1. Genetic Basis of Disease and Cancer Flashcards

1
Q
Genetic basis of disease
• Genetics
– \_\_\_\_% difference between individuals
– Traits
– Alleles
– Continuous Variation
• 1 in 500 bp is diff bt each of us - small amount of change > allows us to be a  \_\_\_\_ species and to be important for survival
	○ Allows us to develop a bigger cortex, adapt, walk upright, etc.
	○ Sometimes these changes are not adaptive > genetic disorders
• Traits - genetic thing, not the genes themselves, they're the things you can observe - the \_\_\_\_ you try to link to a genetic change
	○ Some are simple - rolling your tongue (genetically \_\_\_\_) - one gene that causes it - progresses in a mendelian fashion
• Alleles - everyone has two copies of chromosomes (46, 23 autosome pairs, and XY/XX); each gene has potential to have two copies; alleles are variations of that same gene
	○ A gene can have multiple \_\_\_\_ (some have 5), and some have no alleles (critical - any change in them leads to nonviable offspring)
	○ Things that are different bt two genes - most of them should not dictate survival, unless they have one covering (one good one)
	○ Some lead to dysfunction - they "work-ish"
• Continuous variation - the two above are mendelian genetics (two, one from dad and mom) - one of the kinds of traits that you don't see in \_\_\_\_ fashion
	○ \_\_\_\_ - height
	○ \_\_\_\_-shaped curve, majority in average range, and then there are extremes
	○ Blood pressure is another example
A
0.5
diverse
physical manifestations
dominant
alleles
medielian
quantifiable
bell
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2
Q
MEN 2B
• Multiple Endocrine Neoplasia 2B
– Mucosal \_\_\_\_ on tongue and lips
– \_\_\_\_ cancer (2-3 yr)
– Pheochromocytoma
– \_\_\_\_, loose joints, long face (\_\_\_\_)
	• Neuromas - suggest that person is at higher risk for MTC/PC - fatal if not treated
	• Genetic disorder that manifests in the oral cavity
A

neuromas
medullary thyroid cancer
hypotonia
marfanoid

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3
Q

Genetic Variations

 Mutation-mediated Protein Coding changes
– \_\_\_\_ mutations
– non-sense mutations
– \_\_\_\_
– Trinucleotide repeats
– \_\_\_\_ polymorphisms
-Nonmutational protein changes
– \_\_\_\_polymorphisms
– \_\_\_\_ variations 
– Epigenetics
– \_\_\_\_ RNA
• Change can be single nucleotide change, expansion, deletion, region that's flipped around, etc.
• SNP - all over the genome - used to search across populations of people > here's what's genetically at risk for disease > \_\_\_\_ studies
	○ Look at SNP, and which allele is a risk allele
	○ Missense > wrong AA (within the ORF)
	○ Non-sense > stop codon
	○ FS > usually ends up in a \_\_\_\_ codon, but shift the three > making completely different peptide
	○ Silent > end up having the same AA put in
• CNV > can be small or can be big
	○ Make up \_\_\_\_% of differences bt individuals - underlies most of the issues > bc of coding sequence changes, and finding in parts of genomes where it changes stability and processing
	○ Small > 2 bp > dinucleotide repeats; and trinucleotide > repeat same 3 bp again > you repeat the same AA > large expansion with the same AA inserted into protein
	○ Long copy variation > millions of bp > whole genes that you have repeated
		§ Some things have multiple genes > \_\_\_\_ and nervous system
A

missense
frame-shift
single nucleotide

single nucleotide
copy number
non-coding

genome wide association
stop
50
immune

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4
Q

• Non-mutational protein changes > once its fixed and passed on it isn’t mutated anymore
○ First time it happens it’s a ____, and once it’s fixed it’s an ____
○ Some occur in coding sequences > so they’re mutational
○ Majority in ____ regions > promoter regions, intergenic space, 3’ UTR region, introns
○ Epigenetics - don’t occur within sequence of DNA, but modifications that are ____
§ Cloning of Dolly - nucleus of a cell that’s not a germ cell > sheep wasn’t quite normal, the DNA from mom and dad is marked (one from sperm/egg) and they’re methylated > tells the cell which parent the allele came from; some traits you’ll only express from mom or dad
○ Non-coding RNA (tRNA, rRNA)
§ miRNA > when made they form ____ to existing RNA > change expression of existing mRNA by binding and inducing degradation (____)
§ Long-non-coding RNA > changing ____ how gene is expressed; or own enzymatic functions

A
mutation
allele
non-coding
heritable
antisense
post-transcriptionally
transcriptional machinery
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5
Q

Mendelian Genetics

• Autosomal Recessive Traits
• Autosomal Dominant Traits 
• X-linked Traits
• Single gene mutations 
– Missense
– Nonsense 
– Frameshift
• Pleitropy
• Modifier gene
* AD/AR > \_\_\_\_ chromosomes (1-22)
* X-linked > on X chromosome
* Pleitropy - single genes can affect multiple \_\_\_\_
* Modifier genes - other genes affecting the \_\_\_\_ of select genes; makes the difference bt you and your \_\_\_\_
A

non-sex
traits
functionality
sibling

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6
Q
Autosomal recessive
• Both parents are unaffected \_\_\_\_
• Men and women are \_\_\_\_ affected
• \_\_\_\_% chance of disease transmission
• \_\_\_\_ mating increases incidence
• Usually \_\_\_\_ disorder due to loss of enzyme function
• 2 parents are heterozygous (unaffected, do not see the trait in them)
	○ 1/4: homo dom; 2/4: hetero; 1/4: affected (homo rec)
• Less of them in the population; and increase in chance where you marry within the community (Pennsylvania Dutch) > develop polydactyly
• Usually an enzyme dysfunction and therefore a metabolic disorder > make \_\_\_\_, oxidative phosphorylation > w/o you don't survive; but if you have one copy of enzyme it's enough
• Male = square; females = round
• Genetic counselor > take parents genome > look at sequence for gene at risk > identify the risk for the proband (unborn child) > here the risk is 25%
A
carriers
equally
25
consangineous
metabolic
pigment
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7
Q
Block in metabolic activity
• Usually \_\_\_\_% of enzyme is enough,
• Defect can be due to
– not enough \_\_\_\_ from enzyme
– Toxic \_\_\_\_
– Toxic \_\_\_\_ accumulation from alternate pathway
• Most recessive mutations > block in metabolic activity
• Block in enzyme > no D > cannot function
	○ Now you have too much C > and then another enzyme makes E and too much F
	○ Intermediates are usually \_\_\_\_ > don't normally see them
A
50
product
intermediate
bi-product
transient
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8
Q
Phenylketonuria
• Common in \_\_\_\_
• Defect in \_\_\_\_
• \_\_\_\_ Skin
• \_\_\_\_
• Severe Mental \_\_\_\_
– 2/3 Cannot walk or talk
• \_\_\_\_ and neurologic abnormalities
• Develop cognitive impairment
• Pathway where phenylalanine is converted to \_\_\_\_ > fumarate and acetoacetate
• Tyrosine makes \_\_\_\_ > pigments in skin and hair/eyes > protect us from the sun
• Have defect in P hydroxylase > no tyrosine and cannot make \_\_\_\_
	○ Don't need melanins in terms of survival, but if phenylalanine builds up > phenylpyruvate > \_\_\_\_ > toxic to neurons
	○ Worsens when you have more phenylalanine
		§ Put on \_\_\_\_ diet (low on phenylalanine) > preserve mental function; can treat this disorder via diet; also need some \_\_\_\_ (tyrosine from exogenous sources)
A
skandinavians
phenylalanine hydroxylase
fair
eczema
retardation
seizures

tyrosine
melanins
melanin

phenylketone
anti-atkins

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9
Q

Phenylketonuria
• Restrict ____ intake during childhood and adolescence
• ____ drops if go off diet
• PKU Screening of newborns (among 30 diseases in this category)
• PKU Mothers need to follow diet during ____ to avoid maternal PKU in their children

* Low \_\_\_\_ diet
* If you're at risk for child with PKU > have you follow the diet while you're pregnant because it damage the unborn child
* Anything that contains \_\_\_\_ is also an issue
A

phenylalanine
IQ
pregnancy

protein
aspartame/nutri-sweet

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10
Q

Autosomal Dominant

  • Usually one ____ is affected
  • Males and females affected ____
  • Males and females transmit the disease equally
  • ____% chance of having affected offspring
    • Every ____ has someone affected
    • 50% Aa, 50% aa (from Aa x aa)
A

parents
equally
50
generation

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11
Q

Autosomal Dominant

  • 2 affected parents
  • AA may be ____• Homozygous for dominant trait - it depends on whether or not it is viable
    • 1/3, 1/3, 1/3? (from Aa x Aa)
    ○ So ____ affected and then ____ unaffected
A

lethal
2/3
1/3

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12
Q

Types of Genes Causing Autosomal Dominant Disorders

  • Not enough enzyme activity (e.g. ____)
  • Complex metabolic Pathway (e.g. ____)
  • Abnormal subunit of multimeric complex (e.g. ____)
  • Gain of Function (e.g. ____)
  • Loss of Function (e.g. ____)
  • Cancer susceptibility gene (e.g. ____, Retinoblastoma, APC)• Porphyria - comes from heme-regulatory enzymes (breaking it down); don’t break it down properly > ____ toxicity
    ○ Patients may be normal, but if put under ____ > not enough enzyme > neurological disorder, irritability, constipation
    • FH - ____ receptor defect (removes chol from blood) > more ____ in blood > survive birth, develop heart attacks when 6-12 (____); heterozygous > heart attacks in 20-30’s; cholesterol levels escalated!
    • Collagen - complex structure > forms protein interactions that forms the bone/teeth; OI > defect in building blocks > brittle bones and teeth
    • GOF > enzyme is always on > achondroplasia > a receptor that’s always on (not susceptible to signal via ligand); LOF > Marfan syndrome > defect in fibrillin genes > gives ligaments ____
    • CSG > mutation that leads you to be at a higher risk of developing cancer; will develop it, the question is just when
A
porphyria
familial hypercholesterolemia
osteogenesis imperfecta
achondroplasia
marfan syndrome
neurofibromatosis
iron
stress/drinking
LDL
chol
homogeneous

elasticity

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13
Q
Osteogenesis
Imperfecta
• Brittle \_\_\_\_
• Easily \_\_\_\_
• Collagen \_\_\_\_ defect
• Dentinogenesis Imperfecta type I
• Just \_\_\_\_ alone can break their bones; limbs are short and broken because it may break in \_\_\_\_ during formation
• Do not form \_\_\_\_ (bc collagen is one of the structural proteins that creates dentin)
• Collagen forms \_\_\_\_ helix > high tensile strength
	○ In OI > if one allele has a kink > cannot form the \_\_\_\_ (aberrant forming with the normal bones)
A
bones
broken
I
child birth
utero

dentin
triple
proper helix

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14
Q
Dentinogenesis Imperfecta I
• In conjunction with \_\_\_\_
• \_\_\_\_ is normal
• Defect in dentin 
– \_\_\_\_ teeth
* Always associated with OI
* Shiny teeth, but \_\_\_\_ and brown bc the dentin isn't forming properly
A

osteogenesis imperfecta
enamel
opalescent
discolored

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15
Q

Dentinogenesis imperfecta, Shields type II

• Gene map locus ____ (DSPP-dentin sialophosphoprotein)
• Dentinogenesis imperfecta without ____
• ____dentin and teeth
– brown-blue or opalescent brown teeth
– ____ shaped crown
– ____ roots, small or ____ root canals, absent pulp chambers

• In the absence of OI (for type II and III)
	○ The \_\_\_\_ are normal, but the dentin is abnormal
• DSPP > necessary structural protein in order to make dentin
	○ \_\_\_\_ example
A
4q21.3
osteogenesis imperfecta
opalescent
bulbous
narrow
obliterated

bones
multimeric subunit

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16
Q

Pedigree used to identify DSPP for type II DI

* Large extended family > found out via history and DNA > and mapped the gene to \_\_\_\_
* The red is the \_\_\_\_ (the identifying individual)
A

DSPP

proband

17
Q
Achondroplasia
• \_\_\_\_ defect (most mutated site)
• Cartilage defects
– \_\_\_\_ limbs, trident hand, Genu varum (\_\_\_\_), Prominent brow and depressed bridge of nose
– Maxillary \_\_\_\_
– Small \_\_\_\_
• Homozygous FGF-3 mutation is not \_\_\_\_
• Constitutively active example (GOF)
• FGF-3 is always active > most mutated site in the genome
• Small foramen magnum > compression of \_\_\_\_ and death
• Double mutation FGF3 > unviable
• All people with achondroplasia are \_\_\_\_
	○ 2/3 have achondroplasia, and \_\_\_\_ will be normal
A
FGF-3
short
bowlegs
hypoplasia
foramen magnum
viable

spinal cord
heterozygous
1/3

18
Q

Marfan Syndrome

• Defect in ____
• Tall, thin stature with ____ limbs, fingers, and toes
• Narrow and/or ____-featured face.
– narrow mouth with a high ____
– ____ teeth.
• Off-center ____ in the eye and ____ (ectopia lentis)
• Extra information that’s behind the image
○ Scoliosis and loose joints
○ Decreased ____ of lung tissue, blood vessels, heart valves
○ Prominent ____ marks
○ Caved-in or pushed-out breastbone (growth of ribs)
○ Aortic ____ is most serious complication
§ Reason to identify > higher risk of aorta to bulge out and form a dissection or ____
• Give them ____ to reduce BP, and to give a ____ around aorta to support it

• \_\_\_\_ example
• Fibrillin 1 > forms elastin > helps keep BV to be \_\_\_\_
• They grow very quickly > stretch marks
• Single mutation and \_\_\_\_ effects
• Off center lenses sometimes needs surgery
	○ Ectopia lentis
• Not all marfan patients are very tall…?
A
fibrillin 1 or 2
long
sharp
palate
crowded
lenses
myopia
elasticity
stretch
dissection
aneurysm
beta blockers
cage
LOF
elastic
pleiotropic
19
Q

X-linked

• Chi square 1–affected mother
– All male offspring of an affected mother are ____
– All female offspring of an affected mother are ____

• Used to be known as X-linked recessive/hemizygous
• Genes encoded by X chromosome
	○ Sizable - encodes a number of things that are outside of considering what \_\_\_\_ you'll be
	○ Y chromosome encodes what makes you \_\_\_\_ (testis determining factor, etc.) - nothing essential on Y (bc the women would then lack it)
• Women - two X chromosomes - dysfunctional, one can take over the other X
	○ Men only have one X > you're fucked
• All male are affected bc the mother has the disorder, and all females are carriers of the disorder
A

affected
carriers
sex
male

20
Q

X-linked

• Chi squre 2 –affected father
– No ____ transmission
– All female offspring from affected males are ____.
• ____

• Father has disorder, all females are carriers and no males are affected
A

male to male
carriers
hemophilia

21
Q

X-linked

• Chisquare 3–carrier mother
– 50% of females are ____
– 50% of males are ____
• Example: ____

• Most common - carrier mother
• Half of females are carriers, half of females are not carriers
• Half of males are affected, half are unaffected
• Hemophilia - clotting factors encoded on \_\_\_\_ chromosome
	○ Lacking factor \_\_\_\_ or 9 > present with clotting disorders > bleeding disorders
	○ In royal \_\_\_\_ families > big problem > threatened to wipe out the British monarchy
A

carriers
affected
hemophilia

X
8
european

22
Q
  • Unlike half white/black > one little dot signifies ____

* Mother is a carrier here

A

carrier

23
Q
X-linked Expressivity in Females
• \_\_\_\_ carriers
• Mosaicism
– \_\_\_\_
– Random \_\_\_\_-inactivation
• Calico Cat
– Not Random if fatal mutant
• \_\_\_\_ mutation
• Lyonization - all women are mosaics; the cells are not all the same exact coding genes > have two X chromosomes > once cell diff, one X chromosome inactivates > but which chromosome is active is \_\_\_\_
	○ Some will have mom active and some from dad
• One chromosome has black and one has orange - once SC commits, and will inactivate one of chromosome > carried through > orange/black patches
• If gene mutation on X is not random > non-viable cell for male > women will have offspring of good copy???
A
heterozygous
lyonization
X
ornithine transcarbamylase
random
24
Q
Amelogenesis Imperfecta 1E
• \_\_\_\_ form (14 subtypes)
• Defect in Enamel Matrix deposition (\_\_\_\_)
• \_\_\_\_ teeth
• Color–\_\_\_\_ to Brown
* A lot of AE types
* Ameloblasts necessary for enamel
* Boy > \_\_\_\_% affected
A

X-linked
hypoplastic
small
yellow brown

25
Q

Lyonization in Amylogenesis Imperfecta IE

• In women > \_\_\_\_ > striping of healthy enamel and unhealthy enamel
	○ Depending on which SC is dedicating to formation of enamel > forming good enamel and not good enamel in a striated way
A

lyonization

26
Q

Genotype/Phenotype Correlation

• Genetic Heterogeneity
– Mutation of different genes cause same ____
– e.g. familial ____ Disease, ____ Cancer
• Variable Expressivity
– Varying ____ of disease with same gene mutation
– e.g. ____ (variable # of café au lait, learning, skeletal malformations, and cardiac defects

• Number of mendelian disorders is far less than the complex disorders
• GH - define something by a \_\_\_\_, define by what we see
	○ The cold > symptoms are the same > but don't know which pathogen until you do a test
	○ fAD - not sporadic, a smaller subset here > genetically predisposed (40-50's)
		§ Diagnosis is the same, clinically appear the same, but 3 genes can be dysfunctional to lead to disease
		§ Take amyloid precursor protein > there are \_\_\_\_ known variants of it (3 known alleles of that one gene)
• VE - one gene mutation causes disorder, but way in looks in one person to another is different
	○ Due to \_\_\_\_ and other environment
	○ NF1 > dysfunction in \_\_\_\_ > develop tiny café au lait/neuromas all over body > different \_\_\_\_; some people can live whole life where these don’t develop into cancer, but some where they develop early
A
disease
alzheimer
breast
degrees
neurofibromatosis I
trait
3
modifier genes
TSG
levels/sizes
27
Q

Genotype/Phenotype Correlation

• Penetrance
– % of patients with ____ mutation that develop disorder
– e.g. Hereditary nonpolyposis colorectal cancer
– ____, environment (carcinogens)
– Usually occurs in ____ Disorders

• Penetrance - have gene that's dysfunctional, but only % of people with gene develop the disorder
	○ Taking into account modifier genes and \_\_\_\_ cues
	○ HNCC - people develop polyps within their colon, but not everyone develops \_\_\_\_
A
inherited
modifier genes
autosomal dominant
environmental
cancer
28
Q

Genotype/Phenotype Correlation

• Allelic variation - Mutation in same ____ causes different diseases

– Ret Gene
• MEN2A (Exon ____) –____, MTC
• MEN 2B (Exon ____) –Pheochromocytoma, MTC, ____
• Familial medullary thyroid carcinoma (Exon ____)

• AV - same gene, with different disorders coming from mutations within that gene
	○ Ret - oncogene - delete exon 10-11 > MEN2A (multiple endocrine neoplasia) > PC, MTC; delete exon 15-16 > MEN2B
	○ Delete exon 10-15 > FMTC
A
gene
10,11
pheochromocytoma
15, 16
neuromas
10-15