Week 2 Flashcards
Genotype
genetic make-up of an organism
Phenotype
physical presentation
Do all cells have the same genotype
Yes but they express diff. genes so they make diff set of functional proteins which make the cell function
Locus
location of specific genes on chromosomes
Alleles
two copies of the same gene located on two homologous chromosomes
Mutation
-sudden changes in the seq. of the DNA which can occur due to environmental influences or internal processes - change in the DNA sequence then that’ll affect mRNA which will affect proteins which could lead to lack of function of the protein
Mutation in exon
leads to abnormal protein which leads to a diseased state
Spliceosome
small nuclear RNA and small nuclear proteins that make up a complex that take out non-coding sequence and keep in coding sequence to make mature mRNA
Mutation to spliceosome
change in sequence of mature mRNA; introns might be left in the sequence which could lead to instability of mRNA
Mutation in poly A tail or 5’ cap
lead to instability of mRNA which won’t affect protein struct. But will result in less protein being produced
Mutation of regulatory sequences
-silencors, promotors; -affect transcritpion rate; -would lead to either inc. or dec. amounts of protein but wouldn’t change protein struct.
Loss of protein function
-protein will lose some part of functioning -ex: tumor suppressor gene: no longer able to stop cell cycle
Gain of protein function
-protein will gain function -ex: pro-oncogene: will cause it to become oncogene and increase cell cycle replication -ex: achondroplasia; Hb Kempsey - can’t release oxygen anymore
Novel property function
-provides the protein with novel property -ex: sickle cell: shape of protein is changed by mutation due to misfolding -change in dosage of gene; increased chromosome number; klinefelters, turners
Achondroplasia and endochondral ossification -type of mutation
-Gain of function in FGFR3 (fibroblast growth factor receptor 3) -This is a tyrosine kinase receptor that binds several growth factors that has a casade of events leading to transcription of a gene -Gain of function causes it to stay turned on w/o anything binding to it: constitutive activation -Dec. proliferation of chondrocytes and causes increased hypertrophy
allelic heterogeneity
-Different mutations in the same gene on different alleles causing same phenotype -beta thalacemia: different mutations occurring in one area which leads to beta thalacemia, can vary in severity depending on mutations in that area
locus heterogeneity
- Different mutations on different genes causing same phenotype -ex: hypercholesterolemia: LDLr mutation and APOB (protein present on LDL that helps to bind to LDLR) mutation will both make elevated cholesterol level
clinical/phenotypic heterogeneity
-different mutations in same gene causing multiple phenotypes -beta thalassemia and sickle cell both affect the same gene on the same locus and result in diff phenotypes
alpha thalassemia -categorize what kind of mutation
-could be allelic heterogeneity (mult. Mutations in one alpha genes) or locus heterogeneity (two mutations located on both copies)
cystic fibrosis
-mutation of CFTR gene which produces CFTR protein which is a transport protein for chloride ion channel - expressed more in epithelial cells in digestive tract, bronchioles, sweat glands, tear producing gland - ex: of allelic heterogeinty b/c it’s mult. mutations in CFTR gene at single locus which leads to same phenotype expression
Domains of CFTR protein
-5 domains -#1-2 domains- transmembrane ion channels -NBD1: nucleotide binding domain; ATP binding spot -R domain: regulatory domain; regulates activity of whole protein -mutations in any of domains causes disease
Classes of mutations in cystic fibrosis (6)
1: absent transmembrane MSD1 protein; splice mutation of intron 4 donor site, 2: block in protein maturation; most common type, NBD1 doesnt fold properly so it does not function 3: defective gating; problem w/ closing of channel, NBD1 affected 4: defective conduction due to alteration of Cl channel; transmembrane MSD1 protein affected 5: reduced expression of CFTR gene; reduced amount of transcription, can be due to multiple causes 6: instability at the cell surface; Protein forms okay but when it gets into cell membrane then it is defective
Structure of adult hemoglobin
- Has 4 subunits (2 alpha, 2 beta) - Forms globular protein, ex of Quaternary structured protein - A-H: alpha helices that make up beta globin chain - 2 a.a in hemoglobin, Histidine is linked to iron (ferris) which binds to oxygen; Phenylalanine helps porfirin rings to fit into pocket of globin
If there is mutation in histidine of hemoglobin
-will not bind to iron properly, less ability to carry oxygen
If there is mutation in phenylalanine of hemoglobin
-will not bind to heme properly
What are globins types in hemoglobin -chromosome -number of genes -total number of copies
- 2 alpha; chromosome 16; 2 genes on each chromosome; 4 copies in total -2 beta; chromosome 11; one gene on each chromosome; 2 copies in total
zeta genes
-chromosome 16 -embryonic forms of alpha globin
epsilon gene
-chromosome 11 -embryonic form of beta globin
Hb A: -structure -expression
-2 alpha, 2 beta - At birth; Predominates after 6 mos of age
Hb A2 -structure -expression
-2 alpha, 2 delta -normally present in adult life but in very low amounts; high in B thalassemia
Hb F -structure -expression
-alpha 2, gamma 2 -fetal -Higher affinity for oxygen and can bind to maternal oxygen much more easily because there is decrease of 2, 3 BPG (bisphopshate glycerate) in fetal RBC, and 2,3 BPG cannot bind to fetal Hgb as easily as it does to adult Hgb
Hb M
- Methomyoglobin - Reduced oxygen binding Modified variant of adult Hb (have ferric instead of ferris); His replaced by tyrosine
Thalacemia
-Imbalance of globin chain synthesis -deletion or extra copies due to unequal crossing over during homologous pairing
Genotypes and Phenotypes of alpha thalassemia -name -causes -how many copies -genotype
-Normal: contains all 4 copies; aa/aa -Silent carrier: contains 3 copies-only missing one; aa/a- -alpha thalassemia trait (mild anemia/ microcytosis): contains 2 copies;aa/– OR a-/a- -Hb H disease (moderately severe hemolytic anemia): contains 1 copy; a-/– -Hydrops fetalis: does not have any copies of gene; –/–
Hb H disease (a-/–)
-lack of alpha chains forces beta chains to bind to each other; tetramer of beta chains -has high affinity but will not unload oxygen
Mutations that cause beta thalacemia
-Splice site mutations: leads to B0 -Promoter mutations: mutation in TATA box leads to dec. in expression leading to B+ -Mutations in the 5’ cap: makes mRNAs unstable so there’s reduction in protein produced so leads to B+ -Nonsense mutations: mutations that changes a particular codon to a STOP codon which leads to B0 -Frame shift mutations: deletion or insertion of nucleotide which will lead to incorporation of STOP codon which leads to B0
Classification of beta thalassemia
-minor; B/BO, silent -intermediate; B+/BO, moderate -major; BO/BO, severe
Result of mutations in B globulin for beta thalacemia
-B0: minimum to no production of beta chain -B+: some production of beta chain in individual
Signs and symptoms of beta thalacemia vs alpha thalacemia
-beta: symptoms will not show until later because fetus has gamma globulin instead of beta -alpha: will have symptoms from beginning because both the fetus and adult use alpha globulin
Single gene inheritance
-One gene produces one protein -Can also lead to one gene causing one disease because one specific protein is affected
Genetic diseases -most common -percentage of unknown causes of mutations
-congenital heart defects -80%
Teratogens
stuff happens in utero-medications/drugs/ infections- that affect baby in utero and can cause mutations
Infections that can cross placental barrier
○ Toxoplasmosis ○ Other: Zica (microcephaly) ○ Rubella ○ CytoMegaloVirus ○ Herpes, HIV Syphilis
Multifactorial defects -prevalence
-more prevalent than single gene disorder -600 out of 1000 people have multifactorial disorder; not usually fatal
Pedigree terms: -box/circle -Numbers at top -Blank box; colored box -half and half box - box or circle slashed - dot -two boxes come from same branch -P1 -F1
- Box: male; circle: female - number of people in generation - blank: unaffected; colored: affected - half and half: carrier, may not show disease phenotypically -deceased -obligate carrier; have allele, will not show it phenotypically - twins; if boxes are connected (in triangle) they are monozygotic (come from same oocyte) if not connected they are dizygotic (fraternal; come from diff oocyte) - Parents (parental) - off spring (filial)
Proband
first person from family to present to physician that they have the disease
Consultant
Someone from family that believes their family may have a disease and asks geneticist to check
Degree of separation
- 1st- parents, siblings, children - 2nd- aunts, uncle, grandparents - 3rd- first cousins - 4th - first cousins once removed (1st cousins children)
Relation between probands children and probands first cousins once removed (children of probands 1st cousin)
-second cousins
Consanguity
inbreeding
Modes of inheritance
-autosomal recessive -autosomal dominant -x-linked dominant -x-linked recessive -mitchondrial inheritance -pseudo autosomal
autosomal recessive
- Not sex cell -Need two copies of gene to manifest phenotype
Autosomal dominant
- Not sex cell -Need one copy of gene to manifest phenotype; in both homo and hetero
X linked dominant
-Linked to x chromosome -X-linked activation: when one of x’s is turned off in females
X linked recessive
- Linked to x chromosome -both X’s have to have mutation
Mitochondrial inheritance
Classically inherited from mother, more recently seen that it can be inherited from father
Pseudo-autosomal
X-chromosome and y chromosome interlink and switch some information
Cystic fibrosis -mode of inheritance -symptoms - Cl transport (acute vs chronic) -Pancreas (symptoms, treatment) -Variability in disease
- Autosomal recessive - Clubbing of finger: bulbing at end, cyanotic color (blue): due to having chronic hypoxia - Cl transport is messed up in and out of cells, so surface of epithelial cells is more viscous and sticky (gunky, mucus build up) causes acute SOB or pneumonia, treatment: oxygen, antibiotics; chronically hypoxic -also has blocking of duct in exocrine pancreas, which is responsible for releasing digestive enzymes; lipase will then begin to destroy pancreas because it cannot be released into duodenum; symptom includes fat in stool; treatment: give patient pancreatic enzyme pills (pancrease) which allows for fat to be broken down, encourage low fat diet, supplement with fat soluble vitamins (A,D,E,K) - Allelic heterogeneity: Most severe form affects protein that is responsible for ATP binding; if mutation is outside ATP binding protein, then disease is not as severe
Allelic heterogeneity
different mutations to same allele can cause varying degrees of the disease
Neurofibromatosis -mode of inheritance -causes -symptoms on new born -severity -over time
- autosomal dominant -neurofibromas: lumps and bumps grow on nerve fibers - On newborn baby, will present as multiple café-ole birthmarks (Need to ask parents if one of them had odd bumps/ spots that are similar) - Spots and bumps are progressive over lifetime - Can be mild, moderate, extremely severe
Type II neurofibromatosis
- grow on acoustic nerve only, presents with hearing problems–connected to entirely different gene than type I
Deuchenne muscular dystrophy -mode of inheritance -caused by -signs and symptoms -testing -progressive
-x-linked recessive - Not enough dystrophin - Pelvic muscles first affected causes gowers sign and calf pseudohypertrophy of calves (big but non-functional) -elevated CPK in blood; muscle biopsy -will be in wheel chair by 5-6, eventually will need respirator, and will probably die of heart failure
Incompletely dominant
-heterozygous produces a mixed phenotype -ex: red, white, and pink flower
CoDominance
-heterozygous includes both phenotypes (AB) -Blood type, ABO
Pleiotropy
- One gene produces multiple phenotypes -Ex. Marfan syndrome
Unstable repeat extension
-Genetic defect caused by repeating of AA in genes which extends with each generation it is passed down to - Anticipation: length of repeats elongates, which means over generations you will be affected sooner and more severely
Insertion or Deletion -effect on genetic code -passed on?
-inserts or deletes a single or multiple nucleic acid from sequence -can get passed on if it does not change the fitness of a progeny
Missense mutation
-codes for different AA
Nonsense mutation
-will add stop codon, will shorten protein -protein may not be coded for because it is too small
Polymorphism
Two or more common alleles (forms of gene) that have different sequence of nucleotides
SNP -stands for -prevalence -used as?
-single nucleic polymorphism -single nucleotide change -everyone has them -can be used as markers
Multi-factorial
mutations in multiple genes that can cause a disease
Consensus Sequence
Most common sequence of a gene in the population
What determines if gene acts in dominant or recessive way?
-Dominant: only needs one allele to be mutated in order for protein to show phenotype (not being functional) -Recessive: needs both alleles to be mutated in order for protein to show phenotype
Does gene dosage matter?
yes/no -Yes; if you lose or gain an entire chromosome you are adding or deleting multiple proteins which can cause offspring to die or be in diseased state -No; one allele may be able to produce enough protein for the cell even though the second allele cannot produce a functional protein
Kinds of defects in CTFR? -type; and effect -most common?
- Nonsense mutation; protein would not be synthesized - Misfolding; protein will not make it out of ER - Reduced number of transcripts of gene; not making enough copies of gene - CFTR will not open -Class 2 is most common in cystic fibrosis; delta F508
Class of inheritance for cystic fibrosis?
autosomal recessive
Diagnosing CF
Some patients can have some residual secretion of Cl and if there is enough secretion then the diseased state may not present until there is insult from environment OR will present as very mild symptoms so correctly dx as cystic fibrosis would be hard if genetics were unknown
Men and CF
fathers should not have the disease because then they wont be able to have children due to vas defrens not working
Hardy Weinberg Equation
P2+2PQ+Q2=1 P: dominant Q: recessive
Multi-factorial disorders -involve?
-genetic contribution -environmental contribution (modifiable vs non-modifiable)
Examples of multi-factorial disorders
-ASCAD: -Daibetes
CFTR mutations
- Class I: frame shift,nonsense on MSD1, absent protein
- Class II: missense mutation on NBD1, CFTR mis-folded and nonfuction so degraded in the RER
- Class III: missense mutation on NBD1, defective gating, problem w/ closing of channel
- Class IV: missense mutation on MSD1, reduced channel conductance
- Class V: splicing defect on MSD1, reduced CFTR synthesis
- Class VI: missense mutation, decreased CFTR stability
Hard-weinberg law assumption
-large population (USA) -random selection (Trump as president) -no significant immigration (Trump) -no new mutations (racist) -random mating (racist)
