Chapter 33
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
Questions
1.
The majority of the mutations known to cause neurodegenerative diseases in humans have been
discovered for
a. common complex diseases because they affect the most people
b. diseases with a Mendelian inheritance pattern
c. multi-system atrophy
d. non-genetic diseases
e. diseases with no familial component
2.
A characteristic of modern genetic research is
a. that very few candidate genes are proposed for any given disorder
b. that positive association studies of candidates have been consistently replicated
c. all of the above
d. none of the above
3.
In a genetic study, stratification may refer to
a. unrecognized population sub-types due to recent admixture
b. unrecognized population sub-types due to incorrect matching of cases and controls
c. a method for presumably reducing genetic heterogeneity within a sample by narrowly defining the
phenotype
d. all of the above
e. none of the above
4.
Heterogeneity within a disease may manifest as
a. allelic heterogeneity, in which many variants of a single gene can cause the same
disease
b. locus heterogeneity, in which variants in many different genes may cause the same disease
c. some of the difficulties underlying genetic studies of neurodegenerative diseases
d. all of the above
e. none of the above
5.
Penetrance and expressivity refer to
a. the proportion who get the disease and how the disease manifests respectively
b. redundant terms
c. how the disease manifests and the proportion who get the disease respectively
d. all of the above
e. none of the above
6.
Microsatellites
a. are relatively highly polymorphic genetic markers
b. can by amplified by polymerase chain reactions
c. contain repeated elements
d. all of the above
e. none of the above
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
7.
An advantage to using single nucleotide polymorphisms in genetic studies is that
a. each marker is highly polymorphic
b. they are common and distributed throughout the genome
c. they are always within exons, and therefore cause a functional change
d. all of the above
e. none of the above
8.
Linkage analysis
a. is limited by its exclusive use of restriction fragment length polymorphisms
b. utilizes co-inheritance of a region of the genome with the disease locus to which it is “linked”
c. has the advantage of always identifying causative mutations
d. all of the above
e. none of the above
9.
Allelic genetic association analyses may find positive associations because the
a. allele causes the disease
b. allele is in strong linkage disequilibrium with the disease allele
c. result is a false positive
d. all of the above
e. none of the above
10. Genomic convergence provides
a. a method for greatly increasing the resolution of linkage peaks
b. a method for using non-human primates to identify causative alleles
c. an approach to prioritize candidates for further genetic study
d. all of the above
e. none of the above
11. A modifier gene
a. must cause disease.
b. alters the expression of a disease.
c. must be in linkage disequilibrium with the disease allele.
d. all of the above.
e. none of the above.
12. Variants of the GSTO gene are associated with
a. age at onset in AD
b. age at onset in PD
c. modifier effects
d. all of the above
e. none of the above
13. Causative mutations in which of the following genes have been described in early-onset AD?
a. amyloid precursor protein, presenilin-1, presenilin-2
b. presenilin-1, amyloid precursor protein, apolipoprotein C
c. presenilin-1, presenilin-2, apolipoprotein C
d. apolipoprotein C, presenilin-2, amyloid precursor protein
e. huntingtin, presenilin-1, presenilin-2
2
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
3
14. All of the following have been candidates for a role in late-onset AD, but which is the most widely
accepted and has the best supporting evidence for increasing susceptibility to AD?
a. UBQLN1
b. APOE
c. GAPD
d. α-T catenin
e. VLDL-R
15. Features of the apolipoprotein E-4 allele include
a. increased susceptibility to late-onset AD.
b. modification of age-at-onset in AD.
c. a dose dependent effect on age-at-onset in AD.
d. an association with other neurodegenerative diseases in addition to AD.
e. all of the above.
16. Characteristic of FTDP-17 is
a. a phenotype that may be mistaken for AD
b. linkage to chromosome 17
c. abnormal Tau accumulation
d. all of the above
e. none of the above
17. Which of the following has been proposed as a candidate for susceptibility to amyotrophic lateral
sclerosis?
a. VEGF
b. CNTF
c. glutamate system
d. all of the above
e. none of the above
18. The genetics underlying multiple sclerosis are typical for a neurodegenerative disease in that
a. concordance rates in monozygotic twins is higher than in dizygotic twins.
b. linkage and association approaches have been used to identify likely candidates for a role in the disease
c. there is an important environmental component to the disease
d. all of the above
e. none of the above
19. Huntington’s disease is an example of a dominantly inherited disease because
a. two copies of the disease allele are needed to express the disease
b. the disease locus is on the X chromosome
c. only one copy of the disease allele is needed to express the disease
d. it exhibits classic anticipation
e. it can only be inherited from an affected mother
20. Huntington’s disease exhibits all of the following except
a. autosomal dominant inheritance
b. anticipation, where the disease may become more severe with an earlier age-at-onset in subsequent
generations
c. it is characterized by expansion of a tri-nucleotide repeat
d. an autosomal recessive form of the disease
e. a causative gene has been identified
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
4
ANSWERS
1.
The majority of the mutations known to cause neurodegenerative diseases in humans have been
discovered for
a. common complex diseases because they affect the most people
b. diseases with a Mendelian inheritance pattern
c. multi-system atrophy
d. non-genetic diseases
e. diseases with no familial component
Most of the history of genetic research has focused on “simple” Mendelian diseases and many successes have
been achieved. Common diseases are often complex and progress has been much more difficult.
2.
A characteristic of modern genetic research is
a. that very few candidate genes are proposed for any given disorder
b. that positive association studies of candidates have been consistently replicated
c. all of the above
d. none of the above
Modern genetics has lead to large numbers of proposed candidates (e.g. hundreds for AD, but very few
candidates have been supported by independent replication. Modern technologies have automated genotyping,
so that now hundreds of thousands of genotypes may be done efficiently from a single sample for much less cost
per genotype.
3.
In a genetic study, stratification may refer to
a. unrecognized population sub-types due to recent admixture
b. unrecognized population sub-types due to incorrect matching of cases and controls
c. a method for presumably reducing genetic heterogeneity within a sample by narrowly defining the
phenotype
d. all of the above
e. none of the above
a and b refer to problems that are caused by unrecognized stratification within a sample. C refers to a strategy
used to refine the genetic risk in a study. Since c is generally thought of as unrelated to a or b, the nomenclature
may be confusing.
4.
Heterogeneity within a disease may manifest as
a. allelic heterogeneity, in which many variants of a single gene can cause the same
disease
b. locus heterogeneity, in which variants in many different genes may cause the same disease
c. some of the difficulties underlying genetic studies of neurodegenerative diseases
d. all of the above
e. none of the above
5.
Penetrance and expressivity refer to
a. the proportion who get the disease and how the disease manifests respectively
b. redundant terms
c. how the disease manifests and the proportion who get the disease respectively
d. all of the above
e. none of the above
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
6.
Microsatellites
a. are relatively highly polymorphic genetic markers
b. can by amplified by polymerase chain reactions
c. contain repeated elements
d. all of the above
e. none of the above
7.
An advantage to using single nucleotide polymorphisms in genetic studies is that
a. each marker is highly polymorphic
b. they are common and distributed throughout the genome
c. they are always within exons, and therefore cause a functional change
d. all of the above
e. none of the above
5
There are millions of single nucleotide polymorphisms in the genome and they are widely distributed.
8.
Linkage analysis
a. is limited by its exclusive use of restriction fragment length polymorphisms
b. utilizes co-inheritance of a region of the genome with the disease locus to which it is “linked”
c. has the advantage of always identifying causative mutations
d. all of the above
e. none of the above
There is no assumption of causality with linked markers and there is no restriction on which types of markers
must be used.
9.
Allelic genetic association analyses may find positive associations because the
a. allele causes the disease
b. allele is in strong linkage disequilibrium with the disease allele
c. result is a false positive
d. all of the above
e. none of the above
10. Genomic convergence provides
a. a method for greatly increasing the resolution of linkage peaks
b. a method for using non-human primates to identify causative alleles
c. an approach to prioritize candidates for further genetic study
d. all of the above
e. none of the above
Genomic convergence prioritizes candidates from the mountains of extant reports
11. A modifier gene
a. must cause disease
b. alters the expression of a disease
c. must be in linkage disequilibrium with the disease allele
d. all of the above
e. none of the above
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
6
12. Variants of the GSTO gene are associated with
a.
b.
c.
d.
e.
age at onset in AD
age at onset in PD
modifier effects
all of the above
none of the above
Modifiers, like GSTO, may have roles in the expression of multiple diseases.
13. Causative mutations in which of the following genes have been described in early-onset AD?
a. amyloid precursor protein, presenilin-1, presenilin-2
b. presenilin-1, amyloid precursor protein, apolipoprotein C
c. presenilin-1, presenilin-2, apolipoprotein C
d. apolipoprotein C, presenilin-2, amyloid precursor protein
e. huntingtin, presenilin-1, presenilin-2
14. All of the following have been candidates for a role in late-onset AD, but which is the most widely
accepted and has the best supporting evidence for increasing susceptibility to AD?
a. UBQLN1
b. APOE
c. GAPD
d. α-T catenin
e. VLDL-R
Only APOE is best supported and its role in AD has been replicated literally hundreds of times
15. Features of the apolipoprotein E-4 allele include
a. increased susceptibility to late-onset AD.
b. modification of age-at-onset in AD.
c. a dose dependent effect on age-at-onset in AD.
d. an association with other neurodegenerative diseases in addition to AD.
e. all of the above.
ApoE4 is a susceptibility allele, a modifier and has a role in multiple diseases.
16. Characteristic of FTDP-17 is
a. a phenotype that may be mistaken for AD
b. linkage to chromosome 17
c. abnormal Tau accumulation
d. all of the above
e. none of the above
17. Which of the following has been proposed as a candidate for susceptibility to amyotrophic lateral
sclerosis?
a. VEGF
b. CNTF
c. glutamate system
d. all of the above
e. none of the above
All choices have been candidates for multiple sclerosis. As with many diseases there are a large number of
candidates but replication of positive findings is lacking.
33.
Familial Neurodegenerative Diseases and Single Nucleotide Polymorphisms
Michael Slifer and Jeffrey M. Vance
7
18. The genetics underlying multiple sclerosis are typical for a neurodegenerative disease in that
a. concordance rates in monozygotic twins is higher than in dizygotic twins.
b. linkage and association approaches have been used to identify likely candidates for a role in the disease
c. there is an important environmental component to the disease
d. all of the above
e. none of the above
19. Huntington’s disease is an example of a dominantly inherited disease because
a. two copies of the disease allele are needed to express the disease
b. the disease locus is on the X chromosome
c. only one copy of the disease allele is needed to express the disease
d. it exhibits classic anticipation
e. it can only be inherited from an affected mother
An autosomal dominant disease or trait requires only one copy of the allele to be expressed. While d,
anticipation, is a feature of the Huntington disease, it does not explain autosomal dominant inheritance.
20. Huntington’s disease exhibits all of the following except
a. autosomal dominant inheritance
b. anticipation, where the disease may become more severe with an earlier age-at-onset in subsequent
generations
c. it is characterized by expansion of a tri-nucleotide repeat
d. an autosomal recessive form of the disease
e. a causative gene has been identified
There is no known autosomal recessive form of Huntington’s disease. All of the rest are true.