GM 02: Genetic Basis of Disease

Question 1

The entire human species shares (X)% of our genomes. The thought is that the main sources of variation come from (Y).

Answer 1

X = 99.5
Y = SNPs (single NT polymorphisms)

Question 2

What are SNPs?

Answer 2

Loci on genome where sequence varies at position of a single NT

Question 3

Most SNPs in human genome are found in which region of the gene?

Answer 3

Exon

Question 4

Alternative splicing is essentially using (one/multiple) gene(s) to produce (X) that includes different combinations of (Y).

Answer 4

One;
X = mature mRNA
Y = gene’s exons

Question 5

What’s copy number variation (CNV)?

Answer 5

Regions of genome that differ (from person to person) in total number of copies per genome

Question 6

T/F: If proteins that carryout epigenetic modification exhibit variability, all their target genes will also demonstrate variability.

Answer 6

True

Question 7

Define Familial Clustering.

Answer 7

Comparing probability of developing disorder in individual with affected relative versus member of general population

Question 8

Conducting a twin study is an approach to determine which information about a disease?

Answer 8

If it has a genetic basis

Question 9

A genetic disease would be expected to portray which results in twin study?

Answer 9

Higher concordance (phenotypic similarity) in monozygotic than dizygotic twins

Question 10

Linkage analysis is based on the principle that:

Answer 10

Genes whose loci are close in proximity will be inherited together

Question 11

Due to recombination, an individual will inherit a maternal chromosome that’s a combo of:

Answer 11

Both of their mother’s chromosomes

Question 12

(X) genes, separated by large distance on chromosome, are (more/less/equally) likely to be separated by recombination event than (Y) genes.

Answer 12

X = unlinked;
More likely;
Y = linked

Question 13

List the type of (DNA/mRNA) markers used in linkage analysis.

Answer 13

DNA

1. RFLPs (restriction fragment length polymorphisms)
2. SSLPs (simple sequence length polymorphisms)
3. SNPs (single NT polymorphisms)

Question 14

What are RFLPs (restriction fragment length polymorphisms)?

Answer 14

Loci on genome where sequences variation in population results in creation/elimination of restriction enzyme recognition site

Question 15

What are SSLPs (simple sequence length polymorphisms)?

Answer 15

Simple sequences (such as dinucleotide repeats) can vary in length per individual

Question 16

It’s important to recognize that linkage study analysis is (X), requiring a genetic model that describes:

Answer 16

X = parametric;

1. Mode of inheritance
2. Penetrance
3. Gene frequency
4. Number of loci involved

Question 17

In order to gain enough statistical power to declare particular marker locus as significantly linked to disease locus, one needs to have:

Answer 17

Large pedigrees with multiple cases of affected individuals

Question 18

In the method “affected sib pair analysis”, one expects siblings (by chance) to share (X) copies of their marker alleles.

Answer 18

X = 0, 1, or 2

Question 19

In “affected sib pair analysis”, which phenomenon would been seen if a particular marker locus is linked to disease gene?

Answer 19

Skewing of distribution of allele sharing in affected siblings

Question 20

In “affected sib pair analysis”, which phenomenon would been seen if a particular marker locus is linked to recessive disease gene?

Answer 20

Disproportionate number of affected siblings sharing both alleles of a marker

Question 21

In “affected sib pair analysis”, which phenomenon would been seen if a particular marker locus is linked to dominant disease gene?

Answer 21

Disproportionate number of affected siblings sharing at least one allele of a marker

Question 22

Identity by state versus descent is an issue in which method of analysis? Why?

Answer 22

Affected sib pair analysis;

We don’t have parental DNA information

Question 23

Describe allele sharing from “identity by state”.

Answer 23

Both siblings carry marker because both parents have copy of the same allele for given marker locus

Question 24

Identity by (state/descent) can be misleading.

Answer 24

State

Question 25

In identity by state phenomenon, (one/both) siblings have inherited (same/different) allele at marker locus from (the same/different) parent.

Answer 25

Both; same; different

Question 26

Describe allele sharing from "identity by descent".

Answer 26

Affected siblings share same allele at given marker locus, inherited from the same parent

Question 27

One way to improve detection of identity by (state/descent) is to use (X) as markers because they have (few/many) (Y). This makes it less likely that the parents will (Z).

Answer 27

``` Descent; X = SSLPs Many Y = alleles Z = have identical allele at a given marker locus ```

Question 28

In linkage studies across multiple families, the same (allele/marker), but not necessarily the same (allele/marker) is inherited with the disease gene.

Answer 28

Marker; allele

Question 29

Linkage disequilibrium (in association studies) refers to search for statistical association between (X) and (Y).

Answer 29

``` X = phenotype Y = a single allele ```

Question 30

Linkage disequilibrium would only exist if affected individuals in population all had (X).

Answer 30

X = common distant ancestor

Question 31

The (X) association study design has internal controls in the form of (Y).

Answer 31

``` X = transmission disequilibrium test (Tdt) Y = parental genotypes ```

Question 32

In transmission disequilibrium test (Tdt), if marker allele is not associated with disease phenotype, what are the expected results?

Answer 32

Marked and unmarked allele transmitted to affected offspring with equal probability

Question 33

In transmission disequilibrium test (Tdt), if marker allele is associated with disease phenotype, what are the expected results?

Answer 33

Marked allele will be statistically over-transmitted to affected offspring

Question 34

In transmission disequilibrium test (Tdt), which markers are especially useful?

Answer 34

SNPs

Question 35

List the major sources of human genetic variation.

Answer 35

1. SNPs 2. CNVs 3. Alternative splicing 4. Epigenetic modification

Question 36

For autosomal dominant disorders, we tend to assume affected individual is (homo/hetero)-zygous because:

Answer 36

Heterozygous; Mendelian disorders are rare

Question 37

(Males/females) have greater chance of being affected, and more (mildly/severely), by X-linked dominant disease.

Answer 37

``` Females; More mildly (X-inactivation) ```

Question 38

Locus heterogeneity is:

Answer 38

Phenomenon when multiple different genes can lead to similar clinical presentations

Question 39

McKusick number: list first digits and mode of inheritance implied for each.

Answer 39

1: autosomal 2: autosomal 3: X- linked 4: Y- linked 5: mitochondrial 6: autosomal