Transcript An Aside: X Inactivation in Female Mammals

Today:
•Mendelian Genetics
Wrap-up
•Adding Chromosomes
to the Mix
• Lunch
• Inoculate Cultures
• The Eukaryotic
Genome
Morgan Discovers Sex-Linked
Genes! (and wins Nobel Prize, 1933)
?
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.
An Aside: X Inactivation in Female
Mammals
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.
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.
Practice Question: Sex-Linked
Chromosomal Inheritance

If you see the number
74, then you do not
have red-green color
blindness. If you see
the number 21, you
are color blind to
some extent. A totally
color-blind person will
not be able to see any
of the numbers.
Practice Questions: SexLinked Chromosomal
Inheritance (Part 2)



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?
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
His Results:
High
Frequency
of Parental
Phenotypes!
??
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
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.
Thinking Back to Meiosis: Complications of
Chromosomal Inheritance- Non-Disjunction
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
Aneuploidy results in several human disorders:
3 copies of Chromosome 21
=Down’s Syndrome
(1:700 children born in US)
XXY = Klinefelter Syndromephenotypically male with normal
intelligence, sterile
XYY = no general traits,
except tall
XXX = healthy, “normal”
XO = Turner syndromephenotypically female, sterile,
usually normal intelligence
Chromosomal Alterations can also cause
Human Disorders:
One Other Notable Exception: Extranuclear Genes
Genes 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.
Next:
What’s a
Genome??
Thinking About Genomes…
Understanding
Genome
Structure and
Function!
Why is genome
structure/
function
important?
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”.
Remembering Structure…
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…
During prophase, chromosomes condense further!
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
The Importance of
Gene Expression
Cell Differentiation!
Differences in cell types
are due to differential
gene expression.
How might a cell
regulate gene
expression??
Regulating
Chromatin
Histone
acetylation
(-COCH3)
prevents
adjacent
nucleosomes
from binding
to one another
Lysine Residues (amino acids) in the
Histone Tails have an Acetyl group
added to them
How does this change the structure of
the tail?
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
Other Modifications to Histone Tails
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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
DNA Methylation
Proteins that bind
to methylated
DNA may recruit
histone
deacetylases!
What would this enzyme
do??
Gene Regulation at the Level of
Chromatin Structure
Heterochromatin vs Euchromatin??
New Field: Epigenomics!
Figure: Epigenomics.com
Next Up:
Regulating at the
Level of
Transcription!
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.
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
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
Combinatorial
Control of
Gene
Expression
Post Transcriptional
Regulation: Small
RNAs
We carry 250+ genes
for micro RNAs (~20
base pairs long). How
might these micro
RNA’s affect
translation?
Post-Transcription: RNA
Interference (RNAi)
Experimental Observation: Injecting dsRNA
into a cell can silence the corresponding
gene!
http://www.nature.com/focus/rnai/animations/animation/animation.htm
Post-Transcription: Alternative
Splicing
PostTranscription:
mRNA
Stability
Figure: Analysis of H-ferritin mRNA stability
in control and PMA-treated THP-1 cells;
Biochemical Journal (1996) Volume 319, 185-189
Post-Transcription: mRNA
Editing?!!
Post-Translation: Ubiquitin
Chamber of
Doom?!?
What We’ve
Learned from
Our Own
Genome, and
Comparing
Genomes
http://www.sciencemag.org/sciext/btoy2007/video/bt_video.html
Comparing Prokaryotic
and Eukaryotic Genomes
Genome length (base pairs)
4,640,000
Number of protein-coding genes
4,300
Proteins with roles in:
Metabolism
650
Energy production/storage
240
Membrane transport
280
DNA rep./repair/recombination
120
Transcription
230
Translation
180
Protein targeting/secretion
35
Cell structure
180
12,068,000
5,800
650
175
250
175
400
350
430
250
Essential Components of
Multicellular Genomes
Lessons from Genomics: Many
Repetitive Sequences
Examples:
 Minisatellits (10-40 bp) repeats
 Microsatellites (1-3 bp) repeats
CODIS, our national
DNA database, uses
Short Tandem Repeats
from 13 loci to identify
individuals.
Lessons from Genomics: We
have transposons!!
Transposons make up
>40% of the human
genome!