1. Genetic Basis of Disease and Cancer Flashcards
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
0.5 diverse physical manifestations dominant alleles medielian quantifiable bell
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
neuromas
medullary thyroid cancer
hypotonia
marfanoid
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
missense
frame-shift
single nucleotide
single nucleotide
copy number
non-coding
genome wide association
stop
50
immune
• 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
mutation allele non-coding heritable antisense post-transcriptionally transcriptional machinery
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 \_\_\_\_
non-sex
traits
functionality
sibling
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%
carriers equally 25 consangineous metabolic pigment
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
50 product intermediate bi-product transient
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)
skandinavians phenylalanine hydroxylase fair eczema retardation seizures
tyrosine
melanins
melanin
phenylketone
anti-atkins
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
phenylalanine
IQ
pregnancy
protein
aspartame/nutri-sweet
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)
parents
equally
50
generation
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
lethal
2/3
1/3
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
porphyria familial hypercholesterolemia osteogenesis imperfecta achondroplasia marfan syndrome neurofibromatosis
iron stress/drinking LDL chol homogeneous
elasticity
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)
bones broken I child birth utero
dentin
triple
proper helix
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
osteogenesis imperfecta
enamel
opalescent
discolored
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
4q21.3 osteogenesis imperfecta opalescent bulbous narrow obliterated
bones
multimeric subunit
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)
DSPP
proband
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
FGF-3 short bowlegs hypoplasia foramen magnum viable
spinal cord
heterozygous
1/3
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…?
fibrillin 1 or 2 long sharp palate crowded lenses myopia
elasticity stretch dissection aneurysm beta blockers cage LOF elastic pleiotropic
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
affected
carriers
sex
male
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
male to male
carriers
hemophilia
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
carriers
affected
hemophilia
X
8
european
- Unlike half white/black > one little dot signifies ____
* Mother is a carrier here
carrier
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???
heterozygous lyonization X ornithine transcarbamylase random
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
X-linked
hypoplastic
small
yellow brown
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
lyonization
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
disease alzheimer breast degrees neurofibromatosis I
trait 3 modifier genes TSG levels/sizes
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 \_\_\_\_
inherited modifier genes autosomal dominant environmental cancer
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
gene 10,11 pheochromocytoma 15, 16 neuromas 10-15
