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