Midterm 1 Flashcards
(247 cards)
1
Q
Operation Sea-Spray
A
S. marcescens was released over San Francisco to study dispersal patterns of biological agents (bacteria has a red pigment so it was easy to track)
2
Q
Consequences of Operation Sea-Spray. Why did this happen?
A
Some people exposed to the bacteria either fell ill or died; they were immunocompromised due to genetic defects, making them more susceptible to infection
3
Q
What are congenital malformations?
A
Malformations that occur before birth
4
Q
What does it mean to be genetically predisposed to a disease?
A
People who are genetically predisposed are more at risk of developing/contracting the disease due to their DNA
5
Q
What is APC? How is it inherited?
A
A hereditary condition where people carrying this disease have almost 100% chance of developing colorectal cancer by 39yo if left untreated; single gene disorder where one copy of the mutant causes it. Two copies is lethal (autosomal dominant)
6
Q
What are the objectives of modern medical genetics?
A
- identify and characterize mutations that cause genetic diseases (what is the disease and what are its characterizing traits?)
- understand how mutations affect health
- improve diagnosis
- improve disease management
- develop cure
7
Q
What are the degrees of impact of genetics on individual diseases?
A
- entirely causative
- major role
- minor role
8
Q
Entirely causative gene disorders
A
Single gene disorders and chromosomal disorders are the deciding factors on whether the individual has the disorder or not
9
Q
Major role gene disorders
A
Major risk conferring gene (presence of mutation increases risk of disorder)
10
Q
Minor role gene disorders
A
Multifactorial models (phenotype relies on more than one mutation and/or environmental factors)
11
Q
Multifactorial to single gene to chromosomal genetic disease relative ratio
A
Multifactorial > single gene > chromosomal
12
Q
What is the percentage of people with genetic disease by ages 5 and lifetime, respectively?
A
5%, 67%
13
Q
Environmental disease
A
Entirely caused by environment, preventable (ex. the flu)
14
Q
Genetic disease
A
Entirely caused by DNA (if you have the mutation, you have the disease)
15
Q
Predisposed disease
A
Both environment and genetics play a role. Preventable if you know you are genetically predisposed and treat it before it becomes an issue
16
Q
What is the trend in nongenetic causes of childhood deaths as time goes on? Why?
A
Decrease in deaths due to environmental causes because we are generally better fed, more hygienic, and better health overall
17
Q
What is the trend in genetic causes of childhood deaths as time goes on? Why?
A
Increase in deaths due to an increased understanding of the genetic diseases (more are identified as genetic now than before)
18
Q
What percentage of persons in the population will have a genetic disorder in their lifetime?
A
3-7%
19
Q
What is the most common type of genetic disorder?
A
Multifactorial disorders (both genetic and environmental) (~60%)
20
Q
What are the components of modern medical genetics?
A
- inheritance of diseases
- disease gene identification
- how mutations affect health (molecular mechanisms)
- diagnosis and treatment of genetic disease
- genetic counselling
21
Q
What life stages can genetic diseases be diagnosed?
A
Prenatal, pediatric, and adult
22
Q
Diagnosis
A
Identification of disorder
23
Q
Prognosis
A
Likely course and clinical outcome of disorder
24
Q
What are the components of clinical genetics?
A
- diagnosis
- prognosis
- management
- risks assessment/counselling
- reproductive options (do you want to have a kid knowing they might have the same disorder)
- support
25
What is the most likely life stage to be the greatest growth area for genomic medicine? Why?
Diagnosis of genetic disorders in adults; detection of disease early can allow for primary prevention
26
What is the trend we see in human genome sequencing costs in relation to time?
Costs decrease as time increases due to better and cheaper technology
27
What is the flow of genetic information?
DNA (gene) > RNA > protein
28
What is a gene
A segment of DNA that contains the necessary code to instruct the production of proteins or molecules that perform specific functions in the body
29
What does a gene look like on the coding strand from the 5' end to the 3' end?
5' phosphate > enhancer > promoter > 5' UTR > exons and introns > 3' UTR > poly A addition site > 3' OH
30
Housekeeping genes
Essential genes needed in every cell type (produce replicative machinery, transcriptional and translational machinery, etc)
31
What are enhancers and silencers?
Usually hundreds or thousands of bp away from the promoter that influence transcription through activators and co-activators
32
What is RNA Pol II?
An RNA pol that transcribes mRNA-encoding genes that requires a ~50-protein complex assembled at the core promoter
33
What are basal transcription factors?
TFs that are required for RNA pol to function, always needed
34
What are specific transcription factors?
TFs that modulate transcription in a specific context in differentiated cells
35
Which of the following statements about ‘enhancers’ is true?
a) These are DNA sequences that regulate the transcription of certain genes.
b) These are non-coding DNA sequences present in between two exons.
c) These are proteins that control gene function.
d) They associate with activators and co-activators during gene transcription.
e) A and D
A and D. B refers to introns, and C refers to transcription factors
36
What are post-transcriptional modifications?
5' cap (m7G forms 5'-5' phosphate bridge) and 3' poly A tail (50-250 A's added to 3' end)
37
Haploid human cells have how many chromosomes?
23 unique chromosomes
38
Diploid human cells have how many chromosomes?
46 chromosomes in 23 pairs (paired chromosomes are homologous chromosomes)
39
How many unique autosomes do humans have?
22
40
What are the characteristics of mitochondrial DNA (mtDNA)?
- circular and lacks introns (evidence for endosymbiosis)
- exclusively maternally inherited (oocyte enriched with mitochondria)
- has 37 essential genes
- mitochondrial-specific transcription and translation
41
Describe the organization of mtDNA
- heavy (outer) and light (inner) strands
- D-loop is triple-stranded (associated with 7S DNA) that contains mtDNA control regions (ex. promoter, ori)
- 7S DNA can base-pair with the light strand, which displaces the heavy strand to form the D-loop
- mtDNA replication is independent from nuclear replication
- 1,000 - 10,000 copies of the genome within one mitochondria (100k in oocytes)
42
How many copies of mtDNA do oocytes have?
100,000
43
What is MIDD?
Mutations in mitochondrial genes, exclusively maternally inherited (maternally inherited diabetes and deafness). 1% of diabetic patients
44
What is the human genome project (HGP)?
International collaborative research program aimed to map and understand the genome of humans
45
What were the findings of the HGP?
< 1.5% of the genome encodes proteins, 45% of the genome is unique/single copy, and the rest is repetitive DNA
46
What is the limitation when it comes to sequencing repetitive DNA?
It is difficult to sequence, as researchers overlap fragments of genomic DNA to determine the position of that fragment relative to others
47
How was the reference sequence built if humans have varying genome sequences?
The most common nucleotide at that position was used as a consensus in light of SNPs
48
What are pseudogenes?
Genes that are similar to other known genes, but their products have an unknown function
49
What causes discrepancies in genome annotation algorithms?
Read-through transcription
50
What are the two main genome annotation algorithms?
NCBI Eukaryotic and GENCODE
51
Why does the presence of an ATG in the genome not guarantee that this region is protein-coding?
The ATG may be within an intron or other regulatory sequence
52
What is read-through transcription?
The transcription of two adjacent genes within one mRNA transcript
53
Why does read-through transcription complicate gene counting?
Do we count both genes as a singular gene since they're transcribed in one transcript, or two separate genes?
54
What are conjoined genes?
Genes that may lead to read-through transcription
55
What limited human genome sequencing in recent years?
Read lengths were too short which made it very difficult to sequence large repeats until read lengths were increased from 500 to 100,000
56
What are the two types of DNA sequences?
Single copy DNA and repetitive DNA
57
What is single copy DNA?
DNA sequences that are unique within the genome
58
What is repetitive DNA?
Sequences that appear multiple times within the genome
59
What two categories fall under repetitive DNA?
Dispersed and satellite
60
How much of the genome do single copy, dispersed, and satellite DNA account for, respectively?
45%, 45%, 10%
61
True/False? Dispersed repetitive DNA is generally the same as satellite DNA except for the fact that its sequences are longer
False. While dispersed DNA does have longer lengths, it also does not repeat in tandem (repeated sequences are not right next to each other)
62
Families of satellite DNA
Alpha-satellite, minisatellite, microsatellite
63
Alpha-satellite DNA
171bp that can extend to several million bp. Near centromeres
64
Minisatellite DNA
Blocks of 11bp (or more) tandem repeats up to a few thousand bp
65
Microsatellite DNA
Blocks of 1-10bp long tandem repeats up to a few hundred bp
66
Why are mini- and microsatellites important for human genetics?
They vary in length among individuals, making them highly useful for forensic identification and gene mapping
67
Microsatellite sequencing in cancer can predict:
Clinical outcome
68
Families of dispersed repetitive DNA
SINE, LINE, and segmental duplication
69
SINE DNA
Short interspersed nuclear elements. Each copy is identical and make up 10% of the genome. Each member is ~300bp long
70
LINE DNA
Long interspersed nuclear elements. Each copy is identical and make up 20% of the genome. Each member can be up to 6000bp long
71
True/False? the number of members in SINEs and LINEs is similar
False. LINEs have less members (850k members) because they are quite a bit longer than SINEs (1 mil members)
72
Segmental duplication DNA
DNA blocks that typically share only 90% sequence identity. Make up 5% of the genome and can span hundreds of kbp
73
What unique ability do some dispersed DNA families have?
Can duplicate, excise, and insert themselves into another part of the genome, which may disrupt gene function, causing genetic disease
74
What are the four levels of DNA compaction?
1. "Beads on a string" where DNA is wrapped around histone protein cores to form nucleosomes
2. Nucleosomes form a helical solenoid
3. Solenoids are organized into chromatin loops
4. Chromosomes
75
During what cell cycle phase are cells paused in to allow for karyotype observation? Why?
M phase; the chromosomes are in their most condensed forms
76
What proportion of cell cycle time does G1 take?
Half
77
What proportion of cell cycle time does S take?
Quarter
78
What proportion of cell cycle time do G2 and M take together?
Quarter
79
What happens in G2?
Cell division proteins are synthesized
80
What is the p arm?
The shorter arm of the chromosome
81
What is the q arm?
The longer arm of the chromosome
82
Light regions on a chromosome on a karyotype display what?
Euchromatin
83
Dark regions on a chromosome on a karyotype display what?
Heterochromatin
84
How large can a human chromosome be?
0.2 - 20 micrometers
85
Metacentric chromosome
Arms are equal length and centromere is near the middle
86
Submetacentric chromosome
Centromere is between the middle and tip (has short arms and long arms)
87
Acrocentric chromosome
Centromere is near the tip
88
Describe the structure of an acrocentric chromosome
On the short side, telomeres are replaced with a stalk and a satellite. There are telomeres on the longer arms
89
What is a stalk on an acrocentric chromosome?
It contains ribosomal genes and forms the nucleolus in interphase
90
What is a satellite on an acrocentric chromosome?
It is the very end of the chromosome that replaces the telomeres. It is non-coding
91
True/False? The larger the chromosome, the more genes it carries
False. For example, chromosomes 19 and 17, each relatively small, hold more genes than chromosome 3, which is the third largest chromosome
92
What is ploidy?
The number of different copies of each chromosome present in a cell
93
How is the number of chromatids within a cell denoted?
c
94
Provide the ploidy and chromatid number of a chromosome in a gamete cell
1n 1c
95
Provide the ploidy and chromatid number of a pair of homologous chromosomes in a somatic cell after mitosis
2n 2c
96
Provide the ploidy and chromatid number of a chromosome in a germline cell after meiosis I
1n 2c
97
Provide the ploidy and chromatid number of a pair of homologous chromosomes in a somatic cell after S phase
2n 4c
98
When does recombination occur?
Prometaphase 1
99
When does a meiotic cell become haploid?
After meiosis 1
100
Which phase of meiosis is described to be mitotic-like?
Meiosis 2
101
What are the genetic consequences of meiosis?
- shuffling of genetic materials by recombination
- additional shuffling of the genetic material by random assortment of the homologous chromosomes
- reduction of the chromosome number from diploid to haploid
- segregation of alleles
102
Genes that encode major components of the molecular machinery that synthesizes proteins from mature mRNA molecules.....
a) are contained within the stalk of acrocentric chromosomes
b) are contained within the satellite of acrocentric chromosomes
c) are located on the X chromosome to ensure expression in males and females
d) are specifically present on the p arm of submetacentric chromosomes
e) none of the above
A. Stalk encodes for ribosomal genes
103
What is nondisjunction?
Homologous chromosomes or sister chromatids failed to separate from one another, resulting in cells that have an abnormal amount of chromosomes
104
Gametes from nondisjunction in meiosis I. What would they be called once combined with a normal gamete?
Two gametes have one extra and two have one less; trisomy or monosomy, respectively
105
Gametes from nondisjunction in meiosis II. What would they be called once combined with a normal gamete?
Two gametes are normal, one has one extra and one has one less; normal, trisomy, and monosomy, respectively
106
Provide an example of a good mutation. What causes this?
Lactose tolerance; SNP 14kbp away from the lactase gene
107
What is the prevalence of lactose intolerance?
68%
108
Describe Sanger sequencing
dNTPs and ddNTPs are added to a solution with a template and a primer. They are added onto the primer until a ddNTP is incorporated, which terminates replication because it lacks the 3' OH. Each ddNTP solution is then loaded onto a gel to determine the length of each fragment. Shorter fragments mean that the ddNTP was incorporated relatively soon, and vice versa
109
What is automated base calling?
Done similar to Sanger sequencing, except the ddNTPs are labelled with a fluorescent dye and a computer generates the sequence based on the prevalent colour
110
What is a limitation of Sanger sequencing and base calling?
It still requires a primer (you have to know some of the sequence) and you can only sequence 800bp per reaction
111
What is cytogenetics?
The study of the structure and properties of chromosomes
112
What is clinical cytogenetics?
Practice of medical genetics by studying the structure and number of chromosomes to identify chromosome abnormalities
113
Define aneuploidy
One or more missing or extra chromosome caused by nondisjunction. Focuses on individual chromosomes
114
Define polyploidy
Possessing more than two complete sets of chromosomes caused by genome duplication. Concerns the entire set of chromosomes
115
Trisomy in chromosome 21 causes
Down syndrome
116
Trisomy in chromosome 18 causes
Edwards' syndrome
117
Trisomy in chromosome 13 causes
Patau syndrome
118
Why don't all autosomal chromosomes cause chromosomal disorders when under trisomy?
Trisomy in most chromosomes is lethal
119
Rank the prevalence of Down syndrome, Edwards' syndrome, and Patau syndrome
Down > Edwards' > Patau
120
What is the leading cause of pregnancy loss?
Chromosomal abnormalities
121
What is the prevalence of all autosomal disorders and unbalanced rearrangements?
1/230
122
What is the prevalence of all balanced arrangements?
1/500
123
What is the percentage of oocytes that have aneuploidy?
20-25%
124
What is the percentage of conceptions with chromosomal abnormalities?
10-20%
125
What percentage of pregnancies with chromosomal abnormalities make it to full term?
5% (95% are lost)
126
What is the prevalence of a pregnancy with a chromosomal abnormality in women over 35yo?
2%
127
What are the five clinical indications for chromosomal disorders?
- problem with early growth and development
- stillbirth and neonatal death
- fertility problems
- family history
- pregnancy in a woman of advanced age
128
What are some problems with early development and growth because of chromosomal abnormalities?
- developmental delay
- physical malformations
- ambiguous genitalia
- mental retardation
129
What is the prevalence of stillbirth and neonatal death due to chromosomal abnormalities?
10% for both
130
Stillbirth
Baby is born dead after 28 weeks of pregnancy
131
Neonatal death
Baby dies before it reached 4 weeks
132
What are some fertility problems that may arise due to chromosomal abnormalities?
- amenorrhea (abnormal menstruation)
- recurrent miscarriage
- history of infertility
133
What are the aims of karyotyping?
- determine abnormal chromosomal numbers caused by nondisjunction
- determine abnormal chromosomal structures caused by rearrangements
134
What are the types of chromosomal rearrangements?
- indels
- translocation
- balanced and unbalanced
135
What is translocation?
The transfer of a segment of one chromosome to another chromosome
136
What are the types of translocation?
- Robertsonian
- Reciprocal
137
What is a Robertsonian translocation?
A translocation between 2 acrosomes by fusion at or near the centromere, resulting in one less acrocentric chromosome and the loss of the short arms
138
Why is Robertsonian translocation not usually linked to disease?
The lost segments (stalks and satellites of acrosomes) have redundant functions, so their loss is not very impactful
139
How many fusions are involved in a chromosomal insertion versus a translocation?
2, 1
140
What are the requirements of karyotyping analysis?
- cells must be easy to obtain
- cells must be able to grow rapidly in culture
141
Describe the steps for a routine cytogenic analysis (karyotyping)
1. blood collection
2. add heparin (anticoagulant) and isolate white blood cells
3. culture cells and allow for cell division
4. arrest cells in metaphase and put them in a hypotonic solution
5. fix the cells and stain them (G banding)
6. line up chromosomes and begin analysis
142
Why are cells commonly arrested in metaphase for karyotyping?
They are at their densest, so they're easy to see
143
Describe G banding
Routinely used method. Giemsa stain is used to stain the chromosomes. Stains GC-rich regions light and AT-rich regions dark. It is the most common stain technique
144
What is an ideogram?
A computer generated picture of the karyotyped chromosomes to show their banding patterns
145
Describe Q banding
Staining with quinacrine mustard and used to detect heteromorphism
146
What is heteromorphism?
A morphological variant of a chromosome that is not identical to its homologue
147
Describe R banding
Standard method in Europe. The specimens are heated before staining with Giemsa, which causes a reversal of the banding pattern (light = AT, dark = GC). Used to analyze the distal ends of the chromosomes that stain poorly with G or Q
148
Describe C banding
Xylene substitute used for staining constitutive heterochromatin (centromeric regions) to help diagnose diseases caused by abnormalities near the centromere
149
What is constitutive heterochromatin?
Hyper-condensed, late-replicating, and C-banding positive genomic region that has little to no transcription
150
What methods are used for prometaphase banding?
G or R
151
How is the resolution of a karyotype improved by arresting the cells earlier in mitosis?
Chromosomes are more extended and loose and thus more banding is observable
152
Rank when cells should be arrested for karyotyping from highest to lowest resolution
Prophase > prometaphase > metaphase
153
Describe the steps of fluorescence in situ hybridization (FISH)
1. arrest cells in metaphase
2. denature chromosomal DNA
3. label a complementary probe with fluorophores or modify it so it can be stained after hybridization
4. hybridize the probe and chromosomal DNA
154
When using FISH to detect a specific locus in a diploid organism, how many spots will we see and why?
Four, as each chromatid has been duplicated (S phase) and there are two copies of each chromosome, 2x2=4
155
What is FISH used to detect?
Chromosomal aberrations (gene deletions, duplications, translocations)
156
What are the three ways FISH can be used?
- single copy DNA for specific genes
- repetitive DNA for centromeres, telomeres
- whole chromosome painting
157
What is Smith-Magenis Syndrome and what technique is used to detect it?
The deletion of a gene on 17p that causes a flat face and broadened forehead. Autosomal dominant (heterozygous individuals have the disorder). Detected by FISH and DNA microarrays
158
What is spectral karyotyping (SKY)?
Uses 24 probes (22 autosomal, X, Y) to detect each chromosome with their own unique colour
159
What is SKY used to detect?
Chromosomal translocations
160
What is a plasmid?
An extra-chromosomal DNA molecule found in bacteria and can be replicated independently from the microorganism's own cultures
161
What is a vector?
A plasmid that is engineered for the applications in molecular biology
162
True/False? All vectors are plasmids, but not all plasmids are vectors
True
163
What is a BAC?
A bacterial artificial chromosome vector that contains large DNA inserts using an endonuclease that makes sticky cuts by recognizing a palindromic sequence
164
What is a DNA library?
A collection of clones, each of which carries a vector molecule into which a different fragment of DNA derived from the total DNA or RNA is inserted
165
What is genomic DNA?
A complete or a fragment of a gene, including both noncoding and coding regions
166
What is a genomic library?
A collection of total genomic DNA from an organism (its entire sequence)
167
What is cDNA?
A coding DNA fragment synthesized from an mRNA template using reverse transcription
168
What is a cDNA library?
A combination of cDNA fragments inserted into a collection of host cells, which together constitute the transcriptome of the organism
169
What is comparative genome hybridization (CGH)?
A procedure that compares levels of gene fragments between a control sample and a test sample to determine a higher or lower amount of specific genes
170
What is CGH used for?
Determines the copy number differences between two distinct DNA samples. Identifies both LOF and GOF mutations due to gene deletions or duplications, respectively
171
Describe the differences between traditional and array CGH
Traditional:
- 3 copies of chromosomes needed (test + control + template)
- cannot detect copy number discrepancies smaller than 5-10Mb
Array:
- uses BAC clones as probes separated into wells
- higher resolution (50-100kb)
172
If a person with DiGeorge syndrome's DNA was stained with Cy5, what would we see in a microarray?
A green spot in the well containing 22q11 (LOF)
173
What is a DNA microarray?
A collection of microscopic DNA spotted onto a solid surface for measuring the expression levels of a large number of genes simultaneously or genotype multiple regions
174
What is Rhett Syndrome and what technique can be used to identify it? MECP2 duplication syndrome?
An X-linked dominant neurodevelopmental disorder resulting from a LOF in MECP2; microarray analysis; MECP2 duplication syndrome is a GOF disorder from a mutation in the same gene
175
What are the hybridization techniques and their primary uses??
- FISH (chromosomal aberrations)
- SKY (translocations)
- Traditional CGH (LOF/GOF above 5-10Mb)
- Array CGH (LOF/GOF above 50-100kb)
- DNA microarrays (LOF/GOF)
176
If there is a sequence that is overrepresented after the genome has been sequenced, what might be the cause?
Aneuploidy (only if entire chromosome shows upregulation), gene duplication
177
Describe mosaicism
A mutation happens during mitotic cell division in a developing embryo, causing some, but not all, of the cells to have a mutated phenotype
178
Describe gene duplication and deletion as a result of an unbalanced rearrangement
During meiosis, if homologous chromosomes are misaligned when crossing over, one chromosome will lose a gene and the other will gain it
179
What is haploinsufficiency?
The inability of a single copy of a gene to carry out the function normally performed by two copies
180
What is Pallister-Killian syndrome?
The duplication of all or a portion of the p arm of chromosome 12. Results in characteristic craniofacial features, mental retardation, and other birth defects related to trisomy or tetrasomy for duplicated genes
181
What would a DNA microarray mean ratio graph look like in the case of Pallister-Killian syndrome?
It would show an increase of gene sequence only on half of chromosome 12
182
What is a mar/SMC chromosome? How does it happen?
Through unbalanced rearrangement, two breaks occur on either end of a chromosome, which reunite to form a ring. Their identity is often unknown because there are no missing chromosomes on the karyotype, unless SKY is used
183
What differentiates an SMC from a prokaryotic ring-shaped chromosome?
SMCs have centromeres and are condensed more
184
What is the prevalence of mar chromosomes?
1 in 2500
185
What is an isochromosome?
A chromosome in which one arm is missing (partial monosomy) and the other is duplicated (partial trisomy) due to unbalanced rearrangements
186
What is Turner syndrome?
A genetic disorder in females where one X chromosome is an isochromosome made up of both long arms. Symptoms are solid tumors and hematological malignant neoplasms
187
What are the two mechanisms for isochromosome formation?
- mis-division through the centromere
- defective meiotic crossover
188
Describe how mis-division through the centromere causes isochromosomes
A horizontal split instead of a vertical split will cause the long arms and short arms to stay together. Usually the short arms do not have a long half-life
189
Describe how defective meiotic crossover causes isochromosomes
Defective crossover results in 2 normal chromosomes and 2 abnormal ones consisting of an acentric chromosome and dicentric isochromosome
190
What happens if a dicentric chromosome is left alone?
It becomes lethal, as it cannot divide properly without shearing
191
How do dicentric chromosomes become stable?
They become pseudodicentric chromosomes, in which they either:
- inactivate a centromere
- both centromeres coordinate their movement to one mitotic pole during segregation (which only happens if they are close to each other)
192
True/False? Balanced arrangements result in a normal phenotype and do not cause issues with the reproduction of that organism
False. They do result in a normal phenotype, but they will have unbalanced offspring
193
What are the types and subtypes of balanced rearrangements?
- chromosomal inversions
- paracentric
- pericentric
- chromosomal translocations
- reciprocal
- Robertsonian
194
When does a chromosomal inversion occur?
When a single chromosome undergoes 2 breaks and is reconstituted with the segment between the break inverted
195
Paracentric inversion
- does not include centromere
- both breaks in one arm
- arm ratio not altered
196
What techniques may be used to identify a paracentric inversion?
Identify banding pattern (reversed from what you'd normally expect) or FISH with locus-specific probes (not SKY)
197
Pericentric inversion
- includes centromere
- a break in each arm
- arm ratio may be altered
198
What techniques may be used to identify a pericentric inversion?
Identify banding pattern (reversed from what you'd normally expect) and the proportion of the chromosome arms with FISH
199
What techniques cannot be used for pericentric inversions?
- CGH
- DNA microarray
- Giemsa banding (use C banding instead)
200
What are reciprocal translocations?
Total genetic material stays the same, and the chromosome number is unchanged
201
How are reciprocal translocations identified?
SKY
202
What is the definition of a mutation in human genetics?
DNA changes that cause genetic disease and are not microscopically observable. May happen in coding and regulatory regions
203
Mutations in somatic cells
Not heritable
204
Mutations in germline cells
Heritable
205
Define allele
Alternative forms of a gene
206
Define locus
The location of a gene on a chromosome
207
Define polymorphism
The existence of multiple alleles of a gene in the population
208
What is a molecular disease?
A disease where pathology can be traced back to a single molecular factor (DNA, proteins)
209
What is the primary cause of molecular disease?
Inherited or acquired mutations
210
What is biochemical genetics?
The study of the relationships between genes and the observable traits or phenotypes at the levels of protein production, function, biochemistry, and metabolism
211
What are the types of mutations?
- point mutations
- indels
- splice site mutations
- gene duplications/deletions (unbalanced rearrangement)
- promoter mutations (may inhibit transcription
- mobile element insertion (transposons)
- expanded repeats (slippage of template = deletion, slippage of daughter = insertion)
212
What are the components of an intron that allow it to be spliced out?
- 5' splice site (donor) (GU)
- 3' splice site (acceptor) (AG)
- branch site (A)
213
The genotype ratio of a monohybrid cross in which both parents are heterozygous?
1 (AA) : 2 (Aa) : 1 (aa)
214
When are dihybrid cross punnet squares acceptable?
If the two genes in question are on different chromosomes (independently assort)
215
What do allele combinations depend on if they are located on the same chromosome?
The physical distance between the loci
216
What is the unit of measurement between alleles on the same chromosome?
Centimorgans (cM) = 1% recombination frequency
217
What is the structure and function of RBC?
They are enucleated, biconcave disc-shaped cells that carry oxygen to other cells using hemoglobin
218
How many hemoglobin units are within each RBC?
270 million
219
What is the structure of hemoglobin?
2 alpha units, 2 beta units, and 4 heme units, which each carry one Fe ion
220
What is sickle cell disease caused by?
A missense mutation in chromosome 11 in the protein-coding region for the beta subunit (HBB gene). E6V
221
What does the mutation causing sickle cell disease do to the protein it encodes?
Decreases the solubility of deoxygenated hemoglobin, causing it to polymerize and change the shape of the cell
222
Describe the effects of sickle cell anemia on blood vessels and RBC count
Once cells have become irreversibly sickled, they occlude capillaries and cause tissue death (infarctions). This leads to them being removed from circulation too soon, therefore causing hemolytic anemia
223
What is one way sickle cell anemia can be treated?
Using CRISPR-Cas9 to disable BCL11A function, which usually represses fetal hemoglobin genes and enhances beta-globin transcription
224
Treatment of SCA with CRISPR eventually causes what? What does this mean?
Transfusion independence and allelic editing in bone marrow; the patient no longer needs blood transfusions because their hematopoietic stem cells have uptaken HbF production
225
What is the difference between SCA and beta-Thalassemia?
SCA is caused by one mutation, while B-Thalassemia can be caused by multiple LOF mutations
226
What is OMIM used for?
The detection of genotypic changes associated with phenotypes
227
What were the findings of OMIM relating to the distribution of phenotypes across genes?
There were over 3000 genes associated with producing a single phenotype
228
What are the 4 different effects on protein function mutations can cause?
- LOF
- GOF
- acquisition of a novel property
- misexpression (heterochronic or ectopic)
229
What is the leading cause of disease due to a mutation's effect on protein function?
LOF mutations caused by abnormal protein structure
230
What is heterochronic expression?
The protein is expressed at the wrong time
231
What is ectopic expression?
The protein is expressed in the wrong place
232
Provide an example of a novel property-causing mutation
The aggregation of B-globin in sickle cell anemia caused by a E6V mutation
233
What are LOF mutations?
Mutations that cause loss of function via:
- nonsense mutation
- missense mutation
- mutation that causes protein or mRNA instability and degradation
234
What is Thalassemia (A and B)? What kind of mutation is it in regards to protein function?
Alpha: a-globin chains are deficient, so B- or g-homotetramers form, which have greatly decreased O2 binding capacity (hypoxemia)
Beta: B-globin chains are deficient, forming a-homotetramers that precipitate and damage RBC precursors, causing premature RBC destruction and anemia
LOF (reduction in alpha or beta globulin quantity)
235
Turner syndrome and cancers are examples of what kind of mutation in regards to protein function?
LOF (Turner is X partial monosomy, tumor suppressors)
236
What is retinoblastoma?
A cancer caused by deletion of the tumor suppressor gene RB1
237
Provide 4 examples of GOF mutations and a brief explanation of them
- Achondroplasia: constitutive function of FGFR3
- Down syndrome: trisomy 21
- Charcot-Marie-Tooth disease (CMT1A): decreased muscle control caused by duplication of PMP22
- Hb Kempsey: D99N in beta-globulin causes high O2 affinity. Generally benign
238
Provide an example of ectopic gene expression
Kras (G12D) mutation causes constitutive overexpression in an oncogene, resulting in malignancy
239
Provide an example of a heterochronic gene expression
Hereditary persistence of fetal hemoglobin (HPFH), where the binding site of BCL11A is disrupted, leading to the enhancer (LCR) and co-activator + NF-Y to only express HbF and not HbB. Also an example of a LOF mutation for BCL11A
240
What are the possible problems caused by a mutation in housekeeping genes? Provide an example
- no effect (redundancy in function)
- lethal (no redundancy)
Tay-Sachs disease caused by a LOF mutation in an enzyme that does not have a redundant function
241
What are disorders usually a result of?
Mutations that affect tissue-specific specialty proteins
242
Provide an example of a tissue-specific mutation that causes a disease
Phenylketonuria (PKU) caused by LOF of phenylalanine hydroxylase
243
True/False? Mutated tissue-specific proteins only affect the tissue that encodes the protein
False. May also affect a secondary site where the disease is not produced
244
Genetic heterogeneity
A single phenotype is caused by mutations in multiple loci
245
Pleiotropy
A mutation in a single gene leads to multiple phenotypes
246
What is the prevalence of Down syndrome?
1/700
247
What is the prevalence of Edward's syndrome?
1/6000
