Post Exam 2 Flashcards
What is GWAS?
genome wide association studies
What genetic/genome change causes cancer?
initiation and perpetuation of cell generation
What are 3 examples of ways mutations are inherited?
- autosomal
- x/y linked
- mitochondrial
What is a monogenic disease?
one gene involved (mendelian)
what is a polygenic disease?
multiple genes involved
How do we determine the gene causing a disease?
sequencing the genome or sequencing the exomes
what are 3 locations mutations can be in the genome?
coding
noncoding
regulatory regions
what are 2 reasons we want to know what gene causes a disease?
screening purposes
potentially drugable targets
What is the goal if GWAS analysis?
identify genotypes (mutations in genome) assocaited with specific phenotypes (disease)
What are 3 genotypes for a diease?
copy number variance
sequence variants
single nucleotide polymorphisms (SNP)
What is an example of sequence variants?
chromosome rearrangements
What is the output of GWAS analysis?
block of SNPs (haplotype: set of SNPs from one parents inherited together)
what 2 ways can findings from GWAS be used?
- design drugs/treatment
- asses risk using polygenic risk score
What is a polygenic risk score?
aggregate the association of many SNPs to find a percentage of risk for a certain disease
How do you interpret a manhattan plot?
each dot is a SNP and shows the association each SNP has to a specific trait/disease
GWAS studies determine ____________ of specific SNPs and how they ___________ with that trait of interest
frequency
association
What are the 3 biases of GWAs studies
- pt self reporting
- data collection @biobanks
- sample types
How is data being collected at biobanks biased?
in hospitals have sick people
blood drives skeew demographics
How is sample type a bias?
tumors have different DNA than regular tissue
blood bias against people who dont like needles
saliva has lots of contaminant
What is collecting new SNPs mainly for?
studying phenotypes
What is trio sampling?
samples from mom, dad, and offspring
What is the advantages of trio sampling?
gives more context b/c you will know if SNPs in offspring you are study is from mom or dad
What is genotyping?
exploring an individuals DNA
Why are microarrays good?
cheaply generate data
What are microarrays good at detecting?
common variance
what do microarrays measure?
hetero/homozygosity
What is an issue with microarrays?
must know what SNP you are looking at
What are the steps of microarrays?
- DNA collection
- break DNA into fragments
- run fragments over chip
- hybridize DNA fragments
- DNA fragments stop one nucleotide short of the SNP of interest
- add base at end of fragment
- look down at chip once fluorescent dye is added
What does the red/green dye mean in microarrays?
homozygous
what does the yellow dye mean in microarrays?
heterozygous
What is whole genome sequencing better at?
detecting novel variance
How does exome sequencing work?
hybridize DNA and RNA together then degrade RNA so you are only left with DNA
Cystic fibrous tissue is found where besides the lungs?
pancreas and sweat glands
salty ___________ is a leading diagnosis for CF
salty babies
what does the panceras do?
secretes bile to break down food
people with CF have an ____________________ insufficiency
exocrine pancreatic insufficiency
Is CF a multiorgan disease?
yes
CF is related to an _________ imbalance
ion (salty babies)
From the 1930-80s what was the treatments for CF?
focused on treating symptoms
In the 80s what was discovered about CF?
positional cloning to identify chromosomal regions containing CF gene
CF gene is an __________ recessive gene, making it easily readable on a pedigree map
autosomal
_________ genomics was used to narrow down the regions on the chromosome that were important for CF
comparative genomics
T/F cultured cells from CF patients still had an ion imbalance?
true
What was identified in 1989 in CF research?
CTT deletion (Phe at 508 in protein CFTR)
Around __/__ of CF patients had the CFTR mutation
2/3
What is the CFTR responsible for?
it is an ABC transporter that transports C1
What region of the genome is the CFTR mutation located?
nucleotide binding region
What is a current treatment for CF?
trikalta: cocktail of 3 small molecules that bind to CFTR and mediate C1 transport
Why are males with CF infertile?
thier vas deferns gets clogged with mucus and deteriorates
Now all new borns are tested for CF, how?
genetic testing and sweat conductance test
trikalta is only approved for who?
patients with f508
what is the treatment for patients not approved for trikalta?
using thier stem cells to generate organoids
heterozygous or homozygous mutations are lethal?
heterozygous
what is MIOM (mendelian inheritance of man)
record of all genes that were auto-dominant, auto-recessive, x-linked, y-linked, mitochdrial
also has a standard nomenclature of diseases
what is a aneuploidy ?
the abnormal number of chromosomes
what is cytogenetics
field of studying chromosomes
what are 3 aneuploidy diseases?
- patau syndrome (13)
- edwards syndrome (18)
- down syndrome (21)
most chromosomal trisomies are a result of ______________
non disjunction
when are chromosomal abnormalities usually detected?
in utero
what is amniocentesis?
taking embroy’s cells
What is ataxia telangiectasia?
disease where you have a hypersensitivity to radiation and genotoxic drugs
what is p53?
tumor supressor gene
What does ATM detect?
double stranded breaks
infectious diease has been decreasing but cancer has been __________
increasing
What did Theodor Boreri suggest?
cancer was chromosomal
a ________ set of mutations can induce cancer
small
cancer is a disease of the _______
genome
what are the two types of cells?
somatic and germ line
what type of cell has a variety of life spans?
somatic cells
cell death and birth is very ____________
regulated
What are neoplasm/tumors?
cells that give rise to progeny with uncontrolled growth
are carcinomas or sarcomas more common?
carcinomas
what tissue is carcinomas from?
epithelial skin, lung, gut
what tissue is sarcomas from?
bone, fat mesodermal
what cancer is leukemas?
blood
what are lymphomas?
diff. lymphocytes
what are mylomas?
plasma cells B cells
what is ataxia telangiectasia caused by?
mutation in DNA replication and repair
what is helicobacter pylori?
bacteria that causes stomach cancer
mutations that lead to transformation are assocated with what 3 types of genes?
- oncogenes
- tumor suppressor genes
- apoptosis related genes
What do oncogenes do?
promote cell growth
what do tumor suppreesor genes do?
suppress cell growth
what do apoptosis related genes do?
control cell death
What are 6 hallmarks of cancer?
- self sufficency in growth signal
- insensitivity to antigrowth signals
- evading apoptosis
- limitless replication
- angiogensis
- mutastasis
what are driver mutations?
DNA sequence of genes that cause cells to become cancer cells and grow and spread in the body
what are passenger mutations?
those which do not alter fitness but occurred in a cell that coincidentally or subsequently acquired a driver mutation, and are therefore found in every cell with that driver mutation. (no functional consequences)
how does radiation treat cancer?
induce DNA damage to initate apoptosis
how does chem treat cancer?
induce DNA damage to initiate apoptosis
what are alkylating agents?
crosslink DNA damage to initiate apoptosis
what are antimetabolites?
chemically resemble nucleotides
what are antimicrotubules?
block cell cycle
what 2 things inhibit cancer treatment?
topoisomerase
angiogenesis
what 3 things are involved in triple negative breast cancer?
estrogen receptor
progesterone receptor
HER2
How is cancerous estrogen receptors targeted?
with tamoxifen (competes with ER and blocks cell growth)
How is cancerous HER2 targeted?
with monoclonal antibodies that adds a toxin to HER2
why is neoadjuvant chemotherapy/surgery (personalized med) bad?
very toxic, only works half the time
how does single cell sequencing work?
1.remove single cells form a tumor
2. one cell per plate
3. add a barcode (8-10nt long) to each plate
4. mix together
5. NGS
6. use barcode to deconvolve
What is the process of single cell sequencing?
- remove single cells from tumor
- add one cell per plate
- add a barcode (nt fragment) to each cell
- mix
- NGS
- use barcode to deconvole
what is intratumor heterogencity?
individual cells can accumulate thier own mutations
what are 2 options for chemoresistant cells?
- chemoresistant cells were present all along (not all died off or they were able to adapt)
- chemotherapy caused these cells
What are the challenges of gene therapy?
- so many cells
- how do we get the new DNA in
- need to understand the exact problem
- safety
- expensive
what 3 genes/diseases work best for gene therapy?
- heritable genes
- monogenetic diseases
- tissue specific disease
what are 3 advantages to using lentivirus for gene therapy?
- infect dividing and non dividing cells
- can permanently integrate into host genome
- carry long pieces of DNA
what is a disadvantage of using lentiviruses?
inserts randomly into genome and leaves some viral genome behind
What is Zynteglo?
treatment for B-thalassemia using lentivirus carrying a functional hemoglobin
what are 3 advantages to using adeno-assocaited viruses?
- non pathogenic
- infect dividing and non dividing cells
- stably integrate into one place
what is a disadvantage to using adeno-assocaiated virus?
carries small pieces of DNA
What is Zolgensma?
treats spinal muscular atrophy using adeno-associated virus carrying a functional SMN1
Who was Jesse Gelsinger?
1st person to die in a clinical trial of gene therapy; has orthinin transcarbamylase deficency (OTC) which results in a build up ammonia
why is it easy to place treated blood back in body for therapy?
all RBC come from stem cells so they are being regenerated all the time
What are CAR T cells?
detect cancer cells by binding to cancer/diease protein
What are CAR T cells built in with?
suicide switches that can be injected into pt
what are 3 goals of forensics?
establish paternity
identify remains
implicating suspects
what is DNA fingerprinting?
(aka STR profiling) identifying series of short tandum repeats
How does DNA fingerprinting work?
look for key STR in a suspect for a list of 13 STR and how many repeats occur
Why do you not use gel electrophoresis for DNA finger printing?
use capillary because its more precise
what genetic geneology?
using publicly available genetic data base to find relatives of sample (caught the golden state killer)
What will tell you what tissue your sample is?
look at transcriptomes (microarray)
How is measuring microbiomes helpful in forensics?
each person has thier own
time of death
