Exam 8: Identifying Disease Genes and Genetic Susceptibility to Complex Disease

The first genome-wide human genetic map was created by taking a completely different approach to the approaches used to create genetic maps in model organisms. What was the essential difference?

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Question 1

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In model organisms, genetic mapping relied on phenotypes. That is the genetic maps were obtained by mapping gene mutations that cause readily identifiable phenotypes. In Drosophila, for example, crosses can easily be set up to breed mutant white-eyed flies with flies that have abnormal curly wings; the progeny are then examined to see if the two mutant phenotypes segregate together or not. In humans, however, that kind of approach could never be applied-a different strategy was needed.
Instead of having a genetic map based on gene mutations, the solution to making a human genetic map was to identify general DNA variants (that mostly do not map within coding sequences, and usually have no known effects on the phenotype). Different types of variants were identified and mapped to specific locations in our genome, beginning with restriction fragment length polymorphisms (RFLPs) that created or destroyed a restriction site followed by microsatellite polymorphisms that varied in the copy number of short tandem repeats. These provided anonymous genetic markers for each chromosome and the segregation of alleles at these marker loci were then followed through multigeneration families to identify neighboring markers (because their alleles would tend to segregate together).

Affected members of the pedigree above have an autosomal dominant disorder, and cytogenetic analyses using conventional chromosome banding did not identify a disease-associated chromosomal abnormality. However, recent previous studies in other families mapped the disease locus to a region on the short arm of chromosome 17 and showed that four polymorphic microsatellite markers, P, Q, R and S are closely linked to the unidentified disease locus. (The order of the markers from most distal to most proximal is given by the following sequence: P-Q-R-S). When the same four markers were used to genotype each member of the family above, the alleles obtained were as listed below. a) If we were to assume that the disease locus is also at the same 17p region in this family, what is the disease haplotype originating from I-2 (that is, the sequence of alleles at the four marker loci on the chromosome that has the disease allele)? b) Has the disease haplotype been conserved in all family members? c) Is it likely that the disease in this family is linked to 17p? d) If the disease locus were to be at 17 p in this family, what do you deduce about the position of the disease locus with respect to the marker loci?

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Question 2

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a) 2 (P) - 1 (Q) - 3 (R) - 4 (S).
b) No. III-3 has inherited a maternal recombinant haplotype: 2 (P) - 1 (Q) - 1 (R) - 3 (S).
c) The disease locus does seem to segregate with 17p markers through most meioses - there is the exception of the maternal chromosome inherited by III-3 where alleles for markers R and S are not the expected ones.
d) Because of the presumed recombination in the maternal chromosome 17 inherited by III-3, the disease locus can be inferred to be distal to marker loci R and S.

The human APOE gene has three common alleles, APOEe2, APOEe3, and APOEe4, that gives rise, respectively, to the common alleles apoE2, apoE3 and apoE4 at the protein level. Which, if any, of the following statements is true? a) The e4 allele confers a high risk of Alzheimer disease and people with two e4 alleles have twice the disease risk of people with one e4 allele. b) The e3 allele is a protective factor, conferring reduced risk of Alzheimer disease while the e2 allele has a disease risk that is intermediate between those of e3 and e4. c) The e4 allele is considered the ancestral APOE allele because although the chimp and gorilla also have three apoE proteins the apoE4 protein is the most frequent allele. d) The e4 allele has reached a high frequency because Alzheimer disease has such a late age at onset that reproductive success rates are not diminished.

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Question 3

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None.

The same genomic DNA samples recovered from family members in Which of the following statements is most likely to apply?

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Question 4

Genomewide association (GWA) studies have identified common single nucleotide DNA variants that are very rarely of even moderate effect and that are collectively insufficient to explain the genetic variance of complex diseases. Which of the following can at least partly explain the genetic variance?

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Question 5

What is the difference between parametric and non-parametric linkage analyses and under what circumstances are they applied to studying human genetic disease.

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Question 6

Fill in the blanks Poor family structure means that it may not be easy, or even feasible, to use __1 _2__ in order to map the underlying gene for certain types of single gene disorders. The disorder may be extremely rare so that insufficient samples can be obtained, or the vast majority of affected individuals are sporadic cases that arise through a 3 _4__ mutation, such as in severe congenital 5 disorders. In the past, gene identification in these cases was sometimes possible using cytogenetic analyses to identify a disease-associated chromosome abnormality. Two or more affected individuals might be identified to have a translocation or 6 with a common 7_ or a recurring interstitial or terminal 8_ might be identified. Once the subchromosomal location of the gene had been identified it was possible to use 9_ 10_ or 9_ _11__ gene approaches to identify the underlying gene. More recently, a more direct approach, _12 13 makes it possible to quickly get to the underlying gene without knowing its chromosomal location.

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Question 7

Certain common alleles are known to be associated with specific complex diseases. Why has purifying selection not led to these alleles being eliminated from the population?

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Question 8

With regard to affected sib pair (ASP) analysis which, if any, of the following statements is true.

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Question 9

Strategies to identify the genes that underlie single gene disorders have often relied on first obtaining a subchromosomal location for the disease gene. List two approaches that have been taken to identify subchromosomal locations for these disorders.

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Question 10

Balancing selection might explain why certain common alleles known to be associated with specific complex diseases have not been eliminated by natural selection. List some examples that might suggest this to be the case.

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Question 11

The risk ratio, $\lambda$ , is commonly used in complex disease. What does it mean and how do risk ratios compare in complex disease and monogenic disorders?

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Question 12

Fill in the blanks In a ___1-control study affected individuals ( _1_ ) are compared with control subjects that are suitably _2_ to the 1_ with regard to age, sex and so on. In genetic studies of complex diseases the _1_ and controls are genotyped for genetic _3 in the hope of identifying _3__ that may confer significantly increased disease risk ( 4 _5__ ) or significantly reduced disease risk ( 6 5 ). A popular way of assessing the data is to calculate an _7_ _8___, that is the _7 of being affected if the genetic 3 is present divided by the odds of being affected if the genetic 3 is absent.

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Question 13

List three observations that support the common disease-common variant hypothesis.

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Question 14

Illustrate how the heritability of a disease can change over time using an example of a) a monogenic disorder and b) a complex disease.

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Question 15

Which, if any, of the following statements is true?

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Question 16

Genomewide association studies have been very successful in identifying susceptibility factors in inflammatory bowel diseases, and have provided valuable insights into the pathogenesis of these diseases. What types of insights have they offered?

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Question 17

To what extent do late-onset common Alzheimer disease and rare autosomal dominant Alzheimer disease show common pathologies at the physiological level and what is the evidence for common biological pathways in the Mendelian and complex disease versions of this disease?

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Question 18

Fill in the blanks Once we had a human genetic map, a general method, __1 2, could be applied to identifying genes underling single gene disorders. In order to carry this through, there was first the need to identify families with multiple affected individuals and to obtain samples of 3 4 from both affected and unaffected family members. The individual samples could then be tested by assaying each of several hundred DNA 5_ . The DNA 5 were selected because they were known to be 6 and because they were each known to map to a 7 subchromosomal location. The object was to identify 5 that must map close to the disease gene because alleles from these markers tended to 8__ with disease through generations in families.

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Question 19

Fill in the blanks Imagine a genetic variant that is tightly linked to a disease susceptibility allele. On a single chromosome, the __1 containing the genetic variant and the linked disease susceptibility allele will have a higher 2 than would be expected (that is, it would be higher than the 2 of the genetic variant multiplied by the 2_ of the disease susceptibility allele. This is an example of _3_ 4_ , the non-random _5_ of alleles at two or more loci. Although _3_ 4_ describes any non-random _5_ of alleles at different loci, in practice, the alleles are at very closely _6 loci. Although 3 4_ can occur if a particular combination of alleles offer some advantage and is _7_ selected, it may often simply reflect reduced _8_ between loci (certain regions of the genome, such at the HLA complex, show significantly reduced _8_ ). When a new DNA variant is created by mutation it will show very tight 3__ with alleles at neighboring loci. However, the _3_ 4_ will gradually be eroded by _8__ but that will take a very _9___ time for any locus that is physically very close to the locus with the new mutation.

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Question 20

Showing 1 - 20 of 40

The first genome-wide human genetic map was created by taking a completely different approach to the approaches used to create genetic maps in model organisms. What was the essential difference?

The same genomic DNA samples recovered from family members in Which of the following statements is most likely to apply?

Genomewide association (GWA) studies have identified common single nucleotide DNA variants that are very rarely of even moderate effect and that are collectively insufficient to explain the genetic variance of complex diseases. Which of the following can at least partly explain the genetic variance?

What is the difference between parametric and non-parametric linkage analyses and under what circumstances are they applied to studying human genetic disease.

Certain common alleles are known to be associated with specific complex diseases. Why has purifying selection not led to these alleles being eliminated from the population?

With regard to affected sib pair (ASP) analysis which, if any, of the following statements is true.

Strategies to identify the genes that underlie single gene disorders have often relied on first obtaining a subchromosomal location for the disease gene. List two approaches that have been taken to identify subchromosomal locations for these disorders.

Balancing selection might explain why certain common alleles known to be associated with specific complex diseases have not been eliminated by natural selection. List some examples that might suggest this to be the case.

The risk ratio, $\lambda$ , is commonly used in complex disease. What does it mean and how do risk ratios compare in complex disease and monogenic disorders?

List three observations that support the common disease-common variant hypothesis.

Illustrate how the heritability of a disease can change over time using an example of a) a monogenic disorder and b) a complex disease.

Which, if any, of the following statements is true?

Genomewide association studies have been very successful in identifying susceptibility factors in inflammatory bowel diseases, and have provided valuable insights into the pathogenesis of these diseases. What types of insights have they offered?

To what extent do late-onset common Alzheimer disease and rare autosomal dominant Alzheimer disease show common pathologies at the physiological level and what is the evidence for common biological pathways in the Mendelian and complex disease versions of this disease?

Fundamentals of Dna, Chromosomes, and Cells

Fundamentals of Gene Structure, Gene Expression, and Human Genome Organization

Principles Underlying Core Dna Technologies

Principles of Genetic Variation

Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

Principles of Gene Regulation and Epigenetics

Genetic Variation Producing Diseasecausing Abnormalities in Dna and Chromosomes

Genetic Approaches to Treating Disease

Cancer Genetics and Genomics

Genetic Testing From Genes to Genomes, and the Ethics of Genetic Testing and Therapy

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Exam 8: Identifying Disease Genes and Genetic Susceptibility to Complex Disease

The first genome-wide human genetic map was created by taking a completely different approach to the approaches used to create genetic maps in model organisms. What was the essential difference?

The same genomic DNA samples recovered from family members in Which of the following statements is most likely to apply?

What is the difference between parametric and non-parametric linkage analyses and under what circumstances are they applied to studying human genetic disease.

Certain common alleles are known to be associated with specific complex diseases. Why has purifying selection not led to these alleles being eliminated from the population?

With regard to affected sib pair (ASP) analysis which, if any, of the following statements is true.

Strategies to identify the genes that underlie single gene disorders have often relied on first obtaining a subchromosomal location for the disease gene. List two approaches that have been taken to identify subchromosomal locations for these disorders.

Balancing selection might explain why certain common alleles known to be associated with specific complex diseases have not been eliminated by natural selection. List some examples that might suggest this to be the case.

The risk ratio, λ \lambda λ , is commonly used in complex disease. What does it mean and how do risk ratios compare in complex disease and monogenic disorders?

List three observations that support the common disease-common variant hypothesis.

Illustrate how the heritability of a disease can change over time using an example of a) a monogenic disorder and b) a complex disease.

Which, if any, of the following statements is true?

Genomewide association studies have been very successful in identifying susceptibility factors in inflammatory bowel diseases, and have provided valuable insights into the pathogenesis of these diseases. What types of insights have they offered?

To what extent do late-onset common Alzheimer disease and rare autosomal dominant Alzheimer disease show common pathologies at the physiological level and what is the evidence for common biological pathways in the Mendelian and complex disease versions of this disease?

Fundamentals of Dna, Chromosomes, and Cells

Fundamentals of Gene Structure, Gene Expression, and Human Genome Organization

Principles Underlying Core Dna Technologies

Principles of Genetic Variation

Single-Gene Disorders: Inheritance Patterns, Phenotype Variability, and Allele Frequencies

Principles of Gene Regulation and Epigenetics

Genetic Variation Producing Diseasecausing Abnormalities in Dna and Chromosomes

Genetic Approaches to Treating Disease

Cancer Genetics and Genomics

Genetic Testing From Genes to Genomes, and the Ethics of Genetic Testing and Therapy

Filters

The risk ratio, $\lambda$ , is commonly used in complex disease. What does it mean and how do risk ratios compare in complex disease and monogenic disorders?