Genetics 3 Exam

also uses

CNV, gene expression

several genomic approaches to studying cancer

GWAS- cancer genetic markers of susceptibility large-scale sequencing of cancer genomes exome sequencing ctDNA

most common type of marker used in GWAS

SNPS, different in population more than 1%

Genome wide association studies (GWAS): 1) use statistics to find SNPs that are more likely to be present in people with a particular disorder than in people without the disorder 2) can uncover novel mutations that are at the root of Mendelian diseases 3) are very effective at identifying disease causing mutations as long as the population is big enough

1

The Florida Autism and Developmental Disabilities Monitoring Project studies Autism and related disorders in Florida. In 2008, in a single county in FL, Miami Dade, 7.2 out of every 1000 eight-year olds had Autism Spectrum Disorder. This is an example of: 1) prevalence 2) incidence 3) empiric risk 4) odds ratio

1

in total ___% of births are result of Mendelian diseases

1

parent to child

1 degree 50%

sibling to sibling

1 degree of relatinship 50% how much DNA you share

limitations of GWAS

1) associations not causes 2) small impact of each risk factor 3) risk of false positive result

empiric risk increases with what

1) severity of disorder 2) number of affected family members 3) how closely related

BRCA1 and 2

1/8 women will develop breast cancer if inherit one copy of mutation more liekly to acquire cancer are another mutation allow mutations in other genes to accumulate

cancer stats

10 million new cases diagnosed annually worldwide 1/2 men and 1/3 women in US develop cancer 68% 5 year survival rate for all cancers

exome sequencing is reveling

100s of rare variants in protein coding region that can affect health 315 genes per genome have rare variant 100 loss of function variants 20 genes compeltely inactivated

What factors should play a role when evaluating a 55 year old female patient's risk for the common, multifactorial disorder osteoporosis? Select ALL answers that apply. 1) Coefficient of relatedness for affected family members 2) proportion of women in their fifties who are diagnosed with osteoporosis 3) racial/ethnic background of individual 4) lifestyle factors such as diet

1234

A GWAS on Barrett's Esophagus (BE) reports a risk factor with an OR of 2.5. What does this mean? 1) if you inherit that risk factor, you have a 2.5 % chance of developing BE 2) An individual who inherits that risk factor has a 2.5 increased risk of developing BE than someone without the risk factor 3) If one inherits the risk factor, he/she will develop BE in 2.5 years 4) 2.5% of the population has BE

2

grandparent to granchild

2 degree 25%

uncle aunt or niece/nephew

2 degree 25%

In 2012 in the state of Florida, 32 out of every 100,000 people were diagnosed with colorectal cancer. This is an example of: 1) prevalence 2) empiric risk 3) incidence 4) coefficient of relatedness

3

first cousin to first cousin

3 degree 12.5%

estimate that alterations in

3-7 genes are needed to acquire halmark of cancer

At a broad level, all cancers have a defect in: 1) DNA replication machinery 2) the formation of mitochondria 3) the cell's ability to extract energy from nutrients 4) cell cycle control

4

If you plot out the BMIs (body mass index) of a population of individuals, we would expect to get a bell-shaped curve. Based on this distribution alone, what do we know about the genetics of body mass index? 1) BMI is controlled by a single gene 2) BMI is controlled by the action of more than one gene, each with an equal contribution 3) BMI is not under genetic control 4) BMI is controlled by the contribution of more than one gene, each with varying degrees of impact

4

In Alzheimer's Disease, tangles are formed: 1) When beta amyloid fragments clump together 2) When ApoE4 is not exported from the cell 3) When microtubules clump together 4) When tau no longer supports microtubules

4

DNA repair genes

repiar spontaneous erros made normally during the DNA replication process accumulation of mutations and drastically increases the likelihood of cancer

polygenic traits

result of actions of more than one gene ex) eye color

multifactorial traits

result of genetic and environmental factors

quantitative traits QTLs

result of many genes and they vary in phenotype- display continuous variation height, weight, skin color, cholesterol levels quantitative trait loci many specific qtls remain unknown

The SNP with the higher frequency in the case group is called a _____________ or _________ and is associated with the disease

risk factor risk allele

exome sequencing

sequencing just the 3% of the genome that are protein coding 3% of genome success for mendelian disorder gene mapping- now to complex diseases

cell free tumor DNA

small pieces present in the blood cells of patients nonivasive approach amount correlates with cancer stage detction, staging, guide treatment (is it decreasing) liquid biopsy

traditional treatment

surgery, radiation, chemotherapy use phenotype to select drug, use genotype to select rug- using genotype, use gene expression profile from microarray

new studies say focus of AD should be

tau protein

What must GWAS use

thousands of markers large sample size

growth factors

trigger and control cell cycle bind to receptors in plasma membrane of cell trigger entry into next phase of cell cycle signal transduction pathway

hallmarks of cancer

uncontrollable growth evasion of growth suppressors evading cell death ontaining nutrients becoming immortal invading tissues escaping immune desctriction reprogramming metabolism promoting genomic instability tumor promoting inflammation

genome wide association studies (GWAS)

used to track down genes associated with multifactorial diseases difficult to identify no clear pattern of inheritance need big population of individuals- 1/2 have disorder studying

GWAS used to indentify several other risk factors

SNPs with very small odds rations CALHM1- controls amyloid cutting TREM- promotes

sporadic cancer

a somatic cell has acquired necessary mutations to induce tumorigenesis most of cancer we see

quantitative traits look like a

bell shaped curve

plaques

beta-amyloid plaques enzymes incorrectly cut amyloid proteins into pieces beta amyloid proteins clump and form plaques memory and decision process unknown if cause or product

two main abilities of cancer

cells proliferate uncontrollably ability to spread to other tissues

what drives cancer

changes in the gene that changes the cell- cell cycle disrupted

main causes of cancers

chemicals radiation heredity infectious agents affec the cell at the genetic level- alter that function or expression of our genes

characteristics of multifactorial diseases

child in isolation no simple pattern of inheritance (can be a family history) environmental factors influence severity, age of onset, efficacy of treatment more frequently in one gender but not sex linked particular ethnic group frequency symptoms treated hard to address root cause

common disease, common varient

common genetic variants that have a small effect on the phenotype analyze lots of individuals with and without disease to identify patterns more frequent in individuals with disease- associated with the diease not causation, just association

personalized cancer genomics

compare a patient's tumor genome to compare it to their healthy tissue genome precision medicine

GWAS Success

complex conditions: macular degeneration, cancer, diabetes, inflammatory bowel disease, CV disease OR is usually very low makes no assumptions and unbiased

multifactorial traits are also called

complex traits

each gene confers a ______________ not necessarily the

degree of susceptibility same level of susceptibility

neoplasia

disorganized tissue growth net increase in number of didvidng cells proliferating mass of abnormal cells is a neoplasm in cells lost balance between porliferation and differentiation dedifferentiated cells

escaping immune destruction

don't display normal cell proteins no normal cell features- can escape detection no surface molecules, swallow surface molecules, suppress immune system- deactivate helper t cells pdl1 or pdl2- suppresses activity of T cells- drug designed to block extracellular surface markers

10 hallmarks doesn't directly emphasize is

gene expression- some of alterations are due to level of expression in gene microarray expression patterns reveal unique gene expression patterns of cancer

SNPs common in colon cancer patients are colon cancer _______________

gene markers

multiple genetic changes are necessary to develop cancer

gradual accumulation of mutations in somatic cells risk increases as we age

benign

grow in a confined area

becoming immortal

grow indefintely- maintain telomeres- a lot genes only usually expressed in embryogenesis few years ago- magic bullet to inactivate telomerase

SNPs is within its

haplotype block can be: cause of a disease linked to another SNP in a gene that contributes to the disease- most common

risk factors similiar to those for AMI and stroke

high blood pressure high cholesterol lack of physical activity low dietary folic acid lack of mental acitivty

tumor-promoting inflammation

immune response in inflammation immune cells can release growth factors, reactive oxygen species- can cause even more mutations

cancer cells divide rapidly often

in absence of growth factors may make their owns

empiric risk is based on observations of

incidence in population gender family history- other affected family members

OR= Odds Ratio=

increased risk of having disease if you have one of the risk factors

malignant

invade surroudning tissues and spread via metastatisis usually what cancer means

usually very low

less than 2.0 2 times more likely to develop that disease as compared

HapMap Project

map all of the common SNPs in the human genome HGP common patterns of DNA variation, ancestry, diseases

tangles

microtubules provide support structure for neuron tau- little porteins that provide stability tau tangles and microtubule is not support

individuals who inherit two copies of the ApoE4 allele are ____ likely to develop ___________ Alzheimer's disease, which is a ______________________.

more late onset multifactorial disorder

SNPs

most common type of genetic variation 38 million sites 1 SNP/100-300 mostly harmless, non-coding regions

most common, chronic diseases are

multifactorial

most carcinogens are

mutagens

obtaining nutrients

needs lots of fuel angiogenesis induce blood vessel growth to deliver nutrient to the tumor vegeta proteins

reprogramming metabolism

new organelles and amino acids

proto-oncogenes

normal trigger cell division wrong place or time- oncogenes dominant gain of function mutation 50% of human tumors

tumor suppressor genes

normally control or block cell dibision putting breaks of cell division typically recessive lose function cannot prevent cancer

if a SNP frequency is the same in the cases and controls, then the SNP is _______________ with the disease

not associated

three types of genes targets

oncogenes tumor suppressor genes DNA repair genes

invasion and metastasis

overcome inhibitory signals and invade other tissues requires expression of many genes drill through basement layer, few cancer cells nonrandom- different types of tumors have different metastatic routes

skin color

quantitative trait skin color doesn't represent genetic relationships should base info on ancestry and not skin color

incidence

rate that a certain event occurs in a population ( number of new cases of a disorder diagnoses per year)

Exome sequencing is: 1) Sequencing just the exons of a genome 2) Not a viable method for identifying genes that cause Mendelian disorders 3) A new sequencing technology that uses a device called an exome 4) Sequencing everything but the exons of a genome

1

Jane's mother had Familial Adenomatosis Polyposis (FAP), a colon cancer syndrome caused by mutations in the APC gene. Jane has been diagnosed with colon cancer and analysis of the cancer cells indicates that they have the mutated APC gene. Jane's colon cancer is most likely: 1) a result of a sporadic mutation in APC 2) a result of Jane's smoking habit 3) the result of a mutation in the APC gene that is only present in the colon cells 4) a result of a germline mutation in APC

4

Which technique has the most potential to identify the specific mutation that causes a genetic disease? 1) Empiric Risk estimation 2) Coefficient of relatedness testing 3) GWAS 4) Exome Sequencing

4

early onset alzheimer diseasse

40-60 runs in families very rare- less than 1% autosomal dominant pedigree analysus of families- APP PS1 and PS2 50% chance of passing phenotype onto child mutations in APP- amyoid precursor protein- more common beta-amyloid peptides- form plaques, APP mask the normal cleavage sites gain of function- monkey wrench

exome sequencing the answer?

88% of genetic disorders are due to variants that occur in the coding regions altering gene expression- SNPs in promoters, splic sites, epigenetics- won't be helpful for, might miss copy number variants

late onset AD

95% complex disease each genes carry a small risk ApoE4 allele carries cholesterol in the bloodstream- 20-30% of population, 40% of Alzheimer patients neuron repair and maintenance- least effective 76% of LAD due to genetic factors- 50% of that is ApoE4- 25% is geterozygous- 4 times more likely 2% of population homozygous for APOE4- 10 times more likely many people with don't develop AD who have ApoE4,

who is more likely to have AD

AA and Latino women (2/3)

cell cycle checkpoints

DNA damage checkpoint, apoptosis checkpoint, spindle assembly checkpoint when start ignoring, lose control of cycle- cancer

AD

Mendelian disease (early onset) and multifactorial genetic disease (late onset)

promotes genomic instability

acquire mutations genomes differ unstable genome replication mistakes, mistakes during meiosis, defective DNA repair- now even more mutations can accumulate

evading cell death

evade apoptosis p53 is the gatekeeper for apoptosis- triggers in response to DNA damage and other signals- kind of a tumor suppressor gene most studied human protein "guardian of the genome"- p53

uncontrollable growth

even in absence of growth signals external growth factors can make 25-50% Ras proto-oncogene

germline cancer

every cell in an individual has a variant that increases susceptibility inherited form of cancer childhood cancers- retinoblastoma

ex of exome sequencing in multifactorial diseases

familial hypolipidemia- low LDL cholesterol new function for gene

next step after finding risk factor

find actual gene that is contributing to disease

evading growth suppressors

pRB- retinoblastoma protein- muations lead to a loss of function- 2 mutations 1 in each allele to knock out pRB function-recessive 90% of people with retinoblastoma are cured deletion of chromosome 13- first tumor suppressor gene to be identified if inherit- usually inherit a cell with 1 mutation in tumor suppressor gene- may take a hit that knocks out functioning alleles- 90% of babies born with 1 hit will get tumor

mendelian disorders are mapped through

pedigree analysis

two hallmarks of alzheimers

plaques and tangles

empiric risk is based upon

population observations

each of 10 hallmarks is a

potential target for cancer treatment

prevalence

proportion of individuals in a population that has a particular disorder at a specific time period