2, 3, 4 Flashcards
(137 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
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
Q
define true-breeding
A
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
