can we detect allelic polymorphisms at the molecular level?
- PCR and DNA sequencing
- new technologies
93
principles of allele detection
- ultimately resides at the level of DNA sequence
- can detect polymorphism from DNA to protein level
- analysis performed on diploid nuclear genome
94
what provides the most comprehensive picture of allelic polymorphisms?
PCR amplification and DNA sequencing,
95
2 ways to screen for BRCA1
- gene sequencing: most comprehensive but most expensive (BRCA1 is >80,000 bp)
- SNP detection of 1-3 more common mutations known to cause breast cancer - chapter but much less comprehensive
96
suggested screening strategy for relatives of patients with breast cancer
- for a patient with cancer, use gene sequencing to screen for causal mutation. possible results: causal SNP identified, SNP of uncertain significance, or no causal SNP
- if causal SNP identified, use SNP detection approaches at identified SNP to screen at-risk relatives
97
new technologies for disease screening
next generation sequencing, eg Illumina, allows for massive amounts of sequencing at much lower costs
98
Albinism
- a genetic condition characterized by a deficiency or absence of melanin, the pigment that gives color to skin, hair, and eyes.
- haploinsufficient: biallelic mutations are usually required for the condition to manifest
- straight hairline, no freckles, no hair, round chin, no dimples
99
autosomal inheritance
- human autosomal traits are located on the non-sex chromosomes (1-22)
- they may be inherited as autosomal dominant or autosomal recessive
100
autosomal dominant traits
- homozygous dominant and heterozygotes exhibit the affected phenotype
- males and females are equally affected and may transmit the trait
- affected phenotype does not skip a generation (vertical pattern of transmission)
101
autosomal recessive traits
- only homozygous recessive individuals exhibit the affected phenotype
- males and females are equally affected and may transmit the trait
- may skip generations (horizontal pattern of transmission)
102
define a horizontal pattern of transmission
where a genetic disorder appears in multiple siblings of the same generation, but not in their parents or ancestors
103
why are pedigrees typically used to study human genetics?
humans are not good model organisms: we cannot do controlled breeding experiments on them, so instead use model organisms and pedigrees to dissect mendelian traits of interest
104
define a pedigree
an orderly diagram of a family's relevant genetic features extending through multiple generations
105
what is the purpose of pedigrees?
to help us infer if a trait is from a single gene and if the trait is dominant or recessive
106
male
107
female
108
mating
109
parents and children
110
dizygotic (nonidentical twins)
111
monozygotic (indentical twins)
112
sex unspecified
113
number of children of sex indicated
114
affected individuals
115
heterozygotes for autosomal recessive
116
carrier of sex-linked recessive
117
death
118
abortion or stillbirth (unspecified)
119
propositus/proband
first individual in a family who is identified as having a genetic disorder
120
consanguineous marriage
121
draw a graph for Huntington's Disease
- of all persons carrying the allele, percentage affected with the disease
- age (years)
122
Huntington's disease
rare autosomal dominant; onset is later in life, usually after they've had kids.
123
how can we recognise dominant traits in a pedigree diagram?
- affected kids always have at least 1 affected parent
- as a result, dominant traits show a vertical pattern of inheritance (the trait shows up in every generation)
- two affected parents can produce unaffected children, if both parents are heterozygotes
124
give 2 examples of a vertical pattern of transmission
- brachydactyly (rare dominant trait): abnormally short fingers and/or toes, caused by shortened bones in the hands or feet
- polydactyly (rare dominant trait)
125
why don't harmful dominant traits usually persist in populations unless they are late onset?
because of natural selection — specifically, negative selection against traits that reduce survival or reproduction.
126
how can we identify recessive traits in a pedigree?
- affected individuals can be the children of two unaffected carriers, particularly as the result of consanguineous matings
- all the children of two affected parents should be affected
- rare recessive traits show a horizontal pattern of inheritance: the trait first appears among several members of one generation and is not seen in earlier generations
- recessive traits may show a vertical pattern of inheritance if the trait is extremely common in the population
127
what is the issue with consanguinity?
- Every person carries several recessive mutations that, if present in two copies, can cause genetic disorders.
- These are usually silent because most people are heterozygous (carrying only one copy).
- Related individuals are more likely to carry the same harmful recessive alleles inherited from a common ancestor.
128
define genetic load
the collection of deleterious recessive alleles present in a population.
129
give two examples of recessive traits
- albinism
- cystic fibrosis
130
what is the purpose of a pedigree with consanguinity (inbreeding)?
frequently uncovers traits that are recessive
131
consanguineous mating can often give rise to
inbreeding depression - offspring that are less fit than their parents
132
genetic counselling sessions
- family history
- pedigree construction
- information provided on specific disorders, modes of inheritance, tests to identify at-risk family members
- testing arranged, discussion of results
- links to support groups, appropriate services
- follow-up contact
133
issues associated with genetic screening
- Why carry out genetic screening at all?
- When is a test accurate and comprehensive enough to
be used as the basis for screening?
- Once an accurate test becomes available at reasonable
cost, should screening become required or optional?
- If a screening program is established, who should be
tested?
- Should private companies and insurance companies
have access to employee and client test results?
- What education needs to be provided regarding test
results?
134
if both parents are heterozygous (Bb) what is the probability that they will produce a BB child?
probability of a sperm with B allele = 1/2
probability of an ovum with B allele = 1/2
probability of a BB child = 1/2 x 1/2 = 1/4
135
parents are heterozygous for a trait, Rr. what is the probability that their child is a heterozygote?
probability of child carrying R from father and r from mother (Rr) = 1/2 x 1/2 = 1/4
probability of child carrying r from father and R from mother (Rr) = 1/2 x 1/2 = 1/4
probability of child carrying Rr = 1/2
136
parents are heterozygous for a trait, Rr. what is the chance that their child carries at least 1 dominant R allele?
probability of child carrying RR = 1/2 x 1/2 = 1/4
probability of child carrying Rr = 1/4 + 1/4 = 1/2
probability of child carrying R _ = 1/4 + 1/2 = 3/4
137
Ellen's brother Michael has cystic fibrosis, an autosomal recessive disease. what is the probability that Ellen's child has a cystic fibrosis-causing allele?
- Ellen and Michael's parents must be heterozygous (if not mentioned in q, assume no disease)
- Probability Ellen is a carrier = 2/3 (not affected thus cannot be ss)
- Probability child inherits cystic fibrosis allele = 1/2
- Probability child carries cystic fibrosis allele from Ellen = 2/3 x 1/2 = 1/3
138
issues with Mendel's laws
- incomplete dominance and codominance
- multiple alleles
- pleiotropy
- variable expressivity
- incomplete penetrance
- environmental influence
139
how do we know that dominance is not always complete?
crosses between true-breeding strains can produce hybrids with phenotypes different from both parents
140
incomplete dominance
- F1 hybrids that differ from both parents express an intermediate phenotype
- neither allele is dominant nor recessive to the other
- the heterozygous phenotype is distinct from either homozygous phenotype (an intermediate phenotype)
- phenotypic ratios are the same as genotypic ratios
141
codominance
- F1 hybrids express the phenotype of both parents equally
- phenotypic ratios are same as genotypic ratios
- both alleles are expressed in the heterozygotes
142
draw a table portraying a summary of dominance relationships
143
give an example of incomplete dominance in plants
Antirrhinum majus (snapdragons)
P: red x white
F1 (all identical): pink x pink
F2: 1 red: 2 pink: 1 white
- the genotypic and phenotypic ratios are the same
- this signifies that the alleles of a single gene determine these 3 colours
144
give an example of incomplete dominance in animals
whippets:
- DNA testing has recently identified a mutation on the myostatin gene that tends to make whippets with one copy fast and whippets with two copies overmuscled 'bullies'
145
give an example of incomplete dominance in humans
familial hypercholesteraemia
- results in abnormally high levels of cholesterol
- the general population (homozygous for fh) have <250mg/dl of plasma cholesterol
- heterozygotes for FH have 250-500
- homozygotes for FH have >500
146
can a gene have more than two alleles?
- genes may have multiple alleles that segregate in populations
- although there may be many alleles in a population, each individual carries only 2 of the alternatives
147
give an example of a gene that has more than two alleles
- ABO blood group gene: I
- 3 alleles: IA, IB, and i
- 6 possible ABO genotypes: IAIA, IBIB, IAIB, IAi, IBi, or ii
148
dominance relations are unique to
a pair of alleles; dominance or recessiveness is always relative to a second allele
149
dominance relations in the ABO blood group gene
- IA and IB are completely dominant to i but codominant to IB
150
how many possible phenotypes are there for blood type?
4: type A, type B, AB, or O
151
how is the ABO gene an example of codominant alleles?
the ABO gene encodes a cell surface protein, glycosyltransferase (an enzyme)
A allele: A antigen
B allele: B antigen
O allele: does not produce any antigens
- A and B antigens may be present on the same cell
- Alleles A and B are codominant
152
lentil coat pattern alleles are an example of
codominant alleles
153
describe the genetic mechanisms underlying lentil coat patterns
S allele: spotted
D allele: dotted
P: CSCS x CDCD
F1 (all identical): CSCD x CSCD (spotted/dotted)
F2: 1 CSCS (spotted): 2 CSCD (spotted/dotted): 1 CDCD (dotted)
154
draw a table of blood type and antibodies in serum
O is universal donor
155
draw a table of blood type of recipient vs compatibility with donor blood type
AB is universal recipient
156
how do we establish dominance relations between multiple alleles of a gene?
perform reciprocal crosses between pure-breeding lines of all phenotypes and observe the phenotype of the F1 heterozygote/hybrid
157
dominance series of agouti gene
A-: agouti
atat: black/yellow
aa: black
ata: black/yellow
A>at>a
158
pleiotropy
single gene determines more than one distinct and seemingly unrelated characteristics, controlling several functions and having many symptoms
159
some alleles may cause lethality. what does this mean?
type of pleiotropy where alleles produce a visible phenotype and affect viability: alleles that affect viability often produce deviations from a 1:2:1 genotypic and 3:1 phenotypic ratio predicted by Mendel's laws
160
explain why lethality-causing alleles deviate from Mendelian ratios
- Mendel’s laws assume all genotypes are viable and equally fit.
- however, when an allele causes lethality, the affected genotypes drop out of the population, skewing the observed ratios.
161
King George 3rd's 'madness'
porphyria variegata
- caused by a mutation in the gene for the heme biosynthetic pathway, which encodes an enzyme
- if the enzyme is missing, porphyrin accumulates, resulting in concentrations that are high and toxic to organisms
- leads to multiple effects across urine (dark red urine), digestive system (abdominal pain and constipation), muscles (rapid pulse and weak limbs), and nervous tissue (stupor, delirium, convulsions, mad behaviour)
162
inheritance of coat colour in mice as an example of lethality
AA: agouti
AyA: yellow
- Ay is dominant to A
- yellow mice must be AyA
- inbred agouti (AA) x yellow (AyA) yields 1:1 agouti:yellow
- yellow AyA x yellow AyA mice do not breed true
- Ay is a recessive lethal allele (negatively affects survival of homozygote)
- AyAy die in utero and do not show up as progeny
163
coat colour in mice shows the importance of avoiding
consanguineous mating
164
draw a table summarising Mendel's basic assumptions and a comparison of these assumptions with 20th century contributions
165
sickle cell anaemia
- haemoglobin is composed of four polypeptide chains: 2 alpha (α) globin chains, and 2 beta (β) globin chains
- SCA is caused by a point mutation in the Hbβ gene, which encodes the β-globin subunit
- normal wild-type is Hbβ^A
- ~400 mutant alleles have been identified so far
- Hbβ^s allele specifies abnormal peptide causing sickling among RBCs, which are usually biconcave
- Hbβ^s allele is codominant at the molecular level and recessive at the phenotypic level (Hbβ^A is haplosufficient)
- pleiotropy: Hbβ^s allele affects more than one trait (sickling, resistance to malaria, recessive lethality)
- RBCs are much more fragile and easily broken, leading to a lower lifespan and anaemia
166
how do sickle cells confer resistance to malaria?
infected RBCs break up, or are cleared by the spleen before Plasmodium Falciparum has a chance to reproduce and lyse the cells
167
draw a table analysing the phenotypes at different levels of analysis for sickle cell anaemia
168
variable expressivity
a phenotype that varies in intensity
169
example of variable expressivity
individuals with the same genotype for cystic fibrosis have varying levels of symptoms
170
incomplete penetrance
the phenotype is not always observed among individuals carrying the genotype
171
example of incomplete penetrance
DD or Dd only result in 80% polydactyly
172
opposite of variable expressivity
unvarying expressivity
173
define penetrance
% of individuals with a genotype that express the phenotype
174
why do penetrance and expressivity vary?
- genetic modifiers: other genes (outside the main disease gene) that influence the severity, onset, or presence of a trait
- environmental factors: may act as modifiers
175
complete penetrance and unvarying expressivity
176
incomplete penetrance and unvarying expressivity
177
complete penetrance and variable expressivity
178
incomplete penetrance and variable expressivity
179
give an example of variable expressivity
coat spots/colour on dogs (slide 26)
180
give an example of variable expressivity due to environmental modification
siamese cats are usually homozygous for a mutant form of an allele of the TYR gene that controls melanin production, but is only functional at cooler temperatures.
warmer temperature: colourless precursor -> enzyme nonfunctional -> no melanin -> light fur
cooler temperature: colourless precursor -> enzyme functional -> melanin -> dark fur
thus, the legs, tail, ears, nose are usually darker in colour (exposed to cooler temperatures), whilst the main body is white.
181
why do variations on dominance relations not negate Mendel's law of segregation?
- dominance relations affect phenotype as the gene products control expression of phenotypes differently
- alleles still segregate randomly during gamete formation
182
complementation
occurs when two individuals with mutations in different genes (but causing the same phenotype) are crossed, and their offspring have a normal (wild-type) phenotype.
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complementation genetics assumes that the mutation is ------
recessive
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Astyanax mexicanus
- cave fish descended from surface subspecies, but accumulated mutations in genes required for sight, making them blind.
cave 1 x cave 1: F1 blind
cave 1 x cave 2: F1 can see
cave 1 x cave 3: F1 can see
- deficient copies in one lineage were compensated for by the functional copies in the other lineage (complementation)
- this suggested that although the fish in different caves had all converged upon the same outward appearance (blindness), they had taken different evolutionary paths to do this and had acquired mutations in different genes responsible for sight
- this showed that there are many steps to producing an eye, and that different subspecies have mutations in different steps/pathways required for eye development
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what two possibilities do we have to distinguish between when discussing the effect of mutation on phenotypes?
1. mutations in the SAME gene can give rise to the same phenotype
2. mutations in DIFFERENT genes can also give rise to the same phenotype
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allelic
alleles of the same gene
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how does one WT allele and one mutant allele result in a restoration of function?
the wild type allele is haplosufficient so complements the mutant alleles (compensates for what the mutant is lacking) so that the phenotype is wild type.
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how do we distinguish between complementation and allelism?
- complementation: (WT, M) the wild type allele is haplosufficient so complements the mutant alleles (compensates for what the mutant is lacking) so that the phenotype is wild type.
- allelism (M, M) two mutant alleles cannot complement each other so the phenotype is mutant
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molecular vs phenotypic visibility of allelism
while the locus appears heterozygous at the molecular level (the two mutant alleles are caused by different base pair substitutions), the individual appears homozygous at the phenotypic level (they express the mutant phenotype to the same degree)
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history of tomatoes and why they are good genetic models
- domesticated in south and Central America, ~5000 years ago
- brought by the conquistadors to Europe sometime between 1521 and 1544
- pomi d'oro (golden apples) and pomp d'amour (apple of love)
- by 1622, 4 varieties - red, yellow, orange, golden
- by 1700, 7 varieties
- long history of breeding
- good genetic model
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purpose of testing for allelism
interested in finding genes responsible for a particular trait
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forward genetics experiment
You observe or induce a mutant phenotype and then work forward to discover which gene(s) caused it (phenotype -> gene)
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process of testing for allelism or complementation
1. expose a purebred wild type to mutagenesis
2. isolate pure-breeding lines of mutants that express the mutant trait of interest
3. cross the mutants together and observe the phenotypes of the F1, F2, Fn progeny
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if allelism is the case
- the F1, F2, and Fn progeny will all express the mutant phenotype
- mutant 1 and mutant 2 had the same gene affecting tomato colour
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if complementation is the case
- the F1 progeny will have the wild type phenotype; they are heterozygous for mutant and wild type alleles
- Mutant 1 and mutant 2 contained different genes affecting the same trait, with mutant 1 containing mutations in one gene and mutant 2 containing mutations in the other
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complementation testing
- one of the most powerful tests in genetic analysis
- simultaneously a test for allelism (must be one or the other)
- works when the mutant phenotype is recessive
- allows us to uncover how many different genes control a trait
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draw a flow chart of the two possible outcomes for a complementation/allelism test
wild type -> mutant 1 x mutant 2:
1. F1 progeny: mutant (allelic - mutants uncover 2 alleles at 1 locus)
2. F1 progeny: wild type (complementation - mutants uncover 2 loci controlling the same trait)
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give two examples of complementation in humans
1. if two non-hearing parents with mutations in DIFFERENT hearing genes have children, complementation will occur and all the F1 progeny will be able to hear (AAbb x aaBB -> AaBb)
2. if two parents with ocular-cutaneous albinism (OCA) with mutations in DIFFERENT determining genes have children then complementation will occur and the children will not have OCA (aaBB x AAbb -> AaBb)
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when we know that two genes are acting on the same trait, how do we find out whether they are functioning in the same pathway?
1. take two mutant lines, M1 and M2, and cross them together (aaBB x AAbb)
2. create a dihybrid/heterozygous line (AaBb), resulting in a restoration of WT phenotype due to complementation
3. conduct a dihybrid cross (F1xF1)
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recessive epistasis
genotype ratio: 9 (A_B_): 3 (A_bb): 3 (aaB_): 1(aabb)
phenotype ratio: 9 (A_B_): 3 (A_bb): 4 (aaB_ and aabb)
aa is epistatic to B and b - when homozygous, recessive allele of one gene masks both alleles of another gene
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epistasis
epistasis occurs when one locus masks the effects of another locus acting on the same trait. the locus that is doing the masking is said to be epistatic to the other
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epistatic ratios allow a geneticist to hypothesise about
the order of genes in a particular pathway; in a biosynthetic or biochemical pathway, the epistatic gene encodes an upstream step
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upstream step
earlier in the pathway
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example of recessive epistasis in animals
slide 27
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example of recessive epistasis in humans
- all type A, type AB, type B, and type O people are H-
- people with hh genotype will appear to be type O regardless of their l locus genotype
- gene for substance H is epistatic to the l gene (hh is epistatic to all combinations of l alleles, except for ii)
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complementary gene action/reciprocal recessive epistasis
genotype ratio: 9 (A_B_): 3 (A_bb): 3 (aaB_): 1 (aabb)
phenotype ratio: 9 (A_B_): 7 mutants (A_bb and aaB_ and aabb)
aa is epistatic to B and bb is epistatic to A - when homozygous, recessive allele of each gene masks the dominant allele of the other gene
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example of complementary gene action/ reciprocal recessive epistasis in a plant
slide 31
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dominant epistasis 1
genotype ratio: 9 (A_B_): 3 (A_bb): 3 (aaB_): 1 (aabb)
phenotype ratio: 12 (A_B_ and aaB_): 3 (A_bb): 1 (aabb)
B is epistatic to A and a. when dominant allele of one gene hides both alleles of the other gene
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give an example of dominant epistasis 1 in plants
slide 33
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dominant epistasis 2
genotype ratio: 9 (A_B_): 3 (A_bb): 3 (aaB_): 1 (aabb)
phenotype ratio: 13 (A_B_ and aaB_ and aabb): 1(A_bb)
B is epistatic to A. when dominant allele of one gene hides effects of dominant allele of other gene.
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give an example of dominant epistasis 2 in chicken
slide 35
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do mendelian laws of segregation and independent assortment still apply with gene interactions?
yes.
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what did Walter Sutton discover?
studied great lubber grasshopper:
- body cells contained 22 chromosomes and X & Y chromosomes
- gametes contained 11 chromosomes and X or Y in equal numbers
- after fertilisation, cells with XX were females and cells with XY were males
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anatomy of a chromosome
- metaphase chromosomes are classified by the position of the centromere: metacentric (if it is in the middle of the chromosome) or acrocentric (if located close to an end)
- sister chromatids are held together by centromeres
- homologous chromosomes are a pair of chromosomes—one from each parent—that have the same size, shape, and genes at the same locations, but may carry different versions (alleles) of those genes.
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draw metacentric and acrocentric chromosomes
slide 5
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key stages of mitosis
Replication:
Interphase - cell grows and DNA is copied
Prophase – Chromosomes condense, spindle forms
Segregation:
Metaphase – Chromosomes line up in the middle
Anaphase – Chromatids are pulled apart
Telophase – New nuclei form
Cytokinesis – Cell splits in two genetically identical 2n daughter cells
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key stages of meiosis
Interphase – DNA is copied
Prophase I – Homologous chromosomes pair up and cross over
Metaphase I – Pairs line up in the middle
Anaphase I – Homologous chromosomes separate
Telophase I – Two nuclei form
Prophase II – New spindles form in each cell
Metaphase II – Chromosomes line up in the middle
Anaphase II – Chromatids are pulled apart
Telophase II – Four nuclei form
Cytokinesis – Four haploid cells result
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key differences between mitosis and meiosis
Number of divisions:
Mitosis = 1
Meiosis = 2
Number of daughter cells:
Mitosis = 2 (diploid)
Meiosis = 4 (haploid)
Genetic similarity:
Mitosis = Identical to parent
Meiosis = Genetically different (variation)
Purpose:
Mitosis = Growth, repair, asexual reproduction
Meiosis = Sexual reproduction (gametes)
Homologous chromosomes:
Mitosis = Do not pair
Meiosis = Pair and crossover in Prophase I
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how was movement of chromosomes during mitosis and meiosis understood ?
microscopy provided a means to follow movement of chromosomes during cell division
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gamete
contains one-half the number of chromosomes as the zygote
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haploid
cells that carry only a single chromosome set
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diploid
cells that carry two matching chromosome sets
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n
the number of chromosomes in a haploid cell
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2n
the number of chromosomes in a diploid cell
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is chromosome number constant across species?
no, it varies from species to species but does not correlate with the size or complexity of the animal
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somatic cells
divide mitotically and make up the vast majority of an organism's tissues
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germ cells
specialised role in the production of gametes:
228
process of creation of a diploid offspring
- germ cells arise during embryonic development in animals and floral development in plants
- undergo meiosis to produce haploid gametes
- gametes unite with gamete from opposite sex to produce diploid offspring
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karyotype
- produced by cutting micrograph images of stained chromosomes and arranging them in matched pairs
- sex chromosomes and autosomes are arranged in homologous pairs
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autosomes
pairs of non-sex chromosomes
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sex chromosome
- provide basis for sex determination
- one sex has matching pair, other sex has non-matching sex chromosomes
- variation in sex determination between species
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mammal and drosophila sex chromosomes
female: XX
male: XY
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some grasshoppers sex chromosomes
female: XX
male: XO
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fish, birds, moths sex chromosomes
female: ZW
male: ZZ
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sex determination in humans
children receive only one X chromosome from mother but either X or Y from father
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X chromosomes in females
females typically have two X chromosomes that are genetically identical
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how are chromosome behaviour and inheritance related?
chromosomes determine characteristics of organism (eg its sex); therefore, basis of inheritance must reside there
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mitosis ensures that
every cell in an organism carries the same set of chromosomes
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meiosis ensures that
one member of each chromosome pair is distributed to gamete cells
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gametogenesis
the process by which germ cells differentiate into gametes
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6 links between chromosome and gene behaviour
- each cell contains 2 copies of each chromosome; each cell contains 2 copies of each gene
- chromosome complements appear unchanged during transmission from parent to offspring; genes appear unchanged during transmission from parent to offspring
- homologous chromosomes pair and then separate to different gametes; alternative alleles segregate to different gametes
- maternal and paternal copies of chromosome pairs separate without regard to the assortment of other homologous chromosome pairs; alternative alleles of unrelated genes assort independently
- at fertilisation an egg's set of chromosomes unite with randomly encountered sperm's chromosomes; alleles obtained from one parent unite at random with those of another parent ; alleles obtained from one parent unite at random with those of another parent
- in all cells derived from a fertilised egg, one half of chromosomes are of maternal origin, and half are paternal; in all cells derived from a fertilised gamete, one half of genes are of maternal origin, and half are paternal
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Thomas hunt morganatic
- started using a new genetic model: drosophila melanogaster, the common fruitfully
- in 1910, morgan discovered a white-eyed male among his true-breeding stocks of red-eyed flies (first drosophila mutation identified)
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advantages of drosophila as a model organism
- small size
- short generation time of 10 days at room temp
- each female lays 400-500 eggs
- easy to culture in laboratory
- small genome
- large chromosomes
- many mutations available
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draw a table describing how sex determination in humans differs from drosophila
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nomenclature for drosophila genetics
wild type allele: allele that is found in high frequency in a population (greater than or equal to 1%) is denoted with a +
mutant allele: allele that is found in low frequency (less than 1%): denoted with no symbol
recessive mutation: gene symbol is in lower case
dominant mutation: gene symbol is in upper case
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examples of notations for drosophila
- Cy, Sb, D are dominant mutations
- vg, v, y, e are recessive mutations
- vg+ - wild type allele for vestigial gene locus
- Cy+ - wild type allele for curly gene locus
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eye colour in drosophila
- flies with red eyes carry the wild type allele, w+
- any variation in eye colour carry a mutant allele (eg white eye colour), w
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how was X-linkage of eye colour in drosophila demonstrated?
1. observed true-breeding sex ratios (1/2 male, 1/2 female in both F1 and F2)
2. P cross: crossed a white-eyed male (w/Y) to a red-eyed female (w+/w+). all F1 offspring had red eyes, suggesting the white-eyed trait was recessive
3. F1 cross: crossed w+/w female to w+/Y male. all female offspring were red-eyed; male were white and red-eyed. thus, morganatic proposed that the eye colour gene is on the X chromosome.
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sex linkage
genes for specific traits are carried on sex chromosomes
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hemizygous
means having only one copy of a gene instead of the usual two (eg in males with X-linked genes)
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what was Bridges' hypothesis and how did it arise?
X chromosomes were not segregating properly in meiosis, leading to 1/2000 females being white-eyed and 1/2000 males being red-eyed during a w/w x w+/Y cross
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how was Bridges' hypothesis proved?
he did large enough experiments to observe rare meiotic events he called non-disjunction.
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draw 3 diagrams:
- normal X chromosome segregation
- nondisjunction in meiosis I
- nondisjunction in meiosis II
slide 34
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how did nondisjunction lead to unexpected phenotypes in drosophila?
males receive one X chromosome from father: red eyes
females receive two X chromosomes from mother: white eyes
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reciprocal crosses done to confirm X linkage
reciprocal cross of w/w females with w+/Y males. F1 was red-eyed females and white-eyed males only. F2 cross of w+/w females with w/Y males resulted in half offspring having white eyes, half having red eyes. females 1:1 red: white, males 1:1 red:white.
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what was the final evidence that phenotypes are associated with chromosomes and thus that genes are carried on chromosomes?
- Bridges crossed XXY females (white eyes) to the normal XY males (red eyes) in order to confirm his theory
- unusual inheritance patterns correlate with aneuploidy
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aneuploidy
abnormal number of chromosomes
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X-linked recessive traits exhibit 6 characteristics seen in pedigrees
- Trait appears in more males than females.
- Mutation and trait never pass from father to son.
- Affected male does pass X-linked mutation to all daughters, who are then unaffected carriers.
- Trait often skips a generation.
- Trait only appears in successive generations if sister of an affected male is a carrier. If so, her sons have a 50% chance of showing the trait.
- All sons of affected female show trait and all daughters of affected female are carriers.
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example of X-linked recessive trait in humans
haemophilia A
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X-linked dominant traits exhibit 4 characteristics seen in pedigrees
- Trait appears in more females than males.
- Sons and daughters of an affected heterozygous female have a 50% chance of showing the trait.
- Trait is seen every generation.
- All daughters but no sons of affected male show trait.
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example of X-linked dominant trait in humans
hypophosphatemia
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Y-linked traits exhibit 3 characteristics seen in pedigrees
- Trait appears only in males.
- All sons but no daughters of affected male show trait.
- Females do not show and cannot transmit trait.
263
what unusual observations did Bateson and Punnett make?
when crossing purple flowers, long pollen (PPLL) with red flowers, round pollen (ppll)
they found more parental-type combinations and fewer recombinants than expected.
however, according to Mendel’s law of independent assortment, they expected a 9:3:3:1 ratio in the F2 generation.
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what unusual observations did Morgan make?
crossed red eyed, full size wing (pr+vg+/pr+vg+) with purple eye, vestigial wing (pr vg/pr vg)
again, parental combinations appeared more often than recombinant ones and recombinant types were less frequent than expected by chance.
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what did Frans Janssens observe in 1909? what did Morgan suggest relating to this?
chiasmata, regions in which nonsister chromatids of homologous chromosomes cross over each other. Morgan suggested these were sites of chromosome breakage and exchange resulting in genetic recombination
266
cytogenetics
The study of chromosomes inside cells, especially during cell division.
267
crossovers
- physical exchanges among nonsister chromatids; visualised cytologically as a chiasma (plural = chiasmata)
- typically, several crossing-over events occur within each bivalent or tetrad in each meiosis
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function of chiasmata
physically hold homologous chromosomes together and assure proper segregation at anaphase I
269
Morgan's first prediction and second prediction relating to crossing over
First:
- Crossing over occurs during meiosis between homologous chromosomes, allowing genes to be exchanged.
- This explains how linked genes can sometimes produce recombinant offspring
Second:
- The frequency of crossing over between two genes is proportional to the distance between them on the chromosome.
- Genes closer together have less chance of crossover (more likely inherited together).
270
Mendel's fruit fly test cross progeny ratios
>50% of progeny have parental type (1/4 one, 1/4 other)
<50% have recombinant phenotype
271
genetic recombination depends on
the reciprocal exchange of parts between maternal and paternal chromosomes
272
what did McClintock and Creighton observe?
- They studied corn (maize) chromosomes with visible physical markers (like a knob on one chromosome end and a translocation on the other).
- They tracked the inheritance of these physical chromosome markers alongside genetic traits.
- this provided visual confirmation that chromosomes cross over
- correlation between genetic crossover and chromosomal crossover
- this was verified in drosophila by Stern
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Meiosis contributes to genetic diversity in 2 ways
- independent assortment of non homologous chromosomes creates different combinations of alleles among chromosomes
- crossing over between non sister homologous chromatids creates different combinations of alleles within each locus
274
when does recombination take place?
at the four-chromatid (four-strand) stage of Meiosis I (prophase I)
275
5 stages of crossing over
1. leptotene: thread-like chromosomes begin to condense, becoming visible as discrete structures, although the sister chromatids cannot yet be distinguished
2. zygotene: chromosomes are clearly visible and begin pairing with homologous chromosomes along the synaptonemal complex to form a bivalent, or tetrad
3. pachytene: the homologs synapse fully, recombination nodules appear along the synaptonemal complex
4. diplotene: the bivalent pulls apart slightly, but homologous chromosomes remain connected due to recombination at crossover sites (chiasmata)
5. diakinesis: the bivalent condenses further
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synaptonemal complex
zipper-like elaborate protein structure that aligns chromosomes base pair by base pair
277
terminalization
process where the chiasmata move from the middle of the homologous chromosomes toward the ends (telomeres) as meiosis progresses, especially during diplotene and diakinesis stages
278
what happens after terminalization?
anaphase I
279
Holliday's model for mechanism of recombination
1. Homologues physically break, exchange parts, and rejoin
2. Breakage and repair create reciprocal products of recombination
3. Recombination events can occur anywhere along the length of a DNA molecule, but at some locations with a higher frequency than others
4. The exchange is precise - no gain or loss of nucleotide pairs occurs– thus preventing mutation from occurring
5. Gene conversion - where small segments of information from one homologous chromosome transfers to the next - may result in unequal yield of the two alleles
280
draw a table showing the meiotic products based on crossover between genes
slide 27
281
genetic recombination
mixing of genes during gametogenesis produces gametes with combinations of genes that are different from the combinations received from parents
282
unlinked vs linked genes
- genes on non homologous chromosomes (unlinked genes) assort independently
- genes on the same chromosome co-segregate
283
crossovers result in recombination between
linked genes
284
crossover frequency is a function of
the distance between two loci
285
can crossover ever occur when genes are completely linked?
no; the genes are too close
286
recombination frequency can never exceed
50% (ie more recombinant types than parental types)
287
single crossover vs double crossover
single: parental and recombinant
double: all parental
288
how do you test for linked vs unlinked genes?
test cross to distinguish between linked and unlinked genes, you'd typically cross a heterozygous individual with a homozygous recessive individual for the traits being studied.
2 genes unliked = 1:1 between parental genotypes and recombinant genotypes
2 genes linked = more parental genotypes than recombinant genotypes
