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Today: Today:
•Mendelian Genetics Wrap-up
•Adding Chromosomes to the Mix
• Lunch
• Inoculate Cultures
• The Eukaryotic Genome
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Morgan Discovers Sex-Morgan Discovers Sex-Linked Genes! Linked Genes! (and wins Nobel
Prize, 1933)
?
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Sex Determination Happens in a
Variety of Ways
Sex chromosomes (especially the X
chromosome) carry genes for many other
characters.
In humans, the term “sex-linked” generally refers to genes on the
X chromosome.
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An Aside: X Inactivation in Female Mammals
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In females, one X chromosome is inactivated (at random) and
condenses into a compact Barr body along the inside of the nuclear
envelope. Most genes on this X chromosome are not expressed.
Because it is random which X chromosome forms the Barr body during development,
females are Mosaics of the two cell types.
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In females, one X chromosome is inactivated (at random) and
condenses into a compact Barr body along the inside of the nuclear
envelope. Most genes on this X chromosome are not expressed.
Because it is random which X chromosome forms the Barr body during development,
females are Mosaics of the two cell types.
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Practice Question: Sex-Linked Chromosomal Inheritance
If you see the If you see the number 74, then number 74, then you do you do notnot have have red-green color red-green color blindness. If you see blindness. If you see the number 21, you the number 21, you are color blind to are color blind to some extent. A some extent. A totally color-blind totally color-blind person will not be person will not be able to see any of able to see any of the numbers. the numbers.
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If a color blind man has children with a “wild-type” woman, what are the chances that a daughter of theirs will be colorblind?
What are the chances that their son will be colorblind?
Can females be colorblind? What would the genotype of the parents have to be?
Practice Questions: Sex-Linked Chromosomal Inheritance (Part 2)
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More of Morgan’s Complications
Morgan does further crosses between wild type flies (gray bodies and normal wings) and
mutant flies (black bodies and vestigial wings)
b+ = gray
b = black
vg+ = normal wings
vg = vestigial wings
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His Results:
High Frequency of Parental Phenotypes
!
????
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An Understanding of Linkage Groups allows for LINKAGE MAPPING
One of Morgan’s students, Alfred Sturtevant, develops a method to construct a genetic map.
He hypothesizes that recombination frequencies reflect the distances between genes on chromosomes.
One map unit (or centrimorgan) = 1 % recombination frequency
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A sample Genetic Map of a
Drosophila Chromosome
Note that a linkage map is based on recombination
frequencies. As the frequency of cross-over
is NOT uniform over the length of the chromosome, it
portrays the sequence of genes but not their
precise locations.
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Thinking Back to Meiosis: Complications of Chromosomal Inheritance- Non-Disjunction
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Nondisjunction can result in
ANEUPLOIDY- an abnormal chromosome number
Monosomic- the aneuploid cell has a single copy of a chromosome
Trisomic- the aneuploid cell has three of a given chromosome
If an entire organism has more than two complete chromosome sets it is
POLYPLOID (triploid=3n, tetraploid=4n, etc.)
Red viscacha rat from Argentina = 4n
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Aneuploidy results in several human disorders:
3 copies of Chromosome 21 =Down’s Syndrome
(1:700 children born in US)
XYY = no general traits, except tall
XXX = healthy, “normal”
XXY = Klinefelter Syndrome- phenotypically male with normal
intelligence, sterile
XO = Turner syndrome- phenotypically female, sterile,
usually normal intelligence
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Chromosomal Alterations can also cause Human Disorders:
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One Other Notable Exception: Extranuclear GenesGenes contained in the chloroplasts or mitochondria
are inherited maternally and do NOT display Mendelian inheritance patterns!
In Plants, plastid genes typically responsible
for variegation in leaves.
In animals, defects in proteins involved in the ETC or ATP synthase affect ATP
Synthesis (i.e. mitochondrial myopathy)
Skeletal Muscle: Mitochondrial myopathy, electron microscopy. Number, size and shape of mitochondria are increased and abnormal.
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Next: Next: What’s a What’s a
Genome??Genome??
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Thinking About Genomes…Thinking About Genomes…
Understanding Genome
Structure and Function! !
Why is genome structure/ function
important?
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Remembering Structure…
Nucleosomes are formed of DNA winding around 8 histone proteins, two each of H2A, H2B, H3, and H4. The N-terminus of each
protein extends outward forming a “histone tail”.
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Nucleosomes condense into 30nm fibers due to interactions between the histone tails of one nucleosome, the linker DNA,
and the nucleosomes on either side.
Remembering Structure…
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During prophase, chromosomes condense further!
Remembering Structure…
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Thinking About Genomes…
In metaphase chromosomes,
the same genes always end up at
the same locations.
What does this tell us about
chromosome packing??
Photo: V. Miszalok, U. Klingbeil, I. Chudoba, V. Smolej
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The Importance of Gene Expression
Cell Differentiation! Differences in cell types are due to differential
gene expression.
How might a cell regulate
gene expression??
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Regulating Chromatin
Histone Histone acetylation acetylation
(-COCH(-COCH33) ) prevents adjacent adjacent
nucleosomes nucleosomes from binding from binding
to one to one anotheranother
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Lysine Residues (amino acids) in the Histone Tails have an Acetyl
group added to them
How does this change the structure of the tail?
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Regulating Chromatin
Staining of Acetylated H3 Throughout the Cell Cycle. A field of cells containing interphase, prophase(P), prometaphase (PM) and metaphase (M); Michael J. Hendzel and Michael J. Kruhlak
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Other Modifications to Histone Tails
Histones may also be Methylated (CH3)
New Model: Histone Code Hypothesis!
Figure: two different metaphase spreads (human female) with preferential staining. Barbara A. Boggs, Peter Cheung, Edith Heard, David L. Spector, A. Craig Chinault & C. David Allis
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DNA Methylation
Proteins that bind to methylated
DNA may recruit histone
deacetylases!
What would this enzyme do??
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Gene Regulation at the Level of Chromatin Structure
Heterochromatin vs Euchromatin??Heterochromatin vs Euchromatin??
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New Field: Epigenomics!
Figure: Epigenomics.com
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Next Up: Regulating at the
Level of Transcription!
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Regulating Transcription with
Transcription Factors
A single protein, TFIID, binds to the TATA box in
the promoter. The correct combination of other small proteins must then bind to TFIID
before the RNA Polymerase can bind and
initiate transcription.
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Eukaryotes Also Package Regulator Protein Binding Sites within the
Promoter
Upstream sequences known as
Enhancers, may also
bind proteins and fold over
tohelp initiate
transcription
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Proteins that Bind DNA are (relatively) Easy to Find!
Understanding DNA and Protein Structure allows us to recognize motifs, or structures that allow a protein to interact with DNA
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Combinatorial Control of
Gene Expression
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Post Transcriptional
Regulation: Small RNAs
We carry 250+ genes for micro RNAs
(~20 base pairs long). How might these micro RNA’s affect translation?
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Post-Transcription: RNA Interference (RNAi)
Experimental Observation: Injecting Experimental Observation: Injecting dsRNA into a cell can silence the dsRNA into a cell can silence the
corresponding gene!corresponding gene!http://www.nature.com/focus/rnai/animations/animation/animation.htm
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Post-Transcription: Alternative Splicing
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Post-Transcription
: mRNA Stability
Figure: Analysis of H-ferritin mRNA stability in control and PMA-treated THP-1 cells; Biochemical Journal (1996) Volume 319, 185-189
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Post-Transcription: mRNA Editing?!!
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Post-Translation: Ubiquitin
Chamber of Chamber of Doom?!?Doom?!?
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What We’ve Learned from
Our Own Genome, and
Comparing Genomes
http://www.sciencemag.org/sciext/btoy2007/video/bt_video.html
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Comparing Prokaryotic and Eukaryotic Genomes
Genome length (base pairs) 4,640,000 12,068,000 Genome length (base pairs) 4,640,000 12,068,000
Number of protein-coding genes 4,300 5,800 Number of protein-coding genes 4,300 5,800
Proteins with roles in: Proteins with roles in:
Metabolism 650 650 Metabolism 650 650
Energy production/storage 240 175 Energy production/storage 240 175
Membrane transport 280 250 Membrane transport 280 250
DNA rep./repair/recombination 120 175 DNA rep./repair/recombination 120 175
Transcription 230 400 Transcription 230 400
Translation 180 350 Translation 180 350
Protein targeting/secretion 35 430 Protein targeting/secretion 35 430
Cell structure 180 250 Cell structure 180 250
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Essential Components of Multicellular Genomes
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Lessons from Genomics: Many Repetitive Sequences
Examples:Examples: Minisatellits (10-40 bp) repeatsMinisatellits (10-40 bp) repeats Microsatellites (1-3 bp) repeatsMicrosatellites (1-3 bp) repeats
CODIS, our national DNA database, uses
Short Tandem Repeats from 13 loci to identify
individuals.
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Lessons from Genomics: We have transposons!!
Transposons make Transposons make up >40% of the up >40% of the human genome!human genome!