General Concepts Flashcards
what are the human diseases classification according to geneticists?
- chromosomal disorders
- single gene disorders
- polygenic
how to find whether a certain disease has a genetic component
through the use of
- classic family study
- twin studies
- adoption studies
steps to classic family study
- identify the family
- determine the proportion of the relatives affected
- calculate the lifetime risk
what are the problems with twin studies
- rarity of twins
- concordant pairs are more likely to be enrolled
- MZ twins often share more environment than Dz
what are the practical conclusions to from the liability threshold model?
- closer the sick relative, the greater the risk
- having more than one affected relative means risks are even greater
- more severe the disease is in proband, the stronger the risk for relatives
- sometimes there is a difference in the incidence of the disease between genders
what are the ways to find Common disease common variant genes (CDCV genes)
- linkage analysis
- association studies
- linkage equilibrium analysis
ankylosing sponylitis
HLA B27 disease, associated with spine, back, and inflammation problems
what are the thoughts to get from association to causation?
- polymorphism is causative for the disease
- association is a false positive due to random chance
- polymorphism is a associated bc of some systematic bias in the biology, study samples, and analysis
- polymorphism is in disequilibrium with the true causative allele
how to prove that the variant is actually causative for the disease?
- indirect clues like using snp promoter changes in gene expression
- sherlock holmes method
what are the steps to genome wide association analysis?
- scan the entire genome with a dense collection of genetic markers
- calculate association at teach polymorphic marker position along the genome
- identify regions which show a significant association
- study possible disease contributing genes from the linked region in functional assays
inflammatory bowel disease
associated with NOD2 gene
environmental factors for alzheimers are:
- head injury
- high blood pressure
- heart disease
- stroke
- diabetes
- high cholesterol
- active learning
- smoking
punch drunk syndrome
- env factor for alzheimers
- caused by repeated cerebral injury
- weakness in lower limbs
- unsteadiness of gait
- slowness of muscular movements
- tremors of hand
- dysarthria
- slow thinking
coronary artery disease
- hypertension
- atherosclerosis
- coronary heart disease
- stroke
why is high plasma glucose bad?
- activation of the protein kinase CB
- glycation
- oxidative stress
- depletion of NAD+ (metabolic pseudohypoxia)
what are the environmental and genetic factors of diabetes type 1
env: drinking too much cow milk young, viral infection of coxsackie, mumps, and rubella
Genetic: IDDM1 locus with HLA region and IDDM2 locus with insulin gene
diabetes type 2
- hyperinsulinemia leading to insulin resistance
- treated by diet and hypoglycemics
- high concordance
- associated with obesity
hirschprung disease
- absence of ganglion cells in the parts of the colon and rectum
- short segment affects rectum and small portion of the colon
- long segment affects longer portion of the intestine
- ologogenic disease
hyperhomocysteinemia
- caused by deficiency in vit B and folate in diet or MTHFR to T mutation
- hypothyroidism
- MTHFR C677T
- deep vein thrombosis
what are the summary risks with elevated homocysteine levels
- coronary artery disease
- peripheral artery disease
- dementia
- neural tube defects
what are the different kinds of point mutations
- missense (sickle cell)
- nonsense (familial hypercholesterolemia)
- silent
- frameshift mutations (cystic fibrosis)
what is the damage control for protein length
- mRNAs with pre mature stop codons get degraded
2. if truncated protein made, gets degraded in the er before delivery to membrane
regulatory mutations with interesting phenotypic consequences
- DARC-resistance to infection with malaria
- LCT-lactose persistence
- Pdyn-memory and emotional status
example of alternative splicing is what
phenylketonuria
what are the two possible outcomes for in frame deletions
- protein is too short, doesnt fold right and gets degraded in er
- its short but folds okay and everything is fine
difference between becker and duchenne dystrophy
missense mutation leads to duchenne and in frane deletion leads to becker
what are aspects of retrotransposition
- directly disrupt genes
- provoke illegitimate recombination
- contain regulatory sequences
what are the two outcomes of expanded repeats from unstable repeat expansion?
- suppress expression of the gene (Fragile X syndrome
- results in production of abnormal toxic product (huntingston disease)
how do expanded repeats cause disease
- in protein coding sequences, make toxic proteins
- in RNA coding regions, alter RNA function
- in noncoding regions, reduce transcription or translation
what are the outcomes of loss of function mutatiosn
haploinsufficiency (brittle bone disease aka osteogenesis imperfecta) and dominant negative mutations (p53)
examples of gain of function mutations are:
- RAS oncogenes
2. Huntington disease
what are agents that cause mutations/
- chemical (alkylating agents, aromatic hydrocarbons, intercalating agents, artificial derivatives of DNA bases
- physical-radiation
- biological (viruses or transposable elements)
how are thymine dimers fixed?
- base is damaged
- dna glycosylase removes base
- ap endonuclease makes cut
- excision exonuclease removes stretch of dna
- polymerase synthesizes new dna
- ligase seals nick
what are the outcomes when a repair job leads to a point mutation?
- if mutation is in the germline it may be passed to offspring
- if mutation is in the somatic cells it might lead to cancer
- most cases does not produce effect
what are the three scenarios for spermatogonial mutations?
- functionally neutral mutations
- typical PAE mutations
- intermediate scenario milder selective advantage that enriches little over time
what are the steps to identifying a causative de novo mutation?
- sequence genome
- select only coding mutations
- exclude known variants seen in healthy people
- sequence parents and exclude their private variants
- look at affected gene function and mutational impact
what effects do paternal and maternal age have?
PAE increases point mutations (dwarfism and apert syndrome) and MAE increase non disjunction events (down syndrome aneuploid liveborns)
what are the rate of mutations in human genes
- random gain of mutations (low level natural cause)
- forced gain of mutations (median level xrays, chemical carcinogens)
- very high rates of mutations (in cells that lost one or more major mechanisms of DNA repair)
how and why is hprt assay done
to calculate rate of mutations in human cells, done by treating cells with hprt, administering 6 thioguanine mutation and directly count mutant colonies and compare this number with number of cell seeded on plate
what are reasons that makes individual mutation frequencies so different?
- Polymorphisms of genes metabolizing carcinogens;
- Polymorphisms of genes responsible for DNA repair;
- Alcohol consumption and smoking;
- Exposure to environmental carcinogens;
- Exposure to radiation
what is the procedure for comet assay?
- cells mixed with low melting agarose
- immobilize cells on comet slide
- treat cells with lysis solution
- samples treated with alkali
- samples stained with intercalating dye and visualized by epifluorescence microscopy following alkaline electrophoresis, which reveals dna breaks
what are the cell cycle checkpoints?
- apoptosis checkpoint
- spindle assembly checkpoint
- dna damage checkpoints
what are damage checkpoint pathways?
- control cell cycle arrest
- activate dna repair pathways
- control the movement of dna repair proteins to sites of dna damage
- control telomere length
- activate different transcriptional programs
- induce cell death by apoptosis
ATM ataxia telangiectasia
- loss of motor control owing to purkinje cell loss, maked faces and oculomotor apraxia
- dilated small blood vessels
- recurrent respiratory infections, t cell function reduced
- high risk of leukemia and lymphoma
- example of importance of checkpoint pathways
what are the classification of birth defects?
- malformation (cleft lip, palate, cardiac defects, and neural tube defects)
- disruption (cataract caused by congenital rubella infection and limb defects due to talidomide exposure)
- deformation (congenital hip dislocation and club foot)
- dysplasia (achondroplasia)
- sequence (severe spina bifida or potter sequence)
- syndrome (down, waardenburg, and fetal alcohol syndrome)
- association (vater association)
what are the spina bifida degrees?
- spina bifida occulta
- lipomeningocele
- meningocele
- myelomeningocele
what are symptoms of spina bifida?
- paralysis
- loss of bowel and bladder control
- variable learning disabilities
what does folic acid help with?
- NTD
- CAD
- stroke
- cancer
what are the symptoms of thalidomide fetal exposure
- amelia
- phocomelia
- hypoplasia
- complete absence of some bones
what are the phenotypes of achondroplasia
- abnormal body proportions
- hump on back
- large head
- flat nose at bridge
- short stubby fingers
- trident hand
what is potter sequence and what are the effecrts?
- urethral agenesis
- oligohydramnios
- fetal compression in utero
- growth deficiency
- multiple malformations
- altered facies
- limb positioning defects
what are symptoms of down syndrome
- low muscle tone
- enlarged tongue that tends to stick out
- round head with flat area at the back
- broad short hands
- heart defects
- thyroid disease
- alzheimers
- leukemia
what are the symptoms of waardenburg
piebaldism and deafness, just pie. when kit gene mutation and ret gene when waardenburg
what are the symptoms of fetal alcohol syndrome
- mental retardation
- problems with time and money
- attention and focus problems
what is vater association
V-vertebrae A-Anal anomalies T-trachea problems E-esophagus problems R-radius problems
what are factors that influence teratogenicity
- dose
- route
- frequency of exposure
- duration of exposure
- concurrent exposure
- concurrent illness
- genetic susceptibility
what are the teratogenesis mechanisms?
- mutation
- chromosomal aberrations
- mitotic interference
- nucleic acid metabolism alteration
- energy metabolism interference
- cell membrane alterations
what are the developmental gene pathways?
- fibroblast growth factor and receptors
- sonic hedgehog pathway
- neural crest cell migration network
what are the HOX gene mutations linked to diseases
- HOXA11- radioulnar synostosis and thrombocytopenia
- HOXA13 -hand foot genital syndrome
- HOXD13 synpolydactily
- IDX1- pancreatic agenesis
