Week 2

Question 1

Genotype

Answer 1

genetic make-up of an organism

Question 2

Phenotype

Answer 2

physical presentation

Question 3

Do all cells have the same genotype

Answer 3

Yes but they express diff. genes so they make diff set of functional proteins which make the cell function

Question 4

Locus

Answer 4

location of specific genes on chromosomes

Question 5

Alleles

Answer 5

two copies of the same gene located on two homologous chromosomes

Question 6

Mutation

Answer 6

-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

Question 7

Mutation in exon

Answer 7

leads to abnormal protein which leads to a diseased state

Question 8

Spliceosome

Answer 8

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

Question 9

Mutation to spliceosome

Answer 9

change in sequence of mature mRNA; introns might be left in the sequence which could lead to instability of mRNA

Question 10

Mutation in poly A tail or 5’ cap

Answer 10

lead to instability of mRNA which won’t affect protein struct. But will result in less protein being produced

Question 11

Mutation of regulatory sequences

Answer 11

-silencors, promotors; -affect transcritpion rate; -would lead to either inc. or dec. amounts of protein but wouldn’t change protein struct.

Question 12

Loss of protein function

Answer 12

-protein will lose some part of functioning -ex: tumor suppressor gene: no longer able to stop cell cycle

Question 13

Gain of protein function

Answer 13

-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

Question 14

Novel property function

Answer 14

-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

Question 15

Achondroplasia and endochondral ossification -type of mutation

Answer 15

-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

Question 16

allelic heterogeneity

Answer 16

-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

Question 17

locus heterogeneity

Answer 17

• 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

Question 18

clinical/phenotypic heterogeneity

Answer 18

-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

Question 19

alpha thalassemia -categorize what kind of mutation

Answer 19

-could be allelic heterogeneity (mult. Mutations in one alpha genes) or locus heterogeneity (two mutations located on both copies)

Question 20

cystic fibrosis

Answer 20

-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

Question 21

Domains of CFTR protein

Answer 21

-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

Question 22

Classes of mutations in cystic fibrosis (6)

Answer 22

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

Question 23

Structure of adult hemoglobin

Answer 23

• 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

Question 24

If there is mutation in histidine of hemoglobin

Answer 24

-will not bind to iron properly, less ability to carry oxygen

Question 25

If there is mutation in phenylalanine of hemoglobin

Answer 25

-will not bind to heme properly

Question 26

What are globins types in hemoglobin -chromosome -number of genes -total number of copies

Answer 26

- 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

Question 27

zeta genes

Answer 27

-chromosome 16 -embryonic forms of alpha globin

Question 28

epsilon gene

Answer 28

-chromosome 11 -embryonic form of beta globin

Question 29

Hb A: -structure -expression

Answer 29

-2 alpha, 2 beta - At birth; Predominates after 6 mos of age

Question 30

Hb A2 -structure -expression

Answer 30

-2 alpha, 2 delta -normally present in adult life but in very low amounts; high in B thalassemia

Question 31

Hb F -structure -expression

Answer 31

-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

Question 32

Hb M

Answer 32

- Methomyoglobin - Reduced oxygen binding Modified variant of adult Hb (have ferric instead of ferris); His replaced by tyrosine

Question 33

Thalacemia

Answer 33

-Imbalance of globin chain synthesis -deletion or extra copies due to unequal crossing over during homologous pairing

Question 34

Genotypes and Phenotypes of alpha thalassemia -name -causes -how many copies -genotype

Answer 34

-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; --/--

Question 35

Hb H disease (a-/--)

Answer 35

-lack of alpha chains forces beta chains to bind to each other; tetramer of beta chains -has high affinity but will not unload oxygen

Question 36

Mutations that cause beta thalacemia

Answer 36

-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

Question 37

Classification of beta thalassemia

Answer 37

-minor; B/BO, silent -intermediate; B+/BO, moderate -major; BO/BO, severe

Question 38

Result of mutations in B globulin for beta thalacemia

Answer 38

-B0: minimum to no production of beta chain -B+: some production of beta chain in individual

Question 39

Signs and symptoms of beta thalacemia vs alpha thalacemia

Answer 39

-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

Question 40

Single gene inheritance

Answer 40

-One gene produces one protein -Can also lead to one gene causing one disease because one specific protein is affected

Question 41

Genetic diseases -most common -percentage of unknown causes of mutations

Answer 41

-congenital heart defects -80%

Question 42

Teratogens

Answer 42

stuff happens in utero-medications/drugs/ infections- that affect baby in utero and can cause mutations

Question 43

Infections that can cross placental barrier

Answer 43

○ Toxoplasmosis ○ Other: Zica (microcephaly) ○ Rubella ○ CytoMegaloVirus ○ Herpes, HIV Syphilis

Question 44

Multifactorial defects -prevalence

Answer 44

-more prevalent than single gene disorder -600 out of 1000 people have multifactorial disorder; not usually fatal

Question 45

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

Answer 45

- 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)

Question 46

Proband

Answer 46

first person from family to present to physician that they have the disease

Question 47

Consultant

Answer 47

Someone from family that believes their family may have a disease and asks geneticist to check

Question 48

Degree of separation

Answer 48

- 1st- parents, siblings, children - 2nd- aunts, uncle, grandparents - 3rd- first cousins - 4th - first cousins once removed (1st cousins children)

Question 49

Relation between probands children and probands first cousins once removed (children of probands 1st cousin)

Answer 49

-second cousins

Question 50

Consanguity

Answer 50

inbreeding

Question 51

Modes of inheritance

Answer 51

-autosomal recessive -autosomal dominant -x-linked dominant -x-linked recessive -mitchondrial inheritance -pseudo autosomal

Question 52

autosomal recessive

Answer 52

- Not sex cell -Need two copies of gene to manifest phenotype

Question 53

Autosomal dominant

Answer 53

- Not sex cell -Need one copy of gene to manifest phenotype; in both homo and hetero

Question 54

X linked dominant

Answer 54

-Linked to x chromosome -X-linked activation: when one of x's is turned off in females

Question 55

X linked recessive

Answer 55

- Linked to x chromosome -both X's have to have mutation

Question 56

Mitochondrial inheritance

Answer 56

Classically inherited from mother, more recently seen that it can be inherited from father

Question 57

Pseudo-autosomal

Answer 57

X-chromosome and y chromosome interlink and switch some information

Question 58

Cystic fibrosis -mode of inheritance -symptoms - Cl transport (acute vs chronic) -Pancreas (symptoms, treatment) -Variability in disease

Answer 58

- 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

Question 59

Allelic heterogeneity

Answer 59

different mutations to same allele can cause varying degrees of the disease

Question 60

Neurofibromatosis -mode of inheritance -causes -symptoms on new born -severity -over time

Answer 60

- 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

Question 61

Type II neurofibromatosis

Answer 61

- grow on acoustic nerve only, presents with hearing problems--connected to entirely different gene than type I

Question 62

Deuchenne muscular dystrophy -mode of inheritance -caused by -signs and symptoms -testing -progressive

Answer 62

-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

Question 63

Incompletely dominant

Answer 63

-heterozygous produces a mixed phenotype -ex: red, white, and pink flower

Question 64

CoDominance

Answer 64

-heterozygous includes both phenotypes (AB) -Blood type, ABO

Question 65

Pleiotropy

Answer 65

- One gene produces multiple phenotypes -Ex. Marfan syndrome

Question 66

Unstable repeat extension

Answer 66

-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

Question 67

Insertion or Deletion -effect on genetic code -passed on?

Answer 67

-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

Question 68

Missense mutation

Answer 68

-codes for different AA

Question 69

Nonsense mutation

Answer 69

-will add stop codon, will shorten protein -protein may not be coded for because it is too small

Question 70

Polymorphism

Answer 70

Two or more common alleles (forms of gene) that have different sequence of nucleotides

Question 71

SNP -stands for -prevalence -used as?

Answer 71

-single nucleic polymorphism -single nucleotide change -everyone has them -can be used as markers

Question 72

Multi-factorial

Answer 72

mutations in multiple genes that can cause a disease

Question 73

Consensus Sequence

Answer 73

Most common sequence of a gene in the population

Question 74

What determines if gene acts in dominant or recessive way?

Answer 74

-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

Question 75

Does gene dosage matter?

Answer 75

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

Question 76

Kinds of defects in CTFR? -type; and effect -most common?

Answer 76

- 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

Question 77

Class of inheritance for cystic fibrosis?

Answer 77

autosomal recessive

Question 78

Diagnosing CF

Answer 78

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

Question 79

Men and CF

Answer 79

fathers should not have the disease because then they wont be able to have children due to vas defrens not working

Question 80

Hardy Weinberg Equation

Answer 80

P2+2PQ+Q2=1 P: dominant Q: recessive

Question 81

Multi-factorial disorders -involve?

Answer 81

-genetic contribution -environmental contribution (modifiable vs non-modifiable)

Question 82

Examples of multi-factorial disorders

Answer 82

-ASCAD: -Daibetes

Question 83

CFTR mutations

Answer 83

- 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

Question 84

Hard-weinberg law assumption

Answer 84

-large population (USA) -random selection (Trump as president) -no significant immigration (Trump) -no new mutations (racist) -random mating (racist)