Cells divide twice First step is essentially mitosis but then they divide again First time there is replication so you end up with a normal number of chromosomes after division – you have 46 pairs which is reduced to 23 pairs From the second division there are now half the number of chromosomes -23 left Things can go wrong with either step – termed meiosis I and II The important bit of meiosis
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Cells divide twice First step is essentially mitosis but then they divide again First time there is replication so you end up with a normal number.
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Transcript
Cells divide twice First step is essentially mitosis but then they
divide again First time there is replication so you end up with
a normal number of chromosomes after division – you have 46 pairs which is reduced to 23 pairs
From the second division there are now half the number of chromosomes -23 left
Things can go wrong with either step – termed meiosis I and II
The important bit of meiosis
Nondisjunction in Meiosis IPaired chromosomes fail to separate.
Nondisjunction in Meiosis IISister chromatids fail to separate.
Monosomy?◦ Turner’s (XO)
Autosomal Trisomy?◦ Down’s (Trisomy 21)◦ Chromosome 21 has a small amount of info on it
thus this is compatible with life (also 13,18)
Sex chromosome trisomy Klinefelters (XXY)
Other genetic abnormalities?
◦ Translocation (Chronic Myeloid Leukemia) Chromosomes mingle when the meet which can
cause errors◦ Triplet repeats (Huntington’s)
Excess repeats create too much protein e.g. glutamine
◦ Substitution (Sickle cell) AT subsitution results in abnormal cells
◦ Insertion (Muscular Dystrophy)
What are the 5 pedigrees?◦ Autosomal Dominant◦ Autosomal Recessive◦ X-linked Dominant◦ X-linked Recessive◦ Y-linked
Look if both sexes equally effected◦ If no… look if it skips a generation
If it skips a generation, it’s X linked recessive If not, it’s X linked dominant (affected males don’t
have affected sons)
If yes… its autosomal◦ Look at chances of getting the disease from a
diseased parent◦ ½ = dominant◦ ¼ = recessive
Deciphering pedigrees
X-linked dominant◦ Sex differences◦ No affected males have affected sons◦ 1:1 ratio of affected:unaffected daughters
Autosomal Dominant◦ BOTH SEXES EQUALLY AFFECTED◦ Unaffected normal offspring◦ Affected 1:1 affected:non affected
Pedigrees
Autosomal Recessive◦ BOTH SEXES EQUALLY AFFECTED◦ Affected individuals usually produce normal
(carrier) offspring
X-linked Recessive◦ Only males effected (pretty much)◦ Skips a generation
Y-linked
Exclusively affects males Effected males ALWAYS produce effected
Population with an autosomal gene with two alleles (A and a). Frequency of wild type allele A is represented by p. Frequency of defective allele a is represented by q.
AA (p2)A (p)
a (q) Aa (pq)
A (p) a (q)
Aa (pq)
aa (q2)
A and a are alleles.p and q are frequencies.
Chance that offspring is AA is p x p = p2.Chance that offspring is Aa is (p x q) + (p x q) = 2pq.Chance that offspring is aa is q x q = q2.
Consider the F1 generation when two heterozygotes (Aa) mate.
Since there are only two alleles, p + q = 1.
Applying the Hardy-Weinberg equation
AA (p2)A (p)
a (q) Aa (pq)
A (p) a (q)
Aa (pq)
aa (q2)
p + q = 1
Consider an autosomal recessive that affects 1 in 1600 births.
Incidence is q2 = Frequency of allele a is q = Frequency of allele A is p = Carrier (Aa) frequency is 2pq =
•1/1600•1/40•1-1/40=39/40•2x39/40 x 1/40=1/20
Factors required for Hardy-Weinberg equilibrium (know four)
•Population is large.•No migration into or out of the population.•Random mating.•Mutation rate remains constant.•No selection of alleles (neither negative not positive).
3 types◦ Voltage gated◦ Ligand gated◦ Mechanically gated (e.g. touch)
◦ Passive, facilitated or active
Transporters
ATPADP
Be aware of exchangers and anti porters◦ With vs. anti concentration gradients
May require ATPase – may transfer two ions Important ones: Cl/HCO3 in RBCs, Ca/Na membrane antiporter,
Na/K pump Or just one: Ca ATPase extruded out of the cell, Ca ATPase into SR
j
Cl- HCO3-
Learn this!!
Simplified Nernst equation at 37°C
Eion
61 mV
Zlog
[ion]out
[ion]in
=
Ratio of Ca outside to in is 10,000:1EXCLUDES Ca in sarcoplasmic reticulum – it is only the ions next to the membrane that affect the membrane potential
C
Changing K/Na concentration Ca influx E.g. Ach nicotinic receptor
Action potential
id
4
3
21
0Na+ in K+ out
Na+ outK+ in
0
-90
K+ outCa2+ in & K+ out
Paracrine Endocrine Autocrine Direct contact
With three effects:◦ Change ion balance cascade of effects (e.g.Ca)◦ Alter gene transcription◦ Alter existing enzymes via phosphorylation
Signal types
Learn these ones… Phospholipase C is activated by G-coupled proteins
(Gq alpha units), hydrolyses PIP2 IP3 and DAG IP3 opens Ca channels on the SR IP3 is also converted to IP4 to open another Ca
channel on the membrane And this Ca acts to activate further Ca SR release
PLC IP3 IP4 Ca
PIP2 DAG PKC
Second messengers
DAG, IP3 and Ca2+ and the activation of protein kinase C
CN
ACTIVEDAG
CHCH2 CH2OH
O
C=O
O
C=O
IP3
POH
OH HOP
P
IP3-gated Ca2+ channelin intracellular stores
Ca2+
N
C
Regulatorydomain
Catalyticdomain
INACTIVE
PKC
Adenylate cyclase converts ATPcAMP Guanylate cyclase converts GTPcGMP cAMP acts on protein kinase A (amongst others) cGMP acts on protein kinase G (amongst others) cGMP and cAMP are common second
messengers
The reverse (e.g. cAMPATP) is done by phosphodiesterase
Drugs can impact by inhibiting this process
cNMP’S
Intracellular (e.g. steroids) act on the nucleus NOT membrane receptors
Or they may be receptors in the cytoplasm (e.g. NO guanylate cyclase – note NO is a vasodilator)
Ion channels change membrane potential◦ Na/K
Receptors may haveintrinsic function
Receptor types
It’s important to know that this is how ras is activated by growth factors (cancer)
Ligand binds and stimulates the alpha subunit (all you really need to know)
The alpha subunit has a set function based on its classification
Gs stimulates adenylate cyclase.
Gi inhibits adenylate cyclase.
Gt stimulates cGMP phosphodiesterase.
Gq stimulates phospholipase C.
G protein coupled receptors
Acetylcholine – parasymathetic ns There are five muscarinic acetylcholine receptor
subtypes. M1, M3 and M5 couple through Gq to stimulate
phospholipase C. M2 couples through Gi to open a K+-channel. M4 couples through Gi to inhibit adenylate
cyclase. PLUS the nicotinic acetylcholine receptor (Na+/K+
channel)
Ca in…◦ Voltage gated Ca channels (membrane)◦ IP4 gated Ca channels (membrane)◦ Ca gated Ca channels (sarcoplasmic reticulum)◦ IP3 gated Ca channels (sarcoplasmic reticulum)
Ca out…◦ Plasma membrane ATPase◦ Sarcoplasmic reticulum ATPase◦ Ca/Na exchanger
Calcium channels
Haemaglobin is a quaternary struture 4 globins and a haem 2 alpha/2 beta structure Only two things bind to the haem…
◦ O2◦ CO (NOT CO2 – this binds to the globin)
Proteins
Why is this graph this shape?
Postive allosterism Relaxed haem binds O2 more readily This is essential for it to be able to unload O2
at tissues
What lowers the affinity of haem for O2? (note this shifts the curve to the RIGHT)◦ 2,3, BPG
Stabilises deoxygenated Hb
◦ H or CO2 – effect on pH? Increases acidity – the Boer effect H binds to Hb and stabilizes dexoygenated Hb CO2 is converted to HCO3 and binds to Hb
◦ Immunosuppressive◦ Decreases bone density◦ Decreases muscle mass
CRH
Too much… Cushings◦ Central weight gain (strange)◦ Moon face◦ Bruising◦ Depression, loss of libido
Too little… Addison’s◦ Weight loss◦ Anorexia◦ Nausea and vomiting◦ Depression
Growth hormone releasing hormone and growth hormone inhibiting hormone from hypothalamus
Anterior pituitary then releases growth hormone
Does what you would expect- builds things up e.g. protein synthesis, stimulates IGF-1 ( growth), stimulates gluconeogenesis, stimulates glycogen synthesis
What are these actions the opposite of?
GHRH and GHIH
Excess... Acromegaly/gigantism◦ Distinction is age – acromegaly is after growth