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Bi 1
“Drugs and the Brain”
Lecture 27
Thursday, May 26, 2006
Evolution 1. Inferences from molecular biology.
Mechanisms of speciation
5/23/2017
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What is a theory (as in, “Theory of Evolution)?
Wikipedia
In common usage, people use the word "theory" to signify "conjecture",
"speculation", or "opinion." In this sense, "theories" are opposed to "facts" — parts
of the world, or claims about the world, that are real or true regardless of what
people think.
In science, a theory is a proposed description, explanation, or model of the manner
of interaction of a set of natural phenomena, capable of predicting future
occurrences or observations of the same kind, and capable of being tested through
experiment or otherwise verified through empirical observation. It follows from this
that for scientists "theory" and "fact" do not necessarily stand in opposition. For
example, it is a fact that an apple dropped on earth has been observed to fall
towards the center of the planet, and the theory which explains why the apple
behaves so is the current theory of gravitation.
HAL
A theory is not a mathematical theorem.
A reminder of Henry Lester’s office hours
Monday & Thursday, 1-1:30, outside the Red Door
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DNA changes that might lead to speciation
1. “Break and join” events
2. Repeated elements can lead to gene and exon duplication.
3. How transposable elements move
5. What is the selective advantage of repetitive elements?
5. Point mutations
What is a species?
Populations of the same species can
interbreed, exchange genes, and pass on traits to their offspring.
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Number of base pairs in Genbank, 1982 - present
60
56
52
48
44
40
36
32
28
24
20
16
12
8
4
0
1.E+11
Semilogarithmic plot
1.E+10
Base Pairs
Base Pairs (billions)
http://www.ncbi.nlm.nih.gov/Genbank/genbankstats.html
1.E+09
1.E+08
1.E+07
2-fold / 18 mo
10-fold / 5 yr
1.E+06
1980 1985 1990 1995 2000 2005
1980 1985 1990 1995 2000 2005
Year
Year
These graphs provide one example of the rapidly accumulating data in
biology, leading to entire new fields of study.
Today’s topic, evolution, is one such field.
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like Lecture 15:
Polymerase Chain Reaction (PCR) gives access to genomes of many rare organisms
heat to
separate DNA
strands
cool to
bind primers
heat to
separate DNA
strands
cool to
bind primers
DNA
synthesis
heat to
separate DNA
strands
DNA
synthesis
cool to
bind primers
DNA
synthesis
fragment
of DNA
to be detected
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from Lecture 15:
Lander et al
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1.
“Break and join” events produce conserved synteny.
~180 events between mouse and human, 75 mY ago
Regions where corresponding genes that began as neighbors have remained as
neighbors, strung together in the same sequence in both species.
“synteny”
Human
Little Alberts 9-28
© Garland
Mouse
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See also Lectures 15, 18
Repetitive elements in the human genome
SINE = Short INterspered Element
(L1-like)
(Alu-like)
from Lander Figure 17
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The human Alu sequences are SINEs
1,090,000
copies
(1) length ~ 300 bp
(2) account for 13% of the genome
(3) require reverse transcriptase and
an RNA intermediate to transpose.
(4) occur primarily in GC-rich regions
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from Lecture 20
A Reminder that recombination at meiosis is based on cross-strand exchange
The process involves
(a)
Enzymes that nick
(b)
Base pairing
(c)
Enzymes that ligate
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Gene and exon duplication due to repeated elements
Figure 9-11 shows how
individual exons would be
duplicated by the same
mechanism
Misalignment at meiosis leads to . . . .
“Unequal” crossing over
Little Alberts 9-5
© Garland
This chromosome would not survive
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Long introns may increase the probability that shuffling maintains functional exons
From Lecture 15:
Exons don’t differ much among organisms,
but human introns are longer
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See also Lecture 18
Globin paralogs in the human genome
Two categories
of sequence-related genes:
Orthologs are pairs of genes in different
species that evolved from a common
ancestral gene by speciation. Orthologs
are “the same gene” in two different
genomes.
>90% of genes have orthologs in
human – rat – mouse.
Paralogs are pairs of genes related by
duplication within a genome.
Myr BP
Orthologs often retain the same function
in the course of evolution, whereas
paralogs may evolve new functions,
even if related to the original one.
© Garland publishing
Based on Little Alberts 9-7
(Hemoglobin is a tetramer, a2b2)
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new
mouse-human split, produces orthologs
Globin paralogs in the mouse genome
Globin paralogs in the human genome
chromosome
7
Myr BP
Myr BP
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Hemoglobin paralogs in the mouse genome
Hemoglobin paralogs in the human genome
no duplication
duplication
chromosome
7
Myr BP
Myr BP
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orthologs resemble each other
across species (mouse b vs human b)
Hemoglobin paralogs in the mouse genome
mouse e vs b
paralogs resemble each other,
distant or
closely,
within
a species
Hemoglobin
paralogs
in the
human
genome
human e vs b
gG vs gA
chromosome
7
Myr BP
Myr BP
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Here are remaining repetitive elements that may have produced these duplications
Alu (SINE)
L1 (LINE)
Little Alberts 9-18
© Garland 1998
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3. How transposable elements move, so that they become repetitive
“Move” is the common term, but “copy” is a better term.
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3a. DNA-mediated transposable elements: long-distance movements
“Many details are known, but the process is too
complex to be illustrated here”--Big Alberts
base pairing
and enzymes
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3b. RNA-mediated transposable elements are retrotransposons.
1,090,000
copies
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3b. RNA-mediated transposable elements are retrotransposons.
Discovered by David Baltimore
in retroviruses,
where it functions much more frequently.
A virus is a
“fully mobile genetic element
that can escape from cells”
Reverse transcriptase
encoded by the LINE-1 element
Little Alberts 6-34
© Garland
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4. Selective advantage, if any, of repetitive elements?
A.
None, just “selfish” DNA
B.
In many species, Alu-like sequences are expressed under conditions of stress.
The resulting RNAs specifically bind and block a protein kinase called PKR.
PKR ordinarily blocks protein synthesis
Therefore, SINE RNAs would promote protein translation under stress.
A Bi1 irony:
Some biologists suggest that repetitive elements play roles
resembling those played by lithium and the SSRIs!
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DNA changes that might lead to speciation
1. “Break and join” events
2. Repeated elements can lead to gene and exon duplication.
3. How transposable elements move
4. What is the selective advantage of repetitive elements?
5. Point mutations
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To assess the importance of point mutations vs repetitive elements and other changes
in speciation, we need the complete sequences of two closely related genomes.
Human / chimpanzee (draft available now; full sequence underway)
http://www.genome.gov/11008056
Molecular functions showing the
strongest evidence for positive
selection.
Highly represented: olfactory receptors;
transcription factors & structural
proteins in speech and hearing;
immune defenses;
tumor suppression;
sperm development.
“Human-chimp DNA sequence
divergence is roughly 10 times the
divergence between random pairs
of humans.”
G. Clark et al (2003), Science 302, 1960;
Nielsen et al, PLoS Biology 3, epub
Mouse / rat are now available, April 2004.
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from lecture 15: While we await full sequences . . .
Physical Chemistry of DNA Hybridization:
Studied at Caltech in ‘60’s and ‘70’s
by Norman Davidson
1. The hydrogen bonds that
form double-stranded DNA are
easily disrupted by heating.
2. Some dyes fluoresce when
they bind to double-stranded
DNA.
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DNA Hybridization: a conventional method to assess homology
1. heating.
If there are some mismatches, the
structure is less stable. It therefore
melts at a lower temperature than
perfectly paired DNA.
2. Alternatively, the hydrogen bonds
are disrupted at lowered ionic
strength, because the negatively
charged phosphate groups exert
stronger forces on each other through
the lower dielectric constant of the
solution.
3. These hybridization phenomena
form the basis for several quantitative
measurements of DNA homology.
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Hybridization is appropriate for assessing random mutations:
~ 1% / 9 Myr
bonobo
Alberts Figure 9-15
© Garland
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Bonobos (pigmy chimpanzees)
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Bi 1
“Drugs and the Brain”
End of Lecture 27
5/23/2017
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Bonobos (pigmy chimpanzees)
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