1
Q
What are 3 benefits of identifying a disease gene?
A
- genetic testing
- development of new therapies
- genes involved in rare, inherited types of disease can provide an insight into the causes of more common, non-inherited types of the disease
2
Q
How many base pairs in the human haploid genome?
A
3x10^9
3
Q
how many protein coding genes in human genome?
A
~20,000
4
Q
draw a flow chart showing how we get from a disease to the gene that causes it?
A
Pedigree analysis–> Linkage analysis –> positional cloning of the disease gene
5
Q
What’s pedigree analysis?
A
investigating the occurrence of the disease in families to determine the type of mutation
6
Q
what’s linkage analysis?
A
- looking for evidence of genetic linkage between the disease gene and genetic markers
- mapping the disease gene as precisely as possible
7
Q
What’s positional cloning of the disease gene?
A
- select ‘candidate genes’ in the region of the chromosome
- look for disease associated mutations in each candidate gene
8
Q
What are the 5 modes of Mendelian inheritance?
A
- autosomal recessive
- autosomal dominant
- x-linked recessive
- x-linked dominant
- y-linked inheritance
- maternal inheritance
9
Q
How are autosomal recessive mutations seen in pedigree analysis?
A
- phenotypes can skip generations
- both parents must be carriers to transmit trait to offspring
- affects males and females equally
10
Q
how are autosomal dominant mutations seen in pedigree analysis?
A
- phenotype appears in every generation
- affects males and females equally
- sometimes the homozygous mutant is lethal
11
Q
How are x-linked recessive mutations seen in pedigree analysis?
A
- more males that females are affected
12
Q
why are more males than females affected in x-linked recessive mutations?
A
because males with only one mutant allele are hemizygous- only need one copy
13
Q
How does transmission of an X-linked recessive mutation show up when transmission is through an unaffected female carrier?
A
- half of sons predicted to be affected
- half of daughters carriers- no daughters affected
14
Q
How does transmission of an X-linked recessive mutation show up when transmission is through a hemizygous affected male?
A
- no children affected
- all daughters are carriers
15
Q
How does transmission of an X-linked recessive mutation show up when transmission is through an affected female?
A
- all sons will be affected and all daughters will be carriers
16
Q
What’s seen in the pedigree of an X-linked dominant mutation?
A
- affect males pass on the condition to all of their daughters but none of their sons (no male to male transmission)- because males don’t get an X chromosome from their fathers
- affected heterozygous females with unaffected male partners have half their sons and daughter affected
17
Q
What are Short Tandem Repeats (STRs) also known as?
A
microsatellite repeats
18
Q
what are short tandem repeats?
A
repeats of a short sequence
19
Q
how many nucleotides are in STRs?
A
usually 2-4 nucleotides
20
Q
What sort of sequences do STRs appear in?
A
non- coding
21
Q
How is a DNA profile useful to law enforcement?
A
- individuals- other that identical twins have unique DNA profiles
- so they can be placed at the scene of a crime from DNA analysis through comparison with a database
- if a close but not exact match is found it could implicate close relatives
22
Q
what amplifies STRs?
A
polymerase chain reaction (PCR)
23
Q
What are single nucleotide polymorphisms (SNPs)
A
a variation in a single, particular nucleotide
24
Q
where are most SNPs found?
A
in non-coding DNA
25
what's the HapMap project?
a project that's identified millions of common SNPs in ~1000 humans from 4 different ethnic groups
26
what is a haplotype?
a particular combination of SNPs in a small region of a chromosome
27
How are disease genes discovered with next generation sequencing (NGS)?
sequence whol genomes or exomes from affected and unaffected members of pedigree
identify rare variants shared only by affected individuals
identify potentially causative variants in candidate genes
investigate the consequences of the potentially causative variants
28
What are the 3 approaches to studying genetics?
population
molecular
inheritance and gene function
29
What's population genetics?
looking at how alleles change in a gene pool over time
30
what's molecular genetics?
study of molecular structure and function of genes
31
what's inheritance and gene function genetics?
looking at transmission of genes, genotype vs phenotype and the function of genes in an organism
32
Give an example of how looking at human genes has application
finding a new gene for a disease e.g. in in Iceland a rare breast cancer gene was found. Genetic testing allows an individual to find if they have a gene which causes disease allowing preventative action
33
Give an example of how looking at plant genetics has application
new varieties of crop can be made, therefore can feed more people as the world population grows
34
Give a definition of a gene
1 of
- An inherited factor that affects the characteristics of an individual
- part of a chromosome involved in the transcription of DNA into RNA (can include transcribed and non-transcribed genes)
35
what does a centromere do?
assembles kinetochore that attaches to microtubules
36
What are homologous chromosomes
chromosome pairs with one coming from each parent (one paternal and one maternal)
37
What is Mitosis?
a process that produces 2 genetically identical diploid daughter cells
a single division
occurs in all tissues
38
What is Meiosis?
a process that produces 4 genetically different haploid cells
2 sequential cell divisions
occurs in gonads only
39
what are both meiosis and mitosis part of?
the cell cycle
40
what are the stages of the cell cycle?
Interphase- includes G1, S and G2
| Mitosis/Meiosis
41
what are the stages of mitosis?
```
Prophase
Metaphase
Anaphase
Telophase
(PMAT)
```
42
what occurs in early prophase?- mitosis
chromosomes condense
| mitotic spindle is formed (composed of microtubules)
43
what occurs in late prophase?- mitosis
nuclear envelope breaks down
| chromosomes attach to mitotic spindle
44
what occurs in metaphase?- mitosis
chromosomes line up at the equator of the cell
| sister chromatids are attached to opposite poles by the mitotic spindle
45
what occurs in Anaphase?- mitosis
cohesion between sister chromatids is lost
| chromatids segregate to opposite poles by the microtubules shortening
46
What occurs in telophase?- mitosis
chromosomes decondense
nuclear envelope reforms
cytokinesis begins
47
What are the stages of Meiosis?
```
Prophase I
Metaphase I
Anaphase I
Telophase I
Prophase II
Metaphase II
Anaphase II
Telophase II
```
48
what occurs in prophase I?- meiosis
chromosomes condense
homologous chromosomes undergo synapsis (pairing)
crossing over occurs (exchange of genetic material between non-sister chromatids- 1 paternal, 1 maternal)
49
What occurs in Metaphase I?- meiosis
each pair of homologous chromosomes line up at the equator
50
what occurs at anaphase I? meiosis
homologous chromosomes separate to opposite poles (sister chromatids still attached to eachother)
51
what occurs at telophase I? meiosis
each pole has one of the original pair of homologous chromosomes
each chromosome still consists of 2 chromatids
cytokinesis completes Meiosis I
52
what occurs in prophase II? meiosis
chromosomes attach to spindle
53
what occurs in metaphase II? meiosis
individual chromosomes line up at the equator
54
what occurs in anaphase II? meiosis
sister chromatids separate to opposite poles
55
what occurs in telophase II? meiosis
each haploid daughter cell carries one chromosome of each type from cytokinesis
56
What does independent assortment do?
generates different combinations of chromosomes in gametes
57
How many different gametes can be generated by independent assortment?
2^n
n= 23
so over 8 million possible eggs and 8 million possible sperm
(64 billion possible zygotes)
58
what does crossing over do?
generates new combinations of alleles on chromosomes
59
how many crossovers per human meiosis?
40-95
60
are there more crossover events in males or females?
females
61
What did Gregor Mendel do/ what was the impact?
- looked at the garden pea and 7 of their character traits of which their were 2 possibilities (dominant and recessive)
- work not respected at the time, however re-emerged 30 years later (1900) where it marked the start of classical genetics
62
what's a monohybrid cross?
mating between 2 organisms where 1 gene (locus) with 2 alleles is looked at
63
what's the phenotypic ratio in a monohybrid cross?
3:1 (3- AA, Aa, Aa... 1-aa)
64
which of mendel's laws is a monohybrid cross based on?
1st: Principle of segregation
65
What's a dihybrid cross?
mating between 2 organisms where 2 genes, therefore 4 alleles is looked at
66
What's the phenotypic ratio in a dihybrid cross?
9:3:3:1
67
Which of mendel's law is a dihybrid cross based on?
2nd: principle of independent assortment
68
What does mendel's 2nd law mean? (principle of independent assortment)
that the genes in one homologous pair do not affect (are independent to) the genes in another homologous pair .... e.g. if the genes for hair colour is on one homologous pair and for height on another, they have no affect on each other and all the paternal and maternal chromosomes don't have to line up on the same side
69
What does mendel's first law mean? (law of segregation)
that the 2 alleles for each gene split during anaphase
| e.g. allele for black hair moves to one side and the gene for blonde to the other
70
How does the behaviour of chromosomes during mitosis explain mendel's first law?
alleles of a single gene segregate equally and randomly into gametes. In metaphase I, homologous pairs line up at the equator. In meiosis II segregation of sister chromatids occurs
71
How does the behaviour of chromosmes during meiosis explain mendel's second law?
alleles from different genes segregate randomly into gametes. In metaphase I homologous pairs line up at the equator and can line up differently during anaphase I. at the end of meiosis II, different alleles of the gametes are seen
72
what do punnet squares show?
the possible results during random fertilisation
73
What's mendel's particulate theory of inheritence? (5)
- characters are distinct and hereditary determinants (genes) are particulate in nature
- every adult has 2 genes for each character- different forms of the genes are alleles
- members of thegene pair segregate equally into gametes so that each gamete has only one of the two genes (first law)
- fusion of the gametes at fertilisation restores the pair of genes and is random
- different genes assort independently into gametes (second law)
74
what are the 3 types of mutation?
- silent
- nonsense
- missense
75
what's a silent mutation?
where the mutation in genes still codes for the same amino acid
76
what's a nonsense mutation?
where the genes coding for a protein are changed to a stop codon
77
what's a missense mutation?
change in code where a new amino acid is coded for
78
what are the 2 types of missense mutation?
- conservative
| - semi-conservative
79
what's a conservative missense mutation?
where a similar type of AA is coded for
80
what's a semi-conservative missense mutation?
where a different type of AA is coded for
81
what are the 3 types of gene affecting the protein, depending on mutation?
- Wild Type
- Loss of Function
- Gain of Function
82
What's a Wild type gene?
the normal version of the gene found in the wild (non-mutant)
typically makes a functional protein
for most genes 50% of the normal gene product is sufficient for WT function (dominant)
83
What's a Loss of Function gene?
most mutations do this
produce a non-functional protein
LOF alleles are recessive (so over 50% is needed for phenotype)
84
what's a Gain of Function gene?
mutation gives rise to a protein with a new or enhanced function
tend to be dominant
85
what's incomplete dominance?
```
where the heterozygous phenotype is an intermediate between the 2 homozygote phenotypes
e.g.
HH- normal
Hh- mild disease
hh- severe disease
```
86
What's co-dominance?
heterozygotes show phenotypes of both alleles
| e.g. blood types someone with AB is showing phenotype for A and B protein-coding genes
87
What are multiple alleles?
where there's more that 2 alleles for a gene
88
what's pleiotropy?
where one gene can influence more that one trait
| e.g. the gene coding for the protein involved in cilia and flagella function
89
What are lethal alleles an example of?
pleiotrophy
90
what are lethal alleles?
alleles that cause death in those carrying them
91
What does the normal/wild type allele (A) of the Agouti mouse give?
hair with a black base and tip and yellow band in the middle
92
what does the (a) allele of the agouti mouse give?
black hair (no yellow band)
93
What does the B gene is mice determine?
the pigment
94
what does a wild type B allele code for in the mouse?
black hair
95
what does a mutation b allele code for in the mouse?
cinnamon/ reddish brown hair colour
96
what does the C gene in mice determine?
albinism
97
what does the wild type C allele give in mice?
normal melanin/pigment in hair
98
what does the mutant c allele give in mice?
lack of melanin/pigment ergo no colour--> albino
99
what does the W gene is mice determine?
distribution of pigment
100
what does the normal w allele in mice give?
normal- just one colour all over
101
what does the mutant W allele give in mice?
spotting in fur
102
what is epistasis?
the interaction between 2+ genes that control a single genotype
103
what is usually happening in epistasis?
an allele of one gene masks the phenotypic effect of an allele of another gene `
104
if an allele if epistatic to/over another allele what does it mean?
the gene which is epistatic over another gene acts before the other gene in a biochemical pathway
105
what is dominant epistasis?
where the gene which masks expression of another gene needs to have the dominant allele (homozygous or heterozygous) to mask the expression
106
what is recessive epistasis?
where the gene which masks the expression of another gene needs to be homozygous recessive to mask its expression
107
what's penetrance?
a measure of the percentage of individuals with a given genotype who exhibit the expected phenotype
108
what is expressivity?
a measure of the extent to which a given genotype is expresed at the phenotypic level
109
what's incomplete penetrance?
where an individual with a disease causing allele have an increased likelihood of getting the disease, but won't definitely get the disease
e.g. those with the BRCA mutation are more likely to get breast cancer, but not all will
110
what is variable expressivity?
where the phenotype is expressed to a different degree among those with the same phenotype
e.g. mice with the same gene can be different colours (epigenetic)
111
what are modifier genes?
gene which alone cause no change in phenotype however combined cause digenic inheritence
112
what's digenic inheritence?
where 2 genes combined are needed for a particular phenotype
e.g. the PRPH2 and ROM1 genes alone cause no disease, however together cause retinitis pigmentosa
113
what's allelic variation?
where alleles may vary in the severity of the phenotypes they cause
e.g. CF caused by a number of different mutations in the CFTR gene which have different levels of severity
114
what's true breeding?
used to describe an organism that always passes on the same phenotype- homozygous
115
what do sex- determining genes do?
determine sex
116
what's environmental sex determination?
where the environment is involved in determining sex e.g. temperature for turtles
117
what's sequential hemphitism?
where animals can change sex over their lifetime
118
what's larger X or Y chromosomes?
X
119
how much larger is the X chromosome than Y?
3x larger
120
what region is found on the X chromosome?
X-specific region
121
what region is found on the Y chromosome?
male-specific region
122
what are non-sex chromosomes called?
autosomes
123
where are the pseudo-autosomal regions on the X and Y chromosomes?
the tip of the chromosomes
124
what are the pseudo-autosomal regions on the X and Y chromosomes?
shared/ the same between both X and Y
| contain genes required for X-Y pairing in male meiosis
125
what is aneuploidy?
the presence of an abnormal chromosome number in cells
126
are XO individuals male or female?
female
127
are XXY individuals male or female?
male
128
what's needed to confer maleness?
SRY-region (Y chromosome)
129
how can XX males occur?
when the SRY-region from the Y chromosome translocates to the X chromosome
130
How can XY females occur?
mutation of the SRY region leads to LOF genes in this region
131
How does the SRY gene confer maleness?
codes for a DNA binding protein (transcription factor) which is needed to regulate the expression of genes necessary for testes formation
132
How does the sex of a fetus develop?
week 4: genital ridge made of somatic cells is present
week 6: indifferent gonads form
week 8 onwards: depending on SRY expresion either testes form or they don't (female is default sex)
133
what chromosome is sex-linked inheritance usually linked to?
X (X-linked)
134
What is meant by males being hemizygous for genes on the X chromosome?
only one allele of a recessive gene is required for the gene to be expressed
135
How did sex chromosomes evolve?
started off as autosomes--> a chromosome develops a gene to confer sex (male in humans) --> this chromosome accumulates genes which are advantageous to males --> repression of crossing over as they are advantageous --> end with final X and Y chromosomes
136
what's a glynandromorph?
a sexual mosaic where the cells on one side of the body have female sex chromosomes and male on the other size
137
what's cell autonomous sex identity?
only the cells determine the sex- occurs in birds, not humans as in humans it's related to hormones
138
How is dosage compensation seen in regards to X chromosome inactivation in mammals?
females have XX so double the gene dosage of X-linked genes compared to males --> this creates an imbalance which could be harmful --> therefore one of the X chromosomes in each female cell becomes inactivated (this is dosage compensation)
it happens by becoming highly condensed so it can't express genes
139
when does dosage compensation in regards to X chromosome inactivation occur in mammals?
in early development
140
which stage of the cell cycle does DNA replication occur?
S phase
141
what is the purpose of gene maps?
to show us the relative order of genes on a chromosome and distance between them
142
what are the 3 types of gene map?
- physical
- cytogenic
- genetic/linkage
143
what do physical gene maps show?
distances between genes or DNA markers based on the direct measurement of DNA
144
what do cytogenic maps show?
gene positions with respect to cytogenic markers (banding patterns)
145
what do genetic/linkage maps show?
the relative position of genes or markers on a chromosome based on meiotic recombination frequencies
146
what can gene maps be used for?
- to identify genes responsible for disease
- to help design experiments for studying gene function
- combine traits of economic importance in plant or animal breeding
147
what is genetic distance the same as?
recombination frequency (RF)
148
How is recombination frequency (RF) calculated?
no. of recombinant progeny x100/ total number of progeny
149
what is meant by recombinant progeny?
offspring with different allele combination to parent
150
what are the 4 types of chromosome abnormality?
- Aneuploidy
- Monoploidy
- Trisomy
- Tetrasomy
151
what's aneuploidy?
the loss of a pair of homologous chromosomes (2n-2)
152
what's monoploidy?
loss of a single chromosome (2n-1)
153
what's trisomy?
one extra chromosome (2n+1)
154
what's tetrasomy?
an extra pair of chromosomes (2n+2)
155
when do chromosomal abnormalities originate?
meiosis where non-disjunction can give aneuploid gametes
156
what percent of human conceptions are aneuploid?
20-50%
157
what percent of live human births are aneuploid?
<0.5%
158
are monosomies ever viable?
no
159
by what name is trisomy better known?
down-syndrome
160
what causes trisomy/down syndrome?
- trisomy of the 21st chromosome
- robertsonian translocation (chromosomes 14 and 21's arms combine)
- genetic mosaicism- from abnormalities during embryonic mitosis. gives individuals with a mixture of normal and trisomic cells, therefore varying phenotypes
161
why are older mothers at greater risk of having children with trisomy/down syndrome?
there's a change in the molecular glue called cohesin so the sister chromatids aren't pulled apart so there's more chromosomes in the egg cell
162
other than the nucleus, whereas is DNA found?
mitochrondia
| chloroplast
163
what's different about the genome/DNA found in the mitochondria/chloroplast (as opposed to in the nucleus)?
It's more similar to prokaryotic DNA:
- circular
- the ribosomes are different to that of the cytoplasm and are anti-biotic sensitive
164
what's the endosymbiont theory?
the idea that a eukaryotic cell engulfed a prokaryotic cell- the prokaryotic cell became the mitochondria in animals and a similar process happened in plants where it became the chloroplast
165
what type of genes are found in mitochondrial genomes?
- components required for translation (RNA)
| - structural genes for proteins involved in oxidative phosphorylation (to give energy from oxygen) `
166
what type of genes are found in chlorophyll genomes?
coding for RNAs and proteins involved in photosynthesis
167
In what sort of pattern is mitochondrial and chloroplast DNA past from one generation to the next?
uniparentally- usually maternal inheritence
168
why is the mitochondrial DNA passed maternally?
maternal eggs are larger than the paternal sperm, the mitochondria of the sperm are destroyed when they enter the egg, whereas they aren't destroyed in the egg
169
what sort of defects can mitochondrial DNA diseases cause?
neurological and non-neurological
170
what proportion of individuals have a pathological DNA mutation?
~1/200
171
what proportion of individuals have a mt (mitochondrial) DNA disease?
~1/10000
172
what's heteroplasmy?
where the cell contains 2 different types of mitochondria- normal and wild type
173
why are signs and symptoms of mitochondrial disease varying, even within a family with the same mutation?
during meiosis there's a reduction of mitochondria causing different proportions of mitochondria types (normal and wild type) therefore variations in the mitochondria of offspring
174
what is the name of the treatment to prevent mitochondrial disease?
Mitochondrial replacement therapy
175
what is mitochondrial replacement therapy?
3 person baby-
where a fertilised egg is taken from a carrier couple --> the nucleus is removed and put into the fertilised egg of a healthy donor --> offspring born aren't affected by the disease
176
give 4 examples of complex traits in human medicine:
any 4 from:
- alzeimer's disease
- autism
- crohns disease
- neural tube defects/ spina bifida
- asthma
- cleft lip/palate
- coronary heart disease
- type 1 and 2 diabetes
177
what's the prevalence of complex diseases?
~60/100
178
How many genes cause Mendelian traits?
single gene (with high penetrance)
179
How many genes cause complex traits?
many genes (polygenic) (with low penetrance)
180
what's a more predictable trait- Mendelian or complex?
Mendelian
181
what has a simpler relationship between genotype and phenotype- Mendelian or complex traits?
Mendelian
182
what can complex traits be divided into?
quantitative or continuous
183
what are threshold traits?
complex traits which are discrete/discontinuous where they are present if they are above a genetic/environmental threshold and absent if below
184
what is concordance?
the probability that if one twin is affected by a trait, the other twin is also affected by this trait
185
if concordance= 1.0, what does this mean?
if one twin is affected, the other one will always be too
186
How can looking at twin concordance estimate heritability?
comparing concordance between DZ and MZ twins
187
what do identical twins share?
environment and all of their genes
188
what do non identical twins share?
environment and half of their genes
189
what is the relatedness of monozygotic twins?
r=1
190
what is the relatedness of dyzygotic twins?
r=0.5
191
the higher the genetic complexity...
... more genes each with a small effect
Genes, Evolution and Development
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