Download from Lecture 15

Bi 1
“Drugs and the Brain”
Lecture 20
Tuesday, May 9, 2006
1. Formal and molecular genetics
2. A genetic animal: Drosophila melanogaster
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2. Genetic Diversity:
A.
Meiosis
Formal genetics:
Independent assortment
B.
Recombination
Mapping genes
Complementation
X-linked genes
Genetic animals, and an example of genetic analysis:
Development genes in D. melanogaster
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from Lecture 15:
Humans have 22 pairs of chromosomes, plus the X and Y.
Males are XY; females are XX.
Chromosomes of a male,
arranged in pairs
© Garland; Little Alberts Fig 5-12
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Somatic cells have two copies
(maternal and paternal) of each
chromosome; they are diploid.
One copy is maternal, the other
paternal.
Greek, marry
parents
Gametes (egg and sperm) have
half the somatic number of
copies of each chromosome;
they are haploid. Usually this
means one copy; the copy is
either maternal or paternal.
(Human gametes are also monoploid, because
half the somatic number = 1)
offspring
Little Alberts 20-4
© Garland Publishing
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1st mechanism for genetic diversity:
independent assortment of chromosomes
Mendel’s Laws imply independent
somatic
cells
assortment. That is, genes on the
same chromosome are inherited
together; genes on different
chromosomes are inherited
independently.
With 23 human chromosomes,
there is a possible 223 = 8.4 x 106
distinct gametes.
Little Alberts 1st edition 9-36
© Garland Publishing
(2nd Figure 20-11A is wrong)
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2nd mechanism for genetic diversity:
recombination within chromosomes
Little Alberts 20-11B
© Garland Publishing
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A later lecture will treat the cell cycle and mitosis
(simple division by separating chromosomes)
Interphase is nearly absent between the two cell divisions of meiosis
Big Alberts 17-2
© Garland Publishing
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Meiosis differs from mitosis in two ways
Completion of 1st
Meiotic division
diploid
2. No DNA
replication
between 1st and
2nd divisions
2nd Meiotic
division
1. Crossing-over
(recombination)
Modified from Little Alberts 9-35
© Garland Publishing
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from Lecture 14
Thomas Hunt Morgan
founder of Caltech’s
Biology Division
and of 20th-century genetics
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Quantitative measure of recombination
If two genes are recombined x% of the time,
they are said to be separated by a genetic map distance of x centimorgans (cM).
two DNA double helices with nearly identical sequences
phenotype
(Greek, to show)
dark
eyes
paternal
chromosome
maternal
chromosome
dark
eyes
hairy
legs
hairy
legs
phenotype
(Greek, to show)
DNA molecules that have crossed over
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Quantitative measure of recombination
If two genes are recombined x% of the time,
they are said to be separated by a genetic map distance of x centimorgans (cM).
In mammals, 1 cM ~ 1.3 megabase of DNA.
The human genome is 3 x 109 nt in 23 chromosomes, for an average of 130
megabases/chromosome (range 30 to 300).
Therefore the average chromosome recombines about once per meiosis.
two DNA double helices with nearly identical sequences
dark
eyes
paternal
chromosome
maternal
chromosome
dark
eyes
hairy
legs
hairy
legs
Little Alberts 6-28
© Garland Publishing
DNA molecules that have crossed over
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Recombination at meiosis is based on cross-strand exchange
The process involves
(a) Enzymes that nick & “chew”; (b) Base pairing; (c) Enzymes that synthesize & ligate
This sometimes leads to generation of a 3rd chromosome (“trisomy”).
Little Alberts 6-26
© Garland Publishing
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from Lecture 17:
g b a
OH
Latin, to tie
ligate
a
nick
a
a
a
Little Alberts Fig 3-42
© Garland publishing
a
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The relationship between classical genetics and molecular genetics
Suppose (1) that A, B, and X are on the same chromosome,
and
(2) that the map distances:
(gene A to gene B) > (gene A to gene X)
and
(gene A to gene B) > (gene B to gene X)
Then, by definition,
X lies between A and B on the genetic map.
gene
gene
genetic map:
A
X
physical (DNA) map:
gene
A
gene
B
gene
X
gene
B
And X also lies between A and B physically, on the chromosome (DNA)
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The genetic map and the physical map are colinear, but not quite proportional.
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The genetic map and the physical map are colinear, but not quite proportional.
Lander et al Figure 15.
Distance in cM along
the genetic map of
Chromosome 12
recombines about
twice per meiosis
chromosome 12 plotted
against position in Mb in
the genome sequence.
Female recombination
rates are much higher
than male
recombination rates.
Increased slopes at
either end of the
chromosome reflect the
increased rates of
recombination per Mb.
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How do we know that a genetic event has taken place?
chromosomal shuffle
or
recombination
or
point mutation
1. DNA chemistry
(Expensive, new, unlikely)
2. detectable change in organism
A phenotype! Requires clever experiments
or observations on natural populations
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Now we’ll discuss phenotypes
mutant
wild type
and genotypes
mutant gene
wild type gene
a
wild type gene
b
mutant gene
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Genes are inferred from complementation groups (recessive mutations)
Noncomplementation:
two independent mutations in the same gene
Complementation:
mutations are in distinct genes
homozygous
mutant mother
homozygous
mutant father
homozygous
mutant mother
homozygous
mutant father
a
b
a1
a2
a
b
a1
a2
mutant phenotype
mutant phenotype
a
mutant phenotype
mutant phenotype
a1
b
hybrid offspring shows normal
phenotype because one normal
copy of each gene is present
a2
hybrid offspring shows mutant
phenotype : there are no normal
copies of the mutated gene
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Chromosomes of a male,
arranged in pairs
There are only a few genes on the Y chromosome.
Males are functionally haploid for genes on the X chromosome.
1. Most genes for rhodopsins (the 4 proteins responsible for photoreception in the
retina) are on the X chromosome.
Therefore color blindness is inherited maternally (X-linked).
2. One of the blood clotting proteins is also carried on the X chromosome.
Therefore the most common form of hemophilia is X-linked.
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Bi 1 Cameo
Professor Angela Stathopoulos
Drosophila as a model organism for early development
http://biology.caltech.edu/Members/Stathopoulos
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More and more genomes are being sequenced:
•
Mycoplasma genitalium (human genital tract bacterium)
•
Escherichia coli (bacterium)
•
Saccharomyces cerevisiae (budding yeast)
•
Arabidopsis thaliana (wall cress)
•
Caenorhabditis elegans (nematode worm)
~ 19,000
•
Drosophila melanogaster (fruit fly)
~ 14,000
•
Ciona intestinalis (sea squirt)
~16,000
•
Homo sapiens (humans)
~ 30,000
468 genes
4289
~6300
~26,000
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What determines complexity if not gene number???
FUGU
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Comparison of Human and Fugu huntingtin gene
67 exons align 1:1
180K versus 24K
Size differential due to increased intron size in human gene
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Higher organisms typically contain many gene duplications
-> complicated genetics! (yet another reason to work on Drosophila)
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Drosophila contains genes conserved in higher organisms and
exhibits less duplication
GreenYeast
Blue Yeast, worm
Yellow Only mouse
RedMouse, worm
Pink Mouse,worm, human
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FGF-ligands
Vertebrates >20
Worm
2
Drosophila
3
many functioning redundantly
egl17 and let756
branchless
+
Pyr and Ths
2 FGF receptors (breathless and heartless)
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Thisbe and Pyramus are most similar to egl-17 and FGF-8
ths
pyr
egl-17
FGF-8/17/18/24
bnl
viral FGF-like
let-756
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Heartless FGF receptor activation controls
mesoderm migration
Movie courtesy of FlyMove: M.Leptin
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ths and pyr expression is dynamic
ths
pyr
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pyramus and thisbe double in situ hybridization
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Bi 1
“Drugs and the Brain”
End of Lecture 20
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