Midterm 2 Flashcards
(215 cards)
1
Q
What are the six mechanisms that lead to chromosomal and genomic imbalance?
A
- Nondisjunction
- Recombination at segmental duplications
- Sporadic variable breakpoints
- De novo balanced translocation
- Unbalanced segregation
- Events that reveal imprinted genes
2
Q
What are Microdeletion and Duplication Syndromes?
A
A group of disorders characterized by developmental delay, intellectual disability, and dysmorphic features and birth defects.
3
Q
What are some examples of microdeletion and duplication syndromes?
A
- 1q21.1 deletion/duplication
- Williams syndrome (7q11.23) deletion
- Prader-Willi/Angelman syndrome (15q11-q13) deletion
- Smith-Magenis syndrome (17p11.2) deletion
- DiGeorge syndrome (deletion) /Cat Eye syndrome (duplication) (22q11.2)
4
Q
What are the results of unequal crossing over?
A
Deletions on one chromosomes and duplications on the other.
5
Q
What are the results of a microdeletion of 22q11.2?
A
- 3M basepair deletion.
- There are about 30 genes within those 3M basepairs.
- Leads to craniofacial anomalies, intellectual disability, heart defects, and immunodeficiency.
- Haploinsufficiency for one or more genes
6
Q
What methods are used to detect 22q11.2 deletion syndrome?
A
FISH Analysis
Chromosomal Microarrays
7
Q
What are the results of a microduplication of 22q11.2?
A
- It’s rare in comparison to deletion
- Cat Eye syndrome
- Craniofacial abnormalities, heart defects, ocular coloboma
8
Q
How is Cat Eye syndrome different from a regular 22q11.2 duplication?
A
22q11.2 is the duplication of one of the 22nd chromosomes.
Cat Eye syndrome is trisomy 22, and a duplication on one of the chromosomes, and an inversion of that duplicated chromosomes duplicated half
9
Q
What are genomic disorders usually caused by?
A
Contiguous gene rearrangements via non-allelic homologous recombination
10
Q
What are the three important features of genomic disorders?
A
- Gene Dosage
- Progeny Effect from Balanced Carriers
- Variable Phenotypes
11
Q
How does gene dosage play into genomic disorder?
A
Dosage imbalances for extensive chromosomal or genomic regions are likely to result in clinical abnormalities.
Some conditions or phenotypes are results of an imbalance of a single gene or multiple genes.
Some phenotypes are the result of haploinsufficiency or triplosensitivity (overexpression)
12
Q
How can a balanced carrier impact their progeny?
A
Some duplication and deletion disorders have a distribution that does not appear to be random due to the location of families of segmental duplications, especially in pericentromeric and subtelomeric regions. These regions are predisposed to unequal recombination events.
13
Q
What is the underlying mechanistic basis for rearrangements, duplications, and deletions that cause genetic disorder?
A
Non-allelic homologous recombination
14
Q
What is the underlying mechanistic basis for deletions and rearrangements that cause chromosome abnormalities?
A
There is no underlying mechanistic basis.
15
Q
How many live births have a chromosomal abnormality?
A
1 in 7,000
16
Q
What is Cri-du-chat Syndrome?
A
Cry of the cat syndrome.
Crying infants with this syndrome sound like mewing cats.
1 in 50,000 live births.
10% - 15% of patients are the offspring of translocation carriers.
It is an autosomal deletion syndrome.
It is caused by the terminal or interstitial deletion of the distal portion of chromosome 5p.
The breaking point varies.
17
Q
Approximately how many newborns with a de novo balanced translocation have developmental phenotypes?
A
1 in 2,000
18
Q
Why do some balanced translocations result in developmental phenotypes and some do not?
A
Sometimes the translocation involves the direct disruption of a gene or genes by one or both of the translocation breakpoints.
19
Q
What is reciprocal translocation?
A
Two chromosomes with one breaking point each swap their broken off pieces. They both end up with the other’s broken segment.
20
Q
What is balanced translocation?
A
When there are no duplications or deletions resulting from the translocation. All the necessary information is there, no more, no less.
21
Q
What is Parent-of-Origin effect?
A
For some disorders, the expression of disease phenotypes depends on whether the mutant allele is inherited from the father or the mother.
22
Q
What is genomic imprinting?
A
- Locus specific genome inactivation
- Certain genes are expressed in a monoallelic parent-of-origin specific manner
- When the paternal allele is expressed, maternal copy is silenced, and vice versa
- Imprinted genes, or silenced genes, are typically arranged in clusters and are controlled by differently methylated regions or imprinting centers.
23
Q
How do epigenetics play into genomic imprinting?
A
Epigenetic marks are established in the germ line of the parents during gametogensis. It is normally ideal that neither the paternal nor the maternal copy of the gene is expressed.
24
Q
What is the conversion of parental imprinting process?
A
Both parents have a maternally imprinted chromosome and a paternally imprinted chromosome, from their parents. During oogenesis/spermatogenesis, the imprint is erased and their own personal imprint is added, which then gets passed to their offspring
25
What are imprinting centers?
Also called imprinting control regions.
DNA elements that control the conversion process of imprints.
They're located within the imprinted regions of the genome
26
What three things promote imprinting and transcriptional gene silencing?
- Hyper methylation of imprinted alleles
- Deacetylation of histones
- Chromatin condensation
27
What is Prader-Willi Syndrome?
A common body dysmorphic syndrome.
70% of the cases are due to paternally inherited deletion of chromosome 15 (15q11-q13), this causes the genetic information of 15q11-q13 to derive from the mother only.
28
What is Angelman Syndrome?
A rare body dysmorphic syndrome.
70% of the cases are due to maternally inherited deletion of chromosome 15 (15q11-q13), this causes the genetic information of 15q11-q13 to derive from the father only.
29
What happens to both the paternal and maternal chromosomes to result in Prader-Willi Syndrome?
The paternal PWS region and AS gene are deleted.
The maternal PWS region and AS gene are still intact.
The PWS region from the father is supposed to be expressed.
Instead, the PWS region from the mother is expressed.
30
What happens to both the paternal and maternal chromosomes to result in Angelman Syndrome?
The maternal PWS region and AS gene are deleted.
The paternal PWS region and AS gene are still intact.
The AS gene from the mother is supposed to be expressed.
Instead, the AS gene from the father is expressed.
31
What is uniparental disomy and what causes it?
When the child has the appropriate number of chromosomes, except they're both maternal or they're both paternal.
This can happen when nondisjunction happens in both parents and an egg/sperm with no chromosomes pairs with a sperm/egg with two chromosomes.
This can also happen if either the sperm or egg experiences nondisjunction and has two chromosomes, while the other is normal, and a trisomy rescue event occurs, deleting the single chromosome from the normal sperm/egg.
32
How can uniparental disomy cause Prader-Willi Syndrome or Angelman Syndrome?
If uniparental disomy occurs and there are two maternal chromosomes, the paternal PWS region expression will be lost, resulting in Prader-Willi syndrome. If there are two paternal chromosomes, the maternal AS gene expression will be lost, resulting in Angelman's syndrome.
33
What are all the causes of Prader-Willi Syndrome and Angelman Syndrome?
- 15q11.2-q13 deletion
- Uniparental disomy
- Imprinting center mutations
- Gene mutations
- Unidentified causes
34
What are the four phases of sex determination on the basis of chromosomes?
1. Establishment of chromosomal sex (XY, XX) at time of fertilization
2. Initiation of the process that develops the gonads
3. Continuation of sex specific differentiation for both internal and external sex organs
4. Post puberty development of secondary sexual characteristics
35
True or False: There are a lot of important genes on the Y chromosome?
False. The Y chromosome is gene poor. It encodes for less than 100 genes.
36
What are the five regions that make up the Y chromosome structure?
- Yp pseudoautosomal region
> Pairing and recombination with Xp in meiosis I
- SRY (Sex-determining Region on the Y)
> Gene encodes the maleness TDF (Testis Determining Factor)
> Gain or loss leads to sex determination defects
- AZF (Azoospermia Factor) gene
> Gonadal and genital development
> Deletion leads to azoospermia
- Heterochromatic region
- Yq pseudoautosomal region
> Short and plays a minor role in pairing and recombination
37
What is the Testis-Determining Factor?
Part of the SRY gene on the Y chromosome which initiates and promotes male sex organ growth and development
38
How does recombination of the X and Y chromosomes work?
Xp and Yp pair at the pseudoautosomal regions near the telomere and undergo recombination during male meiosis I. Sometimes they can pair at the q arms as well. This is normal and expected.
39
How can XX males and XY females happen?
If recombination occurs between the X and Y outside of the pseudoautosomal regions and between the X specific and Y specific portions, then the sequences for male gonadal sex determination may be translocated from the Y to the X. This would result in an offspring that has an X chromosome that contains the SRY gene (an XX male), or an offspring that has a Y chromosome that lacks the SRY gene (an XY female)
40
What is Azoospermia?
A lack of detectable sperm in the semen
41
What Y linked genes have an impact on spermatogenesis?
AZF (Azoospermia Factor) on Yq microdeletion which leads to defective spermatogenesis
42
True or False: The pseudoautosomal regions between an X and a Y chromosome are identical?
Kind of true. They're NEARLY identical
43
What is the difference between the SRY and TDF?
TDF is part of the SRY gene.
44
What is dosage compensation?
The process that makes the amount of most gene products from two copies of the X chromosomes equivalent to the single dose of X when there is only one (XY)
45
What is X Chromosome Inactivation?
In the somantic cells of normal XX humans, one of the two X chromosomes is randomly inactivated early in development. Those genes on that X are silenced epigenetically and not expressed. This equalizes the gene expression of the X chromosome.
46
In human X Chromosome Inactivation, is it the same X chromosome in every cell?
No, it's mosaic, so it could be a different X depending on the cells.
47
What causes an X chromosome to inactivate?
The X Inactivation Center on Xq13.2
XIST is the master inactivation control gene.
XIST RNA spreads along the length of one X with epigenetic silencing of most of the X genes.
Without the X Inactivation Center (XIC), both X's would be expressed
48
When does X Inactivation begin and what is the process?
Shortly after the conception of an XX embryo, both the paternally and maternally inherited X's are active, but within the first week of embryogenesis, one or both of the X's is chosen at random to become the future inactive X by the XIC. The inactive X forms the Barr body during interphase
49
What is a Barr Body?
The inactive X chromosome(s) that exists as a highly condensed heterochromatic structure in the interphase.
In individuals with extra X chromosomes, any excess X's are inactivated.
50
True or False: during X inactivation, the entire gene is inactivated every time.
False. At least 15% of X-linked genes escape from inactivation and 10% show variable inactivation
51
Does the active X chromosome have gene expression?
Yes.
52
Does the inactive X chromosome have gene expression?
Most genes are silenced, but about 15% are expressed to some degree.
53
What does the active X chromosome become during the chromatin state?
Euchromatin.
54
What does the inactive X chromosome become during the chromatin state?
Facultative heterochromatin. A Barr body.
55
What is the behaviour of noncoding RNA in an active X chromosome?
The XIST gene is silenced.
56
What is the behaviour of noncoding RNA in an inactive X chromosome?
The XIST RNA is expressed.
57
When does the active X chromosome experience DNA replication?
Synchronously with the autosomes.
58
When does the inactive X chromosome experience DNA replication?
Later in S phase.
59
What are the histone variants like in an active X chromosome?
Similar to autosomes.
60
What are the histone variants like in an inactive X chromosome?
Enriched for macroH2A.
61
What are the histone modifications in an active X chromosome?
Similar to autosomes.
62
What are the histone modification in an inactive X chromosome?
Enriched for heterochromatin marks and deficient in euchromatin marks.
63
When might X inactivation not be random?
When an individual has a structurally abnormal X and a normal X, or an autosomal translocation (balanced or unbalanced) and a normal X may show non-random X inactivation in order to only express the normal X chromosome.
If there is a balanced translocation, the normal X will be inactivated.
64
How common are sex chromosome abnormalities?
They're observed at 1 in 400-500 live births.
They're one of the most common genetic disorders.
65
What is Klinefelter Syndrome?
(47, XXY), (48, XXXY), (49, XXXXY)
There is only one X expressed, and the rest are inactivated. As more X's are present, the phenotype becomes more severe due to a higher dosage of genes that aren't inactivated from the inactive X's.
People with Klinefelter's are tall, thin, have low testosterone, and underdeveloped secondary sex characteristics.
66
What is Turner Syndrome?
(45, X), (46, XX, isochromosome Xq), (46, XX, ring X), (46, XX, deletion of Xp)
99% of 45, X fetuses abort spontaneously.
People with Turner's are short, have a webbed neck, broad chest, and gonadal dysgenesis. They do not experience any intellectual difference.
67
What is "47, XYY" Syndrome?
Observed in 1 in 1,000 live births.
Caused by paternal nondisjunction at meiosis II, producing YY sperm.
Produces an essentially normal phenotype.
68
What is Triple X Syndrome?
(47, XXX)
Occurs at 1 in 1,000 births.
No abnormal phenotype.
Are likely to be undiagnosed.
Usually fertile.
70% have learning difficult.
85% have focal epileptic activity.
As the number of X's increases, the severity of physical phenotype increases.
69
What is a molecular disease?
A disease where the pathology can be traced back to a single molecular factor (such as a protein or a polypeptide).
It's normally caused by mutation (inherited or acquired)
70
What is biochemical genetics?
The study of phenotypes at protein, biochemical, and metabolic levels
71
What are mutations?
An alteration in the number or structure of chromosomes
72
What are the seven types of mutations in the DNA?
1. Base pair substitutions (point mutations)
2. Base pair deletions or insertions
3. Gene duplications or deletions
4. Promoter mutations
5. Splice-site mutations
6. Mobile element insertions
7. Expanded repeats
73
What is sickle cell disease?
An autosomal recessive disorder of hemoglobin where the beta subunit genes encoded on chromosome 11 have a missense mutation. The mutation decreases the solubility of deoxygenated hemoglobin and causes it to form a sickle shape.
74
What is the total number of phenotypes for which molecular mutations are the basis?
Over 7,000
75
What is the total number of genes with phenotype causing mutations?
Over 4,000
76
About how many genes associate with a single phenotype?
Over 3,000
77
Mutation can cause disease through four different effects on protein function. What are those four effects?
- Loss of function of a protein
- Gain of function of a protein
- Acquisition of a novel property
- Misexpression
78
What are the two types of misexpression?
Heterochronic Expression of a Protein: the expression of a gene at the wrong time
Ectopic Expression of a Protein: the expression of a gene in the wrong place
79
What is a Loss of Function Mutation?
Alternations of a gene's sequence by either substitution, insertion, deletion, or rearrangement can lead to loss of function of the gene. The severity of a disease caused by loss of function mutations can be correlated with the degree/amount of function lost.
80
How are Loss of Function Mutations caused?
- The introduction of a premature stop codon
- Missense mutations
- Mutations that cause protein instability which reduces the protein abundance
81
What is a nonsense mutation?
A premature stop codon.
82
What is a Gain of Function Mutation?
Alternations of a gene's sequence which can enhance the normal functions of a protein or increase the production of a normal protein.
83
What is a Novel Property Mutation?
A change in the amino acid residue that can cause disease by conferring a novel property onto the protein without altering its normal functions. The proteins gain a new function entirely. For example, sickle cell disease.
84
What are the eight steps at which mutations could disrupt the synthesis or function of a normal protein?
1. Transcription
2. Translation
3. Polypeptide Folding
4. Post-Translational Modification
5. Assembly of Monomers into a Holomeric Protein
6. Subcellular Localization of the Polypeptide or the Holomer
7. Cofactor or Prosthetic Group Binding to the Polypeptide
8. Function of a Correctly Folded, Assembled, and Localized Protein Produced in Normal Amounts
85
What are the two classes of proteins based on their expression patterns?
Housekeeping Proteins: present in virtually every cell, fundamental for the maintenance of cell structure and function, account for 90% of the mRNAs expressed in humans.
Tissue-Specific Specialty Proteins: expressed in only one or a limited number of cell types, have unique functions, account for 10% of mRNAs expressed in humans.
86
What might be the results of a mutation in a tissue specific protein?
- Disease restricted to that tissue
- Disease is a secondary site where the protein is not expressed
87
What might be the results of a mutation in a housekeeping specific protein?
- It's rare that they would cause huge pathological changes
- Some can be lethal, though.
- Mostly, pathologies are limited to one or a few tissues potentially due to genetic redundancy (where genes with overlapping activities reduce the impact of the loss of function) or the abundance of proteins expressed.
88
What is Genetic Heterogeneity?
A phenomenon in which a single phenotype or a genetic disorder is caused by mutation in one of a multiple number of alleles or loci
89
What is Pleiotropy?
A phenomenon in which mutation of a single gene leads to multiple phenotypes or genetic disorders.
90
What are the three types of genetic variations that lead to the clinical phenotypes in inherited disease?
- Allelic Heterogeneity
- Locus Heterogeneity
- The effect of modifier genes
91
What is Allelic Heterogeneity?
Genetic Heterogeneity due to the presence of multiple alleles at a single locus. This is the most common of the two types. Generally, there is a clear genotype-phenotype correlation between a specific allele and a specific phenotype.
92
What is Locus Heterogeneity?
The phenomenon in which mutations at different genetic loci cause a similar phenotype.
93
What is a modifier gene?
A gene that modifies the effect produced by another gene.
94
What is an enzyme?
A biological catalyst that mediates the efficiency of converting a substrate to a product. The human genome contains >5,000 genes that encode for enzymes.
95
What is enzymopathy?
A metabolic disorder resulting from deficiency or abnormality of a specific enzyme
96
What is Hyperphenylalaninemia?
Elevated blood level of amino acid phenylalanine, which we obtain from our diets. This is an autosomal recessive disorder due to the deficiency of phenylalanine hydroxylase or tetrahydrobiopterin.
97
What is Phenylketonuria?
Classic PKU
An autosomal recessive disorder resulting from mutations in phenylalanine hydroxylase.
Elevated phenylalanine damages the developing central nerve system in early childhood and interferes with the function of the mature brain, resulting in intellectual difficulty.
Occurs at 1 in 2,900 live births
Newborns are screened for this disease a few days after birth because if positive results are no confirmed quickly and initial treatment administered before 4 weeks, there are profound effects on the intellectual outcome of the patients.
98
How do variant PKU and non-PKU hyperphenylalaninemia compare to PKU?
They're both less severe due to residual activity of mutated PAH enzymes.
99
How many different PAH gene mutations have been identified worldwide?
Over 400
100
Most PKU patients are ____ _____.
Compound heterozygotes (2 different mutant alleles at the same locus)
101
What is wild-type PAH?
A defect in the genes involving the formation or recycling of the PAH cofactor, tetrahydrobiopterin.
1-3% of hereditary hyperphenylalaninemia patients have this. These patients still develop neurological problems under administration of a low-phenylalanine diet because it requires two other enzymes.
102
What was the first disorder to benefit from newborn screening?
PKU.
103
What is a Common Variant?
An allele frequency in a population of > 1%
104
What is a Rare Variant?
An allele frequency in a population of < 1%
105
What are the types of small DNA variations?
- Single nucleotide variants
- Small nucleotide insertions and deletions
- Dynamic repeats
- Microsatellites
106
What are copy number DNA variations?
Deletions or duplications of one or more exons.
107
What is a single nucleotide variant?
When two sets of DNA vary by a single nucleotide.
They're the most common type of sequence variation.
There are > 3,000,000 person person.
They have variable effects ranging from benign to disease causing.
108
What part of a gene or a protein is affected by variation?
Any part can be affected.
109
What is a codon?
A sequence of 3 base pairs. There are 64 different codons. Together, a sequence of codons makes a protein. Each codon specifies an amino acid. There are 20 amino acids and 3 STOP codons, and 1 initiation codon.
110
What is the process called when ribosomes read mRNA to make protein?
Translation.
111
In codon nomenclature, which is nucleotide 1? Which nucleotide would be 5? What would the nucleotide before 1 be called?
The A of the ATG initiation codon is 1. The nucleotide two after the start codon would be 5 (ATGCG would be G). The nucleotide before 1 would be -1
112
In codon nomenclature, are the introns included?
No, they're omitted.
113
In codon nomenclature, how would one indicate that the codon ACC just after the initiation codon has become ACT?
c.6C>T
114
In codon nomenclature, how would one indicate a change in an intron?
The number of the first or last coding nucleotide in the nearest exon followed by a + if the intron comes after or a - if the intron comes before. Then, the number of nucleotides into the intron the change is located, and the change itself.
Exon: AGTGCCTATAGA
Intron: TACGCTAGC changed to TACGCTAGG
c.12+9C>G
115
In protein nomenclature, how are amino acids numbered?
p. the amino acid name and what number it came in at starting with the initiation codon as 1
116
What is cytogenetics?
The study of the structure, function, and evolution of chromosomes and their abnormalities.
117
What are the types of mutations on amino acids as a result from nucleotide substitutions within genes?
- Synonymous/Silent
- Non-Synonymous/Missense
- Nonsense
- Read Through
118
What is a Synonymous or Silent mutation?
The DNA sequence change does not alter the amino acid coded. This can happen when a single amino acid has two different codons.
119
What is a Non-Synonymous or Missense mutation?
The DNA sequence change alters the amino acid coded
120
If there was found to be a Synonymous or Silent mutation in the 325th amino acid in a protein, how would you write that out using protein nomenclature?
p.Leu325=
121
If there was found to be a Non-Synonymous or Missense mutation in the 112th amino acid in a protein, how would you write that out using protein nomenclature?
p.Leu112Pro
122
What is a Nonsense mutation?
The DNA sequence change results in a stop codon
123
If there was found to be a Nonsense mutation in the 33rd amino acid in a protein, how would you write that out using protein nomenclature?
p.Leu33Ter or p.Leu33*
124
What is a start codon variant?
When the DNA sequence changes alters the amino acid coded so that it is no longer a start codon.
125
What are some possible problems that could be caused by a start codon variant mutation?
The protein doesn't get coded at all and the protein is missing
126
What is a Read Through mutation?
The DNA sequence change results in the loss of a stop codon, making the protein incredibly long.
127
If there was found to be a Read Through mutation in the 102nd amino acid in a protein, how would you write that out using protein nomenclature?
p.Ter807GlyextTer102
128
What is a splicing variant?
A DNA sequence change at the +1, +2, -2, or -1 position that effects the splice donor or splice acceptor.
129
What is the splice donor?
The beginning of the intron, used to indicate that it is an intron.
130
What is the splice acceptor?
The end of the intron, used to indicate that it's no long meant to be cut out.
131
What happens if the number of bases is not divisible by 3? What causes this?
This is caused by a deletion, a duplication, or an insertion. It results in a frameshift.
132
What is a frameshift?
When an insertion, deletion, or duplication offsets the codons and creates an entirely new protein.
133
What are the differences between germline changes and somatic changes?
Germline is in your DNA at birth, somatic are acquired.
134
How much DNA damage do humans experience on average?
10,000 - 1,000,000 bases per cell every day are damaged.
135
What causes DNA damage?
- Deamination
- Depurination
- UV Light
- Mutagens
136
What is an Expansion Disorder?
A case of too many repeated elements in the DNA
137
What is Fragile X syndrome?
A repeated (CGG) element near the promoter of the FMR1 gene. It is hereditary. Usually the parents of the effected child will have a premutation.
Normal DNA has 6-54 repeats. Premutation DNA has 55-200 repeats. Full expansion has 200-1000+ repeats. It appears in 1/4000 boys.
138
What is a Dynamic Repeat?
The expansion of a simple repeat in coding regions or non-coding regions.
It is a major cause of neurological disorders.
Can result in loss of function or novel function.
139
In a pedigree for an X-linked dynamic repeat, what differences from a dominant or recessive inheritance pattern would you notice?
There could be multiple generations that aren't affected at all followed by a generation that is. This would indicate that all the people in between have a premutation.
140
How would it be possible for two unaffected parents to have one son that has an X with >200 dynamic repeats and is affected, and another son that has an X with only 20 dynamic repeats and isn't affected?
The mother would have to be heterozygous for the premutation allele with maybe one X having 20 dynamic repeats and the other one having maybe 80 dynamic repeats
141
In genetics, what is anticipation?
When a trait is more strongly expressed or expressed earlier in succeeding generations. The size of the expansion correlates with the age of onset, meaning the larger the expansion, the earlier the onset age and the more unstable it becomes for the next generation.
142
What is penetrance?
The frequency, under given environmental conditions, with which a specific phenotype is expressed by those individuals with a specific genotype.
143
What are microsatellites?
Repeated units of 2-5 nucleotides that usually do not have any clinical impact. There are more than 10,000 known microsatellites throughout the genome. They're detected using PCR.
144
What are microsatellites good for and why?
Forensic, DNA fingerprinting, paternity tests, checking relatedness, disease-gene genomic localization.
This is because everyone's microsatellites are varying lengths and the chances of two people having the exact same microsatellite profile is 1 / 5,000,000,000 (except for twins)
145
True or False: microsatellite testing can be used to determine aneuplodies.
True.
146
What is Charcot-Marie-Tooth?
A disease resulting from misaligned chromosomes crossing over and creating a duplication.
147
What is Hereditary Neuropathy with Liability to Pressure Palsies?
A disease resulting from misaligned chromosomes crossing over and creating a deletion
148
What is an exon-level duplication or deletion?
When one or more entire exons are duplicated or deleted. Duplication is rarer.
149
Cystic Fibrosis is an example of what type of molecular consequence?
Loss of function
150
Achondroplasia is an example of what type of molecular consequence?
Gain of function
151
Sickle cell anemia is an example of what type of molecular consequence?
Novel function
152
Osteogenesis Imperfecta is an example of what type of molecular consequence?
Dominant negative
153
Hereditary persistence of fetal hemoglobin and lactose intolerance are examples of what type of molecular consequence?
Misexpression
154
Holoprosencephaly is an example of what type of molecular consequence?
Haploinsufficiency
155
Charcot-Marie-Tooth disease is an example of what type of molecular consequence?
Gene dosage
156
What is a dominant negative mutation?
When a mutant polypeptide not only loses its own function, it also interferes with the product of the normal allele in a heterozygote
157
True or False: genes can only have a gain of function or loss of function, but not both.
False. It can have both, but not at the same time. The gain of function would be one variant and the loss of function would be another variant.
158
What are the ways in which gene variants can reduce protein activity?
- Loss of function
- Haploinsufficiency
- Dominant negative
159
What are the ways in which gene variants can enhance protein activity?
- Heterochronic/ectopic expression
- Gain of function
- New functions/Novel functions
160
What are Mendel's Laws?
The Law of Segregation: every individual has a pair of alleles for each trait from each parent and will randomly pass one on to their offspring.
The Law of Independent Assortment: separate genes for separate traits are passed independently to offspring
161
What is gene linkage?
The tendency of characters (phenotypes or marker alleles) to co-segregate in a pedigree because they lie in close proximity on a chromosome.
162
What is a genetic marker?
DNA sequence that has a classifiable allele or alleles that allow the marker to be tracked through families.
163
What is an allele?
One of the alternate versions of a DNA sequence at a given marker
164
What is the exception to Mendel's Law of Independent Assortment?
Linked loci which will segregate together due to their close proximity.
165
How can one tell if two loci are linked or unlinked?
If they're unlinked, the alleles from marker 1 will be found equally associated with both marker 2 alleles.
If they're linked, one allele from marker 1 is found associated with one allele from marker 2 more than 50% of the time.
166
What is an uninformative marker?
When both parents are AA and one of them is marked, the child will obviously be AA still and it won't tell you anything.
Or when one parent is AB and the other is CC, and that parent is the marked one. It doesn't tell you which chromosome the disease would be coming from either.
167
What is an informative marker?
When one parent is AB and the other is CD, which is the marker parent, this way it can be seen which chromosome the disease is coming from.
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How can you tell the size of a microsatellite?
PCR
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One parent is AA CC, and the other parent is BB BB. They have six children. AA BB, CA BB, CC BB, AC BB, CA BB, and AA BB. Are the markers linked?
They're unlinked because half the children are parental and half the children are recombinant.
170
One parent is AA CC, and the other parent is BB BB. They have six children. AA BB, CC BB, CC BB, AA BB, CC BB, and AA BB. Are the markers linked?
They're linked because there are no recombinants.
171
One parent is AA CC, and the other parent is BB BB. They have six children. AA BB, CC BB, CC BB, AC BB, CC BB, and AA BB. Are the markers linked?
It is likely that they are linked. The recombination rate is 0.167, the parental rate is 0.833.
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What is a genetic map?
An ordered map of markers (usually microsatellites) generated by genotyping large families. The distance between the markers is the recombination rate. 1% recombination = 1 centiMorgan. This provides the framework for linkage mapping.
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There is a parent with AC who does not have the disease and there is another parent with AA who does have the disease. They have a child who is AC and does have the disease. That child, with someone who is BB and does not have the disease, has six children, they are as follows: AB with disease, CB without disease, CB with disease, AB without disease, CB with disease, AB with disease.
Is the disease locus linked to this marker?
No.
If they were linked, we would expect the affected children to inherit the A allele and the unaffected children to inherit the C allele.
If they were unlinked, we would expect both the unaffected children and the affected children to equally inherit the A allele
Since there are 2 affected children and 1 unaffected child with the A allele, and 2 affected children and 1 unaffected child with the C allele, we can say they are unlinked.
174
There is a parent with AC who does not have the disease and there is another parent with AA who does have the disease. They have a child who is AC and does have the disease. That child, with someone who is BB and does not have the disease, has six children, they are as follows: AB with disease, AB without disease, AB with disease, CB without disease, AB with disease, AB with disease.
Is the disease locus linked to this marker?
Possibly. All the affected children have inherited the A allele from the affected parent, but one of the unaffected children has the A allele. It's possible recombination took place between the disease locus and the marker locus.
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What are the uses of genetic linkage?
It was used clinically before DNA sequencing was widely available to determine the risk of being a carrier or being affected.
It was also used for positional cloning to identify the genomic location of a disease gene without any prior knowledge on where or what the causative gene was
176
There is a parent that is AC and is affected. There is another parent that is BB and is unaffected.
They have six children: AB affected, AB unaffected, AB affected, CB unaffected, AB affected, and AB affected.
The first child, who is AB affected, has a child with CD unaffected. Their children are CA unaffected and DB unaffected.
What is the risk of developing the disease for those two unaffected children of AB affected and CD unaffected if the recombination rate is 0.02?
CA has a 98% chance of developing the disease.
DB has a 2% chance of developing the disease.
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There is a parent that is AC CA and is affected. There is another parent that is BA BA and is unaffected.
They have six children: AC BA affected, AA BA unaffected, AC BA affected, CA BA unaffected, AC BA affected, and AC BA affected.
The first child, who is AC BA affected, has a child with CB DB unaffected. Their children are CB AC unaffected and DB BA unaffected.
What is the risk of developing the disease for those two unaffected children of AC BA affected and CB DB unaffected if the recombination rate is for marker 1 is 0.02 and for marker 2 is 0.05?
CB AC has a 99.9% chance of developing the disease.
DB BA has a 0.01% chance of developing the disease.
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If there are two markers and one disease in the middle, with both having a recombinant rate of 0.05, what are the odds of nonrecombinant gametes, marker-marker recombinant gametes, and double recombinant gametes?
90% for nonrecombinant.
10% for marker-marker recombinant.
< 0.025% for double recombinant.
179
There is a marker with a recombinant rate of 0.02. The gene is X linked. There are two unaffected parents, one C and one AB. They have seven children: CB unaffected, CB unaffected, B fatally affected, B fatally affected, CA unaffected, CA unaffected, and A unaffected.
The first child, CB unaffected, has three children with E unaffected: B affected, EB unaffected, and an unknown child.
In the second generation, what is the carrier risk of females with the genotype CB or CA?
What is the carrier risk of the EB child?
If the unknown final child is male and inherited the C allele, what is the risk of him being affected?
CB would have a 98% chance of being a carrier.
CA would have a 2% chance of being a carrier.
EB would have a 98% chance of being a carrier.
The hypothetical C child would have a 2% chance of being affected.
180
There is a marker with a recombinant rate of 0.02 between the disease and the marker, and a recombinant rate of 0.03 between the disease and the second marker. The gene is X linked. There are two unaffected parents, one CD and one AC BF. They have seven children: CD BF unaffected, CD BF unaffected, BF fatally affected, BF fatally affected, CD AC unaffected, CD AF unaffected, and AC unaffected.
The first child, CD BF unaffected, has three children with EA unaffected: BF affected, EA BF unaffected, and an unknown child.
Who in the pedigree has had a recombination event?
What is the carrier risk of EA BF unaffected in the third generation?
The sixth child in from the first parents, CD AF has had a recombination event.
EA BF unaffected has nearly a 100% chance of being a carrier.
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What is dideoxy sequencing?
The process when you compare DNA sequences from affected individuals against the unaffected controls. PCR is used to amplify it.
182
What is homozygosity mapping or identity by descent mapping?
It's a type of mapping that is used when the assumption is that the variant was introduced into the population by one ancestor. Each affected individual carries the same variant on both chromosomes. The amount of identity to the original chromosome diminishes with each succeeding generation. This is a type of positional cloning.
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What is the difference between identity by descent and identity by state?
Identity by State is when there are two identical alleles or two identical segments of DNA. They do not share a common ancestor.
Identity by Descent is when there is a matching segment of DNA that two individuals have inherited from a recent common ancestor.
184
What are the problems with Sanger Sequencing?
- Expensive
- Laborious
- Some regions are large and have lots of genes
185
Kabuki Syndrome is often seen in the first child of non-consanguineous parents. It has a prevalence of 1 / 32,000 to 1 / 86,000. It's very rare that there's a recurrence in the family. The rate is equal in females and males.
What are the possible modes of inheritance for Kabuki Syndrome?
186
What is the process for Next Generation Sequencing or Massively Parallel Sequencing?
1. Collect the genomic DNA
2. Generate a library of random DNA breaks
3. PCR amplifies the DNA
4. Add universal DNA sequences to the DNA fragments
5. Fix the DNA to a solid surface and amplify
6. Wash the nucleotides over the surface and incorporate
7. Check that incorporation is complete
8. Generate the sequence for each reaction from the previous step
9. Map each sequence back to the reference genome
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What are the differences between Dideoxy Sequencing and Next Generation Sequencing?
Dideoxy Sequencing:
- Low throughput
- Labour intensive
- Relatively quick (days)
- Expensive
- Position dependent (you need to know where the sequence came from)
- Longer sequencing (> 500 bp)
- High accuracy (> 99.9%)
- No bioinformatics necessary (meaning you can teach it to anyone in a matter of hours)
NGS:
- High throughput (multiplexed)
- Slower (1 week)
- Inexpensive
- Position independent (have to figure out where the sequence came from)
- Short sequencing (< 300 bp)
- Not as accurate (< 99.9%, which can be overcome by sequencing each base 20 - 1000 times)
- Extensive bioinformatic support required
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What is exome sequencing?
When you sequence only the protein coding exons. It comprises 2% of the genome. There are fewer variants and sequence changes. However, not all disease variants are coding and not all exons are captured. Exon level deletion and duplications are also difficult to detect. Inversions and dynamic repeats expansions are not detected at all.
189
What is the process for exome sequencing?
1. Collect the genomic DNA
2. Construct shotgun library
3. Have DNA fragments
4. Hybridize them
5. Wash them
6. Put the captured DNA into the DNA sequencing machine
7. Map and align the variants
190
What is the cohort strategy for determining mode of inheritance?
Collecting a bunch of people who have the same disorder and finding commonalities between the families.
191
What are the pros and cons of whole genome sequencing or short read sequencing?
Pros: Able to detect single nucleotide variants, copy number variants, dynamic repeat expansions, intronic variants, and GC rich regions.
Cons: Variant interpretation is challenging, there is not a lot of instrument capacity, and there is not enough data storage to do this often.
192
What are the pros and cons of long read sequencing?
Pros:
- Very long reads (15,000 to 4,000,000 bp)
- Increased detection of structural variants and repeat expansions
Cons:
- Expensive
- Decreased throughput
- Decreased accuracy (90%)
193
What are the consequences of nondisjunction? Give an example.
Aneuploidy
Possible examples:
- Down syndrome
- Klinefelter syndrome
- Uniparental disomy
194
What are the consequences of recombination at segmental duplications?
Duplication/deletion syndrome.
Copy number variations.
195
What are the consequences of sporadic, variable breakpoints? Give an example.
Deletion syndromes
Possible examples:
- Cri du chat syndrome
- 1p36 deletion
196
What are the consequences of de novo balanced translocations?
Gene disruption.
197
What are the consequences of unbalanced segregation?
Offspring of balanced translocations and offspring of pericentric inversions.
198
What are the consequences of an event that reveals imprinted genes? Give an example.
The imprinted genes are expressed when they shouldn't be.
Possible examples:
- Prader-Willi Syndrome
- Angelman Syndrome
199
What are the three non-mosaic trisomy disorders that allow for post-natal survival?
Trisomy 21
Trisomy 18
Trisomy 13
200
What is the most common trisomy prenatally?
Trisomy 16
201
Why is it that trisomy 13, 18, and 21 allow for postnatal survival, but others, like 16, don't?
Because 13, 18, and 21 have very few genes in comparison to ones like 16, so there is less effect that could prove fatal.
202
How common are Trisomy 13, 18, and 21?
13: 1/12,000-20,000
18: 1/6,000-8,000
21: 1/850
203
Pregnant parents over what age have a higher incidence rate of Down Syndrome?
35
204
What percentage of trisomy 21 fetuses make it to birth?
20 - 25%
205
95% of people with Down Syndrome received an extra chromosome 21 from what type of event?
Meiotic nondisjunction during maternal meiosis. 75% in meiosis I.
206
What is Translocation Down Syndrome?
When someone with Down Syndrome had 46 chromosomes, but one underwent a Robertsonian translocation between chromosome 21q and the q arm of another acrocentric chromosome.
Usually it's 14 or 22.
This can be inherited or de novo.
It has a high recurrence risk.
It's present in 4% of people with Down Syndrome.
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What is Mosaic Down Syndrome?
When someone with Down Syndrome is mosaic for the extra chromosome 21.
Some cells have two 21's and some have three 21's.
It does not have the same phenotype as non-mosaic trisomy 21, it results in a "milder" clinical expression.
Increased risk for recurrence.
Only seen in about 2-4% of those with Down Syndrome.
208
What is Partial Trisomy Down Syndrome?
A partial duplication of chromosome 21q.
Sometimes only a few genes are duplicated, but different regions can result in different phenotypes.
Extremely rare.
209
What is Trisomy 13?
Patau Syndrome.
Extremely rare.
Very high prenatal mortality (50% of babies die within the first month of life)
Increased maternal age is a risk factor.
Most commonly caused by nondisjunction of meiosis I
20% due to unbalanced translocation.
210
What is Trisomy 18?
Edwards Syndrome.
Second most common autosomal trisomy.
Estimated that < 5% of conceptions survive to term.
Increased maternal age is a risk factor.
May be due to trisomy, translocation, or mosaic.
211
True or False: >70% of children with autosomal trisomies are born to parents who have known risk factors.
False. >70% are born to parents who have no known risk factors.
212
What is prenatal screening?
- Screening for diseases and conditions in the fetus during the first trimester.
- A blood test is performed
- An ultrasound is performed
- Non invasive
- Informs the parents of the risks for particular birth defects and genetic disorders
213
What is a prenatal diagnostic test?
- Performed after a high risk prenatal screen
- Voluntary
- Usually invasive
- Provides definitive diagnoses with almost 100% accuracy
- Chorionic villus sampling (sampling of the placental tissue)
- Amniocentesis (sampling of the amniotic fluid)
- Low risk to the fetus
214
What is Chorionic Villus Sampling (CVS)
It's a cervical or abdominal procedure that is performed using an ultrasound to guide the needle. It's performed at 10-11 weeks gestation. Cells are taken from the placenta for testing.
215
What is Amniocentesis?
An abdominal procedure that is performed using an ultrasound to guide the needle. It's performed at 15-17 weeks gestation. Cells are taken from the amniotic fluid around the baby, which is made up of amniocytes shed by the fetus
