Cancer Genetics, Epigenetics, Trx of Genetic Diseases, Multifactorial Genetics

Question 1

Cancer can result from?

Answer 1

Somatic mutations: lead to increased proliferation in somatic cells (due to gene mutations, translocations/deletions, genomic imprinting, and gene amplification)

Microsatellite instability shows DNA repair mutations

Question 2

Genomic imprinting

Answer 2

Methylation causes condensation of chromatin leading to it not being expressed. Parent of origin difference in gene expression.

Question 3

Clonal expansion

Answer 3

Uncontrolled division of defective cells leading to tumor formation.

Question 4

Three classes of cancer genes

Answer 4

(1) Tumor suppressor genes (2) Oncogenes (3) Mutator genes

Question 5

Tumor suppressor genes

• Do?
• Dominant or recessive oncogenes? Why? Inheritance has what pedigree?
• Examples?

Answer 5

• Tumor suppressor genes inhibit cell proliferation, repair DNA, make sure DNA damage checkpoints are passed.
• Are considered recessive oncogenes because two copies of the gene need to be mutated in order to become tumorigenic. Autosomal dominant.
• Retinoblastoma, p53 (leads to Li-Fraumeni syndrome), BRCA1/BRCA2

Question 6

Two-Hit Hypothesis

Answer 6

In relation to tumor suppressor genes.
First hit mutation is inherited making individual more susceptible to cancer because now only one copy of the gene needs to be knocked out for cancer to result. Leads to loss of heterozygosity.

Question 7

Oncogenes

• Do?
• Dominant or recessive oncogenes? Why? Originate from? Inheritance is?

Answer 7

• Activate proliferation by leading to deregulation of cell cycle control.
• Dominant – only need one gain of function mutation for cell to be tumorigenic. Originate from proto-oncogenes – genes involved in basic regulation of normal cell growth. Mutation in proto-oncogene turns it into oncogene. Inheritance is autosomal dominant.

Question 8

Mutator genes

Answer 8

• Mutations in genes involved with DNA repair and accurate replication. They are autosomal recessive inactivating mutations leading to complete loss of function of protein (no DNA repair enzymes). It is mutation to its ability to repair DNA that leads to cancer.

Question 9

Tumorigenic cell growth

Answer 9

Normally, proto-oncogenes signal cell to grow and tumor suppressor inhibit cell growth and proliferation. In cancer, mutated/gain of fn oncogenes cause cell overproliferation and tumor suppressors are mutated/lose function, leading to nothing preventing cells from overproliferating.

Question 10

Loss of heterozygosity (LOH)

Answer 10

Cancers from mutation to tumor suppressors often result from LOH, in which one mutation is inherited (initial genotype Aa) and other mutation undergoes somatic lesioning of other allele mutates other allele (final genotype aa)

Question 11

Gene amplifcation

Answer 11

Increase of copy number in gene often involved in oncogene-driven cancers

Question 12

Fusion proteins

Answer 12

Fused protein product due to translocation. Can drive cancer. Often implicated in leukemia/lymphoma.

Philadelphia chromosome leads to BCR-ABL fusion protein leading to chronic myelogenous leukemia. Gleevec inhibitor of BCR-Abl.

Question 13

Epigenetic changes

• Are
• Common types?

Answer 13

• Heritable changes in gene expression not coded in DNA itself.
• (1) Histone modifications (2) DNA methylation

Question 14

Histone modifications

Answer 14

Regulate the degree to which DNA is bound to histones

(1) Acetylation: histone acetyl transferases increase DNA expression. Histone deacetylase complexes deactivate DNA
(2) Methylation: increases expression at Lys 4 and decreases at Lys 9
(3) Phosphorylation and ubiquitylation

Question 15

DNA methylation

Answer 15

Methylation of C5 of cytosine/guanine pairs (CpG) in DNA silences it.

Question 16

CpG islands

Answer 16

Located in the promoter. Targets for proteins that bind to unmethylated CpGs and initiate gene trx. Methylation of DNA normally used to diferentiate unmethylated daughter strand from methylated parent strand after DNA replication

Question 17

Genomic imprinting

Answer 17

Occurs when one chromosome (or section of chromosome) is turned off based on parent of origin. Because parent of origin is important for expression for some genes, genomic imprinting can lead to gene not being expressed.

Question 18

Uniparental disomy

Answer 18

Occurs when both copies of a chromosome are inherited from one parent. All genes present, but not all expressed.

Question 19

Prader-Willi syndrome

Angelman syndrome

Answer 19

PW: can be due to deletions in paternal chromosome or uniparental disomy of maternal chromosome.

Angelman: can be due to deletions in maternal or uniparental disomy of paternal. Familial inheritance is abnormal – mutations in paternal chromosome don’t matter because gene is silenced, but when mother passes gene to son, imprinting is removed leading to 50% chance of it passing to kids.

Question 20

ncRNAs

Answer 20

Non-coding RNAs. Genome produces thousands of them - do not code for protein. Expressed in a tissue-specific manner. There are both large and small ncRNAs.

Question 21

miRNAs

Answer 21

micro RNAs. Classic example of small ncRNA. Bind mRNA transcripts and prevent translation or faciliate their degradation.

Question 22

Large ncRNAs

Answer 22

Trx by RNA pol II. Play a role in regulation of gene expression, X inactivation, nuclear organization, chromatin state.

Question 23

Genetic traits fall on a spectrum with regards to _______.

Models of complex traits (3)

Answer 23

The number of loci that cause them.

(1) Major gene: single locus has major influence on risk
(2) Oligogenic: few loci account for most of risk
(3) Polygenic: many loci influence risk, each with small effects

Question 24

Continuous traits

- examples

Answer 24

Anthropometric (height, weight etc.)
Pigmentation
Behavioral traits

Question 25

Additive polygenic model

Answer 25

Of continuous traits. Phenotype dependent on alleles at different loci. There are many loci each with two alleles. The more genes that play a role in a phenotype, the more individuals found at center of distribution.

Question 26

Discrete/discontinuous multifactorial traits

Can be conceptualized using the ________. Describe.

Answer 26

No spectrum. Either have disease or not.

Polygenic threshold model. Certain alleles provide risk but trait only emerges when the risk passes a certain threshold based on genetic and environmental factors.

Question 27

Tools for allele identification

Answer 27

• Linkage analysis and association analysis
• Examine tendency of markers to be linked (transmitted with) certain disease alleles. Based on fact that likelihood of recombination between two loci decreases as distance between them decreases. So markers that are close to an allele of interest will be found more often in people with that allele

Question 28

Linkage analysis requires?

Genome-wide association studies use?

Answer 28

• Family pedigree

- Population data