Genetic Variation Flashcards
MUTATION
•Mutations are the source of genetic variation
•
•Can be silent, beneficial or harmful
TYPES OF MUTATIONS
Table Slide 3
INSERTIONS & DELETIONS
LARGE AND SMALL
•Can be as small as a base or two
•i.e. common BRCA1/2 mutations
•
•Can encompass the entire gene or close to it
•i.e. Duchenne muscular dystrophy
IN-FRAME AND FRAMESHIFT
TRINUCLEOTIDE REPEATS
TRINUCLEOTIDE REPEAT EXPANSION
•
___ ____leads to excess number of repeats
•
_____ a certain range, extra repeats are harmful
Can happen in____ or ____
•
•Polymerase slippage leads to excess number of repeats
•
•Above a certain range, extra repeats are harmful
Can happen in middle of exon or in promoter
HUNTINGTON DISEASE
___ repeat
Expands when passed on by ____
More repeats= ___ ____
CAG repeat
Expands when passed on by father
<= 26 normal
27-35 intermediate: risk of expanding into disease causing range in offspring. You still okay
36-39 Reduced Penetrance: may or may not develop signs
> = 40 Full penetrance
More repeats= earlier onset
SPLICE-SITE
GU-Intron-AG
Intron Retention
Exon Skipping
sometimes protein fcnal
SPLICE-SITE MUTATION
Intron retention: GU affected
Exon skipping: AG affected
CRYPTIC SPLICE SITE (exon)
new splice site created due to mutation
in exon–> exon skipping. new GT site in exon
in intron: intron retention: new AG site in intron
POLYMORPHISMS
•Variation that occurs in at least __% of the population
•
•Can be located within a ___ or___ of a ___
Types
-
_ _ _ _
- ___ ___ ___ ____
- Located in ______ (______ bps)
- ___ ___ ____ ___
- ___ ___ __ ___
- Located in ____ (____ bps)
IN satellite areas of repetitive DNA you can have anywhere from____ bses that get repeated over and over with ____ number of repeats
- ___ ___ ___
- ___ ____ ____
- ____ portions (__-__)
Missing or extra part of csome.
- •___ ____ ____
- •A ___ base of DNA
- •Variation that occurs in at least 1% of the population
- •
- •Can be located within a gene or outside of a gene
- Types
- •STRPs
- •Short tandem repeat polymorphism
- Located in microsatellite (2,3,4 bps)
- •VNTR
- •Variable number tandem repeats
- Located in minisatellite (10-100 bps)
IN satellite areas of repetitive DNA you can have anywhere from 2-100 bases that get repeated over and over with variable number of repeats
- •CNPs
- •Copy number polymorphism
- •Chromosomal portions (200bp-1.5Mb)
- Missing or extra part of csome.
- •Single nucleotide polymorphism
- •A single base of DNA
SNPs
•Some have ___ ____
•
•Can be ___ ____ of disorder OR contribute to ___ ___
Linked SNPS: ___ of a gene. __ effect on ___ ____
Causative SNPS: __ ___
___SNP: ____ seq. Changes ___ of protein
___ SNP: ____ region. Changes ___ seq
•Some have no consequence
•
•Can be directly causative of disorder OR contribute to disease risk
Linked SNPS: outside of a gene. No effect on protein production
Causative SNPS: in gene
Noncoding SNP: regulatory seq. Changes amount of protein
Coding SNP: coding region. Changes aa seq
GWAS
Compare ____ and ____ DNA to discover snps ____ with diseases.
look at snps at ____ of locations
If patients have a snp ___as frequent as nonpatient then you can say ______________
Just an ___
Done in ____
____ avialable now
Compare paitent and nonpatient DNA to discover snps associated with diseases.
look at snps at tons of locations
If patients have a snp 2X as frequent as nonpatient then you can say that if you ahve the snp you are 2X as likely to get disease
Just an association
Done in periodontitis
Cloinally avialable now
LATE ONSET ALZHEIMER’S DISEASE (LOAD)
- Characterized by dementia, memory loss and gradual loss of function
- Death usually caused by pneumonia or malnutrition
- Onset is >65y
____ allele associated with i___ ___k, BUT ___ ___ ___
There are people with a____s without ___ andd _______
•Characterized by dementia, memory loss and gradual loss of function
•
•Death usually caused by pneumonia or malnutrition
•
•Onset is >65y
•
•ApoE4 allele associated with increased risk, BUT NOT DIRECTLY CAUSATIVE
There are people with alzehimers without allele and vise versa
HOW DO GENE MUTATIONS OCCUR?
- DNA replication errors
- Proofreading mechanism catches _____% of errors
- Overall mutation rate is ____ per ____ ____ per ____ ____
- DNA repair errors
- Caused by ___ ___, ____, etc.
- Often result in ____ changes to the DNA sequence
- DNA replication errors
- Proofreading mechanism catches 99.9% of errors
- Overall mutation rate is 10-10 per base pair per cell division
- DNA repair errors
- Caused by chemical mutagens, radiation, etc.
- Often result in permanent changes to the DNA sequence
DNA REPAIR MECHANISMS
SINGLE-STRANDED
__ ___ ___
___ ___ ___
___ ____
DOUBLE-STRANDED
___ ____
___ ___ ___ ___
SINGLE-STRANDED
•Base excision repair (BER)
•
•Nucleotide excision repair (NER)
•
•Mismatch repair
(MMR)
DOUBLE-STRANDED
•Homologous recombination
•
•Non-homologous end joining (NHEJ)
•
BER
____ is removed from ___ ____ (deoxyribose)
•Then ___ with correct base
- Base is removed from DNA backbone (deoxyribose)
- Then replaced with correct base
NER
•
__ ____ including___ ___ must be removed
•
____- _____ and _____ genes are important in NER
•
•Entire nucleotide, including DNA backbone must be removed
•
•XPA-XPG and ERCC1 genes are important in NER
MMR
___ and _____complex ___ ___ and ___ the ____ (___ ___ __ ___)
Genes involed are ___ ____ ___ ____
Germline mutation in these causes___ ___ ___ called ___ syndrome. Increased risk for ___, __ and __ cancer
Mut S and Mut L complex recognize mismatch and recruit the machinery (endonuclease, helicase, poly, ligase)
Genes involed are MLH1 MSH2 MSH6 and PMS2
Germline mutation in these causes heretiary cancer syndrom called Lynch syndrome. Increased risk for colon, endometrial and stomach cancer
CONSEQUENCES
______
•Can be ____or____ mutations in genes that control:
___ ___
___ ____ ____
___ ____
_____
•CANCER!!!
- Can be somatic or germline mutations in genes that control:
- DNA repair
- Cell cycle check points
- Growth promotion
- Apoptosis
ONCOGENESIS
TUMOR SUPPRESSOR: _____
___or ___
•Regulate__ ___, ____, or ___ ___ ____
•___ ____ must be mutated before cancer results
Wont ___ ___ but they are there to ___ it ___ ____
ONCOGENE: _____
•Activation causes ___ ___ ___ and ____
•Induce ___ ____and____ ____
____________needs to be mutated to cause problems
Not supposed to be ___. Get turned __ due to a ____
TUMOR SUPPRESSOR: brakes
•“Gatekeepers” or “caretakers”
•
•Regulate cell cycle, growth, or DNA damage repair
•
•Both copies must be mutated before cancer results
Wont cause cancer but they are there to prevent it from happening
ONCOGENE: accelerator
•Activation causes abnormal cell division and proliferation
•Induce growth factors and suppress apoptosis
•Only one copy needs to be mutated to cause problems
Not supposed to be expressed. Get turned on due to a mutation
TWO-HIT HYPOTHESIS (KNUDSON’S)
Sporadic cancer:
Cencer predisposition syndrome (germline)
Sporadic cancer: start with 2 normal copies
Cencer predisposition syndrome (germline) start with 1 hit. Get cancer at earlier age
XP, Lynch
ONCOGENESIS
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
- Colon cancer is inevitable without colectomy
- Caused by mutations in ___ gene: ___ ___ ___
- Polyps begin to develop at ___y, on average
•Dental abnormalities in __% of patients
__ ____
___ ___
____
___ ___
•Colon cancer is inevitable without colectomy
- Caused by mutations in APC gene: tumor suppressor gene)
- Polyps begin to develop at 16y, on average
•Dental abnormalities in 17% of patients
•Tooth agenesis
•
•Supernumerary teeth
•
•Odontomas
•
•Dentigerous cysts
MEN2
- MEN2A
- Medullary thyroid carcinoma
- Parathyroid hyperplasia
- Pheochromocytoma (on adrenal glands)
•MEN2B
•Medullary thyroid carcinoma
•Pheochromocytoma
___ __ (___ ___ on ___)
•Marfinoid habitus (long skin lanky bodies)
•
•Familial Medullary Thyroid Carcinoma (MEN2C)
•Caused by mutations in ____
•MEN2A
•Medullary thyroid carcinoma
•Parathyroid hyperplasia
•Pheochromocytoma (on adrenal glands)•MEN2B
•Medullary thyroid carcinoma
•Pheochromocytoma
•Muscosal neuromas (bumpy lesions on tongue)
•Marfinoid habitus (long skin lanky bodies)
•
•Familial Medullary Thyroid Carcinoma (MEN2C)
•
•Caused by mutations in RET
