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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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Chromosomes of a male,

arranged in pairs

from Lecture 15:

Humans have 22 pairs of chromosomes, plus the X and Y.Males are XY; females are XX.

© Garland; Little Alberts Fig 5-12

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parents

offspring

(Human gametes are also monoploid, because half the somatic number = 1)

Little Alberts 20-4© Garland Publishing

Greek, marry

Somatic cells have two copies (maternal and paternal) of each chromosome; they are diploid. One copy is maternal, the other paternal.

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.

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Mendel’s Laws imply independent

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.

somaticcells

Little Alberts 1st edition 9-36© Garland Publishing(2nd Figure 20-11A is wrong)

1st mechanism for genetic diversity:independent assortment of chromosomes

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2nd mechanism for genetic diversity:recombination within chromosomes

Little Alberts 20-11B© Garland Publishing

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Interphase is nearly absent between the two cell divisions of meiosis

A later lecture will treat the cell cycle and mitosis(simple division by separating chromosomes)

Big Alberts 17-2© Garland Publishing

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2nd Meiotic division

Completion of 1st Meiotic division

Modified from Little Alberts 9-35© Garland Publishing

Meiosis differs from mitosis in two ways

2. No DNA replication

between 1st and 2nd divisions

diploid

1. Crossing-over (recombination)

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Thomas Hunt Morganfounder of Caltech’s

Biology Divisionand of 20th-century genetics

from Lecture 14

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If two genes are recombined x% of the time, they are said to be separated by a genetic map distance of x centimorgans (cM).

paternalchromosome

maternalchromosome

dark eyes

hairy legs

hairy legs

dark eyes

two DNA double helices with nearly identical sequences

DNA molecules that have crossed over

phenotype (Greek, to show)

phenotype (Greek, to show)

Quantitative measure of recombination

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paternalchromosome

maternalchromosome

dark eyes

hairy legs

hairy legs

dark eyes

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

DNA molecules that have crossed overLittle Alberts 6-28© Garland Publishing

If two genes are recombined x% of the time, they are said to be separated by a genetic map distance of x centimorgans (cM).

Quantitative measure of recombination

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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

Recombination at meiosis is based on cross-strand exchange

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OH

Little Alberts Fig 3-42© Garland publishing

ligate nick

Latin, to tie

from Lecture 17:

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geneA

geneBgenetic map:

geneX

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.

The relationship between classical genetics and molecular genetics

geneA

geneBphysical (DNA) map:

geneX

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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Lander et al Figure 15.

Distance in cM along

the genetic map of

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.

Chromosome 12 recombines about twice per meiosis

The genetic map and the physical map are colinear, but not quite proportional.

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chromosomal shuffle

or

recombination

or

point mutation

How do we know that a genetic event has taken place?

1. DNA chemistry (Expensive, new, unlikely)

2. detectable change in organism A phenotype! Requires clever experimentsor observations on natural populations

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Now we’ll discuss phenotypes

and genotypes

wild type mutant

a

b

mutant gene

wild type gene mutant gene

wild type gene

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Genes are inferred from complementation groups (recessive mutations)

homozygousmutant mother

a

a

mutant phenotype

homozygousmutant father

b

b

mutant phenotype

Complementation:mutations are in distinct genes

a

b

hybrid offspring shows normal phenotype because one normal copy of each gene is present

a1

a2

hybrid offspring shows mutant phenotype : there are no normal copies of the mutated gene

homozygousmutant mother

a1

a1

mutant phenotype

homozygousmutant father

a2

a2

mutant phenotype

Noncomplementation:two independent mutations in the same gene

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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.

Chromosomes of a male,

arranged in pairs

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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) 468 genes

• Escherichia coli (bacterium) 4289

• Saccharomyces cerevisiae (budding yeast) ~6300

• Arabidopsis thaliana (wall cress) ~26,000

• Caenorhabditis elegans (nematode worm) ~ 19,000

• Drosophila melanogaster (fruit fly) ~ 14,000

• Ciona intestinalis (sea squirt) ~16,000

• Homo sapiens (humans) ~ 30,000

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FUGU

What determines complexity if not gene number???

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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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Green-Yeast

Blue -Yeast, worm

Yellow -Only mouse

Red-Mouse, worm

Pink -Mouse,worm, human

Drosophila contains genes conserved in higher organisms andexhibits less duplication

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FGF-ligands

Vertebrates >20 many functioning redundantly

Worm 2 egl17 and let756

Drosophila 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 pyregl-17

bnl viral FGF-likelet-756

FGF-8/17/18/24

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Heartless FGF receptor activation controls mesoderm migration

Movie courtesy of FlyMove: M.Leptin

Shortcut to Gastrulation copy.mov.lnk

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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