Genetic Variations, Terminology associated with Mendelian/Monogenic Inheritance

Question 1

What is Knudson’s hypothesis?

Answer 1

The two-hit theory for tumor suppressor genes, which are typically recessive (as opposed to protooncogenes, which are dominant)

One mutated gene is inherited, but it’s recessive and so there is initially not a problem. However, a somatic mutation of the remaining allele occurs more easily, which is called LOH: loss of heterozygosity. LOH -> unregulated cell proliferation -> neoplasia such as retinoblastoma, frequently in children

Question 2

What are the 2 forms of deamination? When is it more significant?

Answer 2

1. Adenine -> hypoxanthine
2. Cytosine -> uracil
   Normally deamination can be repaired

More significant if cytosine is methylated, because then it converts to thymine and is not necessarily repaired. Occurs in “mutation hot spots” - CpG islands

Question 3

What mutation is the result of UV radiation?
How is it repaired?
What disease does mutation of these repair mechanisms cause?

Answer 3

thymidine dimerization

Repaired by nucleotide excision repair

Mutation of genes of NER leads to xeroderma pigmentosum, easily-developed skin cancer

Question 4

How do alkylating compounds have mutagenic effects?

Answer 4

Ethyl or methyl groups attach to nucleotides, and for example guanine becomes modified to where it binds thymine instead of cytosine. During repair, the base will be altered more permanently.

Question 5

How are mutagenic DNA adducts formed?

Answer 5

Pollutants like polyaromatic hydrocarbons (PAH) are taken into the body, the liver metabolizes them into epoxides, and they become adducts that bind DNA

Question 6

Difference between missense, nonsense, and sense mutations

Answer 6

Missense: codon changes -> different amino acid in a protein

Nonsense: codon changes to a stop codon -> protein is shortened

Sense: codon changes but the same amino acid is incorporated (some codons code for the same AAs) -> no consequences

Question 7

Difference between transition and transversion mutations

Answer 7

Transition: either a purine is replaced by another purine, or pyrimidine replaced w/ another pyrimidine

Transversion: purine base replaced with pyrimidine, or vice versa

Question 8

What is suppressor tRNA?

Answer 8

When there is a DNA mutation that would be coding for a different AA, yet there is also a mutation of the tRNA that “corrects” the DNA mutation, keeping the original AA configuration

Question 9

What type of DNA damage normally occurs from radio or chemotherapy?

What mechanisms are used to repair it?

Answer 9

Double-stranded breaks

Repaired by:
1. Homologous Recombination (HR) - sister chromatid is used as template for synthesis of repaired region (safer)

2. Non-Homologous End Joining (NHEJ) - just patch the broken parts together (much worse, a lot can be deleted)

Question 10

What 3 types of DNA damage result from replication errors?

How are they repaired?

Answer 10

Insertions, deletions, mismatches

Repaired by Mismatch Repair (defective in hereditary non-polyposis colon cancer)

Question 11

How do reactive oxygen species normally damage DNA?

How is it repaired?

Answer 11

Cause single-stranded breaks

Repaired by single-strand break repair

Question 12

Differences between loss-of-function and gain-of-function mutations

2 exceptions?

Answer 12

Loss-of-function mutations: gene product has less/no function. Usually recessive, homozygote forms. e.g. PKU: Phe hydroxylase loses its function

Gain-of-function: protein has new/abnormal function. Usually a dominant phenotype, occurs in heterozygotes. e.g. Achondroplasia, EGFR becomes unregulated - doesn’t need ligand

2 Exceptions: both exceptions occur in instances dominant inheritance with loss of function instead of gain of function

1. Haploinsufficiency (heterozygote w/ allele that makes insufficient protein to be healthy) e.g. Marfan
2. Dominant negative effect (heterozygote w/ defective allele that produces protein that screws up the normal protein from the healthy allele)

Question 13

What is abnormal in polyglutamine diseases?

What are 2 examples?

Answer 13

Lots of CAG repeats (CAG codes for Glu). >40 CAGs. Repeats are usually in the coding regions of the DNA. Usually have neurodegenerative effects

Examples: Huntington’s chorea and Kennedy Disease

Question 14

What is abnormal in polyalanine diseases?

2 examples?

Answer 14

CGN repeats. Mainly in transcription factor regions. Usually have loss of function. Caused by uneven crossing over.

Examples: synpolydactylia, hand-foot-genital syndrome

Question 15

Muscular dystrophy and fragile X syndrome: what type of DNA abnormalities and in which DNA regions are the DNA abnormalities?

Answer 15

DNA trinucleotide repeats, mostly in untranslated region (UTR)

Question 16

What is replication slippage?

What is the effect of replication slippage over multiple generations?

Answer 16

During replication, a long repeat sequence becomes looped. Then the replication apparatus detects the loop as if it was not fully completed, so it adds even more repeated sequences onto it

With multiple generations, leads to “anticipation” - younger and younger onset of severity.

Question 17

Example of transposon relation to disease?

Answer 17

Hemophilia A is often cause by transposon Alu sequence, causing a gene inversion

(transposons are genes that jump from one region to another)

Question 18

Two techniques for mutagenicity tests:

Answer 18

1. Ames test: have mutated salmonella that can’t synthesize histidine, then add mutagenic susbtance to see if the the bacteria will be able to produce histidine again (back/reverse mutation)
2. Sister Chromatid Exchange (SCE) - a small degree of sister chromatid exchange occurs in somatic cells, but this is increased dramatically with mutagenic substances

Question 19

Difference between locus and allelic heterogeneity?

Answer 19

Locus heterogeneity: mutation of several different genes results in similar phenotype (e.g. retinitis pigmentosa and deafness can be caused by genes from many different gene loci)

2. Allelic heterogeneity: different mutant alleles from the same gene result in similar symptoms/diseases (e.g. FGFR3, LDLR and dystrophin mutations)

Question 20

What occurs when a disease has complex/compound heterozygosity? What is an example?

Answer 20

A person with a disease has 2 different mutant alleles at the same locus.

Example: CFTR gene in cystic fibrosis can be mutated via deltaF508, but there are other known mutant alleles that can also cause cystic fibrosis

Question 21

What type of mutations normally cause gain-of-function?

And loss-of-function?

Answer 21

Gain-of-function: normally missense, especially of regulatory proteins. Altered proteins function independently, making them usually dominant.

Loss-of-function: usually nonsense or frameshift mutations make the protein inactive. Usually recessive, but may also be dominant with haploinsufficiency or dominant negative effect

Question 22

What is incomplete dominance?

Answer 22

A dominant disease where the heterozygous form does not have very severe effects compared to the homozygous form (e.g. familial hypercholesterolemia: heterozygous normally live a decently long time but homozygous die by the time they are teenagers)

Question 23

Difference between expressivity and penetrance?

Answer 23

Both are complications of how Mendelian inheritance of dominantly-inherited diseases

Expressivity: “strength” of a gene, how badly a person with the gene is affected. If some people with Marfans are only mildly affected, it is from “variable expressivity” - often explained by environmental effects/other modifier genes

Penetrance: not everyone in heterozygous form of some dominant diseases actually has the disease phenotype (“incomplete penetrance”). P% = 100 x # of affected persons/# of obligate carriers

Question 24

Difference between pleiotropy and heterogeneity?

Answer 24

Pleiotropy: single gene controls/influences many traits (e.g. CFTR gene, cystic fibrosis involves changes in secretions of the sweat, pancreas, and lungs)

Heterogeneity: many genes affect the same traits (such as deafness, many genes have to make products that enable hearing. any defect -> same expression of deafness)

Question 25

What is a phenocopy?

Answer 25

Variation of phenotype due to environmental conditions without a genetic mutation, but it mimics a similar phenotypical change that is normally caused by genetic mutations.

e.g. deafness from Rubella virus infection instead of genetic mutation

In the opposite way, a genetically-inherited disease can have no phenotypical expression due to environmental effects (e.g. low Phe diet for PKU -> no disease symptoms/ phenotype)

Question 26

What is epistasis?

What is the word for the type of inheritance that involves epistasis?

Answer 26

Phenomenon where the effect of one gene is dependent on the presence of one or more modifier genes (and often little is known about modifier genes)

If modifier genes do influence the genetic expression of the inheritable disease, the inheritance of those diseases is called “oligogenic”

Question 27

What is meant by a disease being “ecogenic?”

Answer 27

The disease will only be manifested with certain environmental situations, e.g. porphyria, G6PD deficiency. Only have symptoms in response to medications, stress, etc.