Genetics according to Mendel and Morgan, a reminder: XY XX A A A A ♂ = ♀ ♂ ♀ A: autosome X...
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Transcript of Genetics according to Mendel and Morgan, a reminder: XY XX A A A A ♂ = ♀ ♂ ♀ A: autosome X...
![Page 1: Genetics according to Mendel and Morgan, a reminder: XY XX A A A A ♂ = ♀ ♂ ♀ A: autosome X ou Y: sex-associated chromosomes ♂ ♀ Our chromosomes:](https://reader036.fdocuments.us/reader036/viewer/2022062407/56649d565503460f94a34567/html5/thumbnails/1.jpg)
Genetics according to Mendel and Morgan, a reminder:
XY X X
A A A A
♂ = ♀
♂ ♀
A: autosome
X ou Y: sex-associated chromosomes
♂ ♀
Our chromosomes:
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+ = wild-type, dominant ;
m = mutation,recessive
♂♀
A1
A2
A2A1
A1 + / A1 + A1 + / A2 m
A1 + / A2 m A2 m / A2 m
♀ = ♂ : ¾ [+], ¼ [mutant]
♀, ♂ ♀, ♂
♀, ♂ ♀, ♂
For the meiosis of Autosomes:
+
+ m
m
[+]
[+] [mutant]
[+]
[+]
[+]
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♂♀
X1
X2
YX1
X1/ X1 X1/ Y
X1/ X2 X2/ Y
¾ [+], ¼ [mutant] but! ♀ ♂
♀
♀
♂
♂
A similar – but not identical - situation holds for sex chromosomes :
[+][+]
+
m
[m]
[+]
[+]
[+]
+
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Daltonism, or Red-Green color blindness: a syndrome associated with the X chromosome
X A
Color perception and photoreceptors:Red green and blue
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A A
Y X
Color perception and photoreceptors:Red green and blue
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♂♀
X1 A
Y AX1 A
X1/ X2; A/A
♀ ♂
Sex Chromosomes vs. Autosomes
X2 A
[+]
[+]
[+]X1/ X1; A/A X1/ Y; A/A
X2/ Y; A/A [Red-green Color Blind]
Red
[+]
[+]
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Woman normal
Woman carrier
Man normal
Man Color blind
X
A
R+ V+ B+ R+ V+ B+ R+ V+ B+ V+ B+
X X X
A A A A A A A
XX Y Y
Color perception and photoreceptors:Red green and blue
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Where do nearly identical DNAs for Red and Green come from?
X A
Color perception and photoreceptors:Red green and blue
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* ** * * * *
Duplication then Divergence
Common ancestor
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Recent duplication
Divergence
Color perception and photoreceptors:Red green and blue
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More ancient duplication
divergence
duplication
divergence
Origin of photoreceptors:Red Green Blue
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High frequency of Daltonism. Where do so many mutations come from???
X A
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One example: illegitimate recombination … And the loss of normale function.
Normalpairing
Inappropriatepairing
Recombination by error
X
New mutations
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in the nucleus after spreading
Giant chromosomes of Drosophila
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Traditional karyotype for a human cell (e.g. amniocentesis)
Trisomy for chromosome 21with associated defects (mongolism)
2 copies = normal
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Fluorescent In Situ hybridization: FISH
Fluorescent DNAs, different colors for different chromosomes
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T+
Chr21
Karyotype by FISHFluorescent In Situ hybridization
=>Trisomy / Chromosome 21
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E.g. Burkitt’s Lymphoma
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Regulatory DNA Sequences Coding DNA Sequences
A normal gene :
function
mRNA
proteinWhere?When?
How much?
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FISH applied to disease diagnosis
Strong immune expression IgH protein
One normal gene :
General expression C-myc oncogene
Another normal gene :Breakage/repair with error
Strong immune expression IgH protein
General expression C-myc oncogene
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Fluorescent In Situ hybridization: FISH
Normal :
General expression C-myc oncogene
Also normal :
Strong immune expression c-myc oncogene
Strong immune expression IgH protein
Abnormal :
Fluorescent DNA-1
Fluorescent DNA-2
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And what about the lab?
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(XX)
(XO)
The nematode C. elegans as a laboratory model
~1 mm
Eating E. coli
Hermaphrodite
+
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mutagen
+ m
+ +/ + +/ m
+ m
+ +/ + +/ m
m +/ m m/m
New, recessive mutation m
Screening for mutants
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+ m
+ +/ + +/ m
m +/ m m/m
m m
m
m m/mm/m
m/mm/m
Inbreeding in the lab is helpful
A new mutant line
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2 x ‘2n’
A
a
2n
A
a
4n
a
A
A
A
a
a
4 x 1n (gametes)
Meiosis: one mother cell becomes four gametes
Here, we only look at one pair of chromosomes among several…
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2 x ‘2n’
A
a
4n
4 x 1n (gametes)
Linkage of DNA sequences on the same chromosome (Mendel I);Independent transmission of different chromosomes (Mendel II)
A
a
2n
A/a = forms of a gene
= transposable element insertions
a
A
OU
a
A
A
a
A
a
1/4
1/4
1/4
1/4
1/2
1/2
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Additional variation from physical exchanges (recombination)
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A
a
4n
4 x 1n (gametes)
Recombination generates still more diversity
A
a
2n
A/a = forms of a gene
= transposable element insertions
A
a
A
a
<1/4
<1/4
<1/4
<1/4
xa
a
A
A
4xParental 4xRecombinant
f < 0.5
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11 22 33 44 55 XX
X
(XX)
(XO)
Bristol
Autosomes Sex chromosome
dpy-6 lin-14 sma-5
X
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Vulva: muscles, nerves, skin…
+
lin-14
= [Bag of worms]
Defective vulva
Isolating mutants that affect vulval development: the bag of worms screen
Defective vulva
Egg-laying
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11 22 33 44 55 (XX)
(XO)
Bristol
(XX)
(XO)
Bergerac
Autosomes Sex chromosome
lin-14-
lin-14-
lin-14- lin-14 -
lin-14+
lin-14+
lin-14 +
(but otherwise +)
(& otherwise +)
lin-14+
Tc1 elements
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Berg
Brislin-14-
lin-14 -
lin-14 +
X(effect female-specific)
lin-14-
lin-14+
[lin-14+]
Brislin-14-
lin-14 -X
« Backcross » N°1
Meiosis + recombination
lin-14+
lin-14+
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lin-14-
lin-14+
[lin-14+]
Brislin-14-
lin-14 -X
« Backcross » N°1
Meiosis + recombination
lin-14-
lin-14+
[lin-14+]
Brislin-14-
lin-14 -X
« Backcross » N°2
x x x x x x x x x x x
Serial dilutions, genetic-style
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Meiosis + recombinationlin-14-
lin-14+
[lin-14+]
Brislin-14-
lin-14 -X
« Backcross » N°2
lin-14-
lin-14+
[lin-14+]
Brislin-14-
lin-14 -X
« Backcross » N°3
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lin-14-
lin-14+
[lin-14+]
« Backcross » N°9
Self-fertilize, select normal hermaphrodites, giving only normal offspring
=> lin-14+ / lin-14+, pure homozygous stock.
Associating the repeated elements closest to lin-14+
Dilution = 29
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dpy-6+ lin-14+ sma-5+
X
lin-14+
lin-14+
lin-14+
Tc1 Tc2
The approximate location is identified by the Tc1 repeats. Candidate genes in the known genome sequence can be tested.
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Genetic analysis of Aniridia, a rare eye syndromecaused by a Dominant mutation
Dominant
+/+ An/+
Iris reduced=> pupil open
≥ 1 base pair changed out of 3 billion (3x109)
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Aniridia (human) : a dominant autosomal syndrome caused by mutation of a single gene, Pax6
Pax-6 Autosomal
and dominant:
An/+ x +/+
↓
½ [An], ½ [+]
♀ = ♂
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=> Aniridia results from dominant loss-of-function mutations of Pax6 (haploinsufficient: not enough active protein)
Pax6a (Faux-sens)*
Pax6Δ (deletion)
Pax6+ Pax6a/Pax6+/ Pax6Δ == [Aniridia]
Pax6+
+
pf
pf
Pax6+
+
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Small eye (Sey) :Small eye, reduced iris, cranio-facial defects (as for Aniridia)
Origin: dominant, haploinsufficient mutations of the mouse Pax6 gene
+Sey/+
Small eye, a mouse version of Aniridia
Sey/+
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♂♀
A1
A2
A2A1
A1 + / A1 + A1 + / A2 Sey
A1 + / A2 Sey
Expected : ♀, ♂ equivalent: 1/4 [+], 2/4 [Sey], ¼ [?]
♀, ♂ ♀, ♂
♀, ♂
Genotype/phenotype for Sey
+
+ Sey
Sey
[+]
[Sey]
[Sey]
[Sey]
[Sey]
?
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( and ¼ Sey/Sey [dead] )
Genotype/phenotype for Sey
♂♀
A1
A2
A2A1
A1 + / A1 + A1 + / A2 Sey
A1 + / A2 Sey A2 Sey / A2 Sey
♀, ♂ ♀, ♂
♀, ♂ ♀, ♂
+
+ Sey
Sey
[+]
[Sey] [dead]
[Sey]
[Sey]
[Sey]
Observed : living ♀ = ♂ : 1/3 [+], 2/3 [Sey]
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Sey/Sey+/+
Dead how? As eyeless embryos…=> Pax6 / Sey required for normal eye differentiation
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Localised expressionof Pax6(mRNA)
Normal eye development follows a genetic program
and requires Pax6+
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Normal Pax6 expressionis necessary for eye development
Localised gene expression
= normalNo expression
= absence of function
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The Drosophila eyeless (ey) gene encodes dPax6
+ ey-
Pax6 is necessary for normal Drosophila eye development - as in man and mouse -
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+
+mPax6 -/-
-/-dPax6+
dPax6 gf
Human,mouse
Drosophila
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Very different eyes
with a common origin?
humain
calamar
mouche
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Can mis-expression of Pax6 re-program development?
localised gene expression= normal
No expression= loss of function
Novel expression
=> ???
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The Test :
Cross appropriate lines …
Transgenic driver Line :
Fly regulatory sequences Yeast GAL4 Protein
Transgenic expresser Line :
UAS (GAL4 target) dPax6 (or other)
Regulatory DNA Sequences Coding DNA Sequences
A normal gene :
functionWhere? When? How much?
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Fly regulation GAL4
UAS dPax6 x
?
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dPax6 induces supplementary eyes
*
**
mPax6, expressed in the fruit fly, does the same
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Frog Pax6 makes new eyes in Xenopus
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Hence the idea that Pax6 is an eye selector, since early in evolution
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●A DNA binding motif in many selector genes:
The Homeodomain (60 amino acids long)
● proteins are composed of 20 different amino acids (a.a.)
● For a given homeodomain (60 a.a.), p = 1 / 2060 ~ 0
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lof gof
mx
lab
proboscipedia (pb) is a conserved selector gene
The fly and human pb homeodomains are 57/60 identical; Probability that this happened by chance: ~ 0
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* ** * * * *
Divergence of homologous genes
Common ancestorEmergence of new species
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Eye Selector
Leg Selector
Wing Selector
We possess the same genes
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These selector genes encode Transcription factors,that regulate other genes in developing eyes, legs, wings…
DNA
Pax6 Transcription of target genes
Pax6
-- DNA of which target genes? Their functions? -- Functional organisation of gene networks?
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mRNA
Gene expression involves transcription followed by translation
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Looking at gene expression for 15,000 genes:
The fly transcriptome
Systems biology:
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dPax6 can induce supplementary eyes
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**
Such mutations help to look at genetic programs : Including via the transcriptome
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Mutant cell mRNA Normal cell mRNA
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Using mutations to look at whole-genomes:
The transcriptome
Mutant cell mRNANormal cell mRNA +
Hybridize with miniaturized plates carrying DNA sequences for each gene
Most mRNAfrom normal cells
Most mRNAfrom mutant cells
Equal amounts
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Mostly normal
Mostly mutant
Mutant = Normal
Mutant cell mRNANormal cell mRNA +
Different gene in each spot
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Tests of a genetic program in vivo
-/-
+/- +/-
Confocalmicroscope
genotype differentiation
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Systems biology (e.g. transcriptome) to generate predictions
Genetics to test them in vivo