Genetics of Common Disorders with Complex Inheritance

Question 1

Polymorphisms:

Answer 1

• the 1% of the genome that differs between individuals
• can be small insertions/deletions, differences in number repeats, or single nucleotide differences
• most polymorphisms are silent, a small percentage are functional

Question 2

What do functional polymorphisms affect?

Answer 2

• either the expression of a gene or the activity of a protein

Question 3

Mutation definition:

Answer 3

• a DNA change that severely alters the activity or expression of a gene

Question 4

Silent Polymorphism definition:

Answer 4

• a silent change in the DNA that does not alter the expression or activity of the gene

Question 5

Functional polymorphism definition:

Answer 5

• subtle changes that alter the levels or activity of a gene, but still in the NORMAL range

Question 6

Relative risk equation:

Answer 6

Question 7

Heritability equation:

Answer 7

• 0 = trait NOT due to heritability
• 1 = trait due completely to heritability
• DZ = dyzygotic twins
• MZ = monozygotic twins

Question 8

Regarding twins, a 100% heritable trait will be passed on to:

Answer 8

both monozygotic twins

Question 9

Penetrance definition:

Answer 9

“all or none”

• the amount of people in the population who have the mutation and demonstrate the phenotype.
• if <100% of people who have the mutation express the phenotype, then incomplete penetrance exists.

Question 10

Expressivity definition:

Answer 10

“phenotype severity”

• when the severity of the phenotype among individuals with the same disease-expressing genotype differs

Question 11

Dominant inheritance:

Answer 11

• passed on to 50% of progeny
• no carriers

Question 12

Recessive Inheritance:

Answer 12

• carriers exist

Question 13

Semi-dominant disease:

Answer 13

• when heterozygous for dominant trait, lesser phenotype.
• when homozygous for dominant traint, more severe phenotype.

Question 14

What kind of pedigree is this?

Answer 14

Incomplete Penetrance

• When some people with the a dominant mutation do not develop features of the disorder.

Question 15

What kind of pedigree is this?

(assume all are homozygotes)

Answer 15

differential expressivity

• people with varying phenotype despite same genotype

Question 16

Genetic Linkage:

Answer 16

• detects the polymorphic region that shows linkage to a disease
  
  • it is present in a majority or all of those with the disease and not in those without the disease

Question 17

Genetic Linkage detects a polymorphic region linked to a disease. How do you then identify the causative gene?

Answer 17

1. sequence all the genes in the polymorphic region and look for mutation that segregates disease in all pedigrees
2. look for presence of different mutations in different families
3. confirm mutation affects expression or activity of gene

Question 18

Hirschsprung’s Disease:

Answer 18

• neural crest defect for cells that go on to form the enteric nervous system of the intestines
  
  • result: enlarged colon
• complex inheritance
  
  • three individual mutations from different loci all have to be inherited in order to have the disease
  • RET gene and two unknown genes

Question 19

Phenotypic overlap of common diseases:

Answer 19

• some major common diseases share mutations in the same genes.
• co-inheritance of other mutations will push someone toward developing a specific disease.

Question 20

Multifactorial inheritance definition:

Answer 20

• inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes, or interaction with the environment, or both.

Question 21

Polygenic definition:

Answer 21

• a trait whose phenotype is influenced by more than one gene, and is the result of the combined action of multiple genetic loci

Question 22

Mendelian disorders are caused by mutations in how many genes?

Answer 22

1

Question 23

Where does evidence for polygenic diseases come from?

Answer 23

• genetic studies
  
  • disease phenotype does not follow simple recessive or dominant inheritance pattern
• twin studies
  
  • disease does not demonstrate clear heritability

Question 24

The three risks for common polygenic diseases:

Answer 24

1. genetic
   
   • mutations and polymorphisms
2. epigenetic
   
   • methylation; can be influence by environment
3. non-genetic environmental factors
   
   • ​​hormones, diet, infection can alter cell pathways

Question 25

Common variants regarding the overall population:

Answer 25

• functional polymorphisms
• occur frequently in the population
• less individual risk, more population risk

Question 26

Rare variants regarding the overall population:

Answer 26

• mutations
• more individual risk, less population risk

Question 27

Single nucleotide polymorphisms:

Answer 27

• sequence variation occurring commonly within a population in which a single nucleotide differs between members of a biological species or paired chromosomes.

Question 28

Common single nucleotide polymorphisms are identified via:

Answer 28

association studies

Question 29

Genome wide association analysis process:

Answer 29

1. do microarrays with thousands of affected individuals and thousands of controls
2. find common variants for disease of interest
   
   • If certain genetic variations are found to be significantly more frequent in people with the disease compared to people without disease, the variations are said to be “associated” with the disease.

Question 30

Three types of regulatory RNAs that affect gene expression:

Answer 30

• enhancer RNAs
• miRNAs
• long-noncoding mRNAs
  
  • possible anti-sense function

Question 31

How do you identify common variants?

Answer 31

association studies

Question 32

How do you identify rare variants?

Answer 32

genome sequencing

Question 33

What does the Epigenetic Hypothesis state?

Answer 33

• risk of common disease are due to epimutations
  
  • changes in the epigenetic signature that affects gene regulation
  • provide interface between environmental factors and gene expression
  • provide basis for phenotype heterogeneity

Question 34

What is the transcriptome?

Answer 34

• the transcriptional profile of certain diseases
• can be the basis of diagnosis and treatment options

Question 35

What is the proteome?

Answer 35

• the proteins produced by a disease
• can be utilized to determine the basis of disease and treatment options by targeting specific proteins related to disease

Question 36

What is metabolomics?

Answer 36

• Understand the metabolic profile of diseased cells.
• Target the metabolic pathways contributing to the disease phenotype with specific drugs.