Lecture 21 Slides
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Life Sciences 1B: Genetics, Genomics, & Evolution
Lecture 21 --- Human Unique Adaptations
Maryellen Ruvolo
April 17, 2014
Treasure your exceptions!
- William Bateson
Pablo Picasso
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Genotypic difference(based on protein-coding genes)
Phenotypic difference
King & Wilson in 1975 based this conclusion on protein electrophoresis data.
Inference: the basis for phenotypic evolution must
therefore lie mostly within genetic regulatory regions.
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Gene regulatory differences may thereforebea significant sourceof species phenotypic differences
(perhaps more so than DNA protein-coding differences).
The paradox of Phenotypic versus Genotypic evolution
Gene regulatory differences can change levels of gene expression,
(how muchof a polypeptide is made), or whichtissuesa protein is
made in, or whenit is made during development.
How?
King & Wilson 1975
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Small part of an actual yeast DNA chip with 1764 spots,
each specific for hybridization with a different mRNA sequence.
(Fig. 10.14)
Each spot is a
known fragment
of DNA (e.g.,
a PCR product)
DNA Microarrays are one way to study gene expression
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Closely-related Cancers show gene expression differences
Top 50 gene
predictorsare useful
diagnostically
Golub 1999 Science 286, 531
Eachcolumn
is an
individual
with
leukemia.
Each rowshows
the
expression
pattern of
one gene
that is agood
predictor
of
leukemia
type.
ALL AML
Expression
levels in
individual
samples are
high (red)
or low (blue)
ALL: acute lymphocyticleukemia
AML: acute myeloid
leukemia
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Human
Chimpanzee
Orangutan
Rhesus macaque
Amounts of gene expression change can be assigned to
terminal branches of the primate tree.
We can compare gene expression patterns between species
to see whether patterns are consistent in a tissue type
(and if anything unusual has happened in humans!)
*
Gene expression differences between species are a type of
genetic distance measure that can be used to build trees.
Species differences in gene expression
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Gene expression differences among primates in different tissues
macaque
Enard 2002
This branch is relatively longer
(suggesting accelerated change
in human brain).
These branch lengths
are relative and scaled
differently on each tree.
In absolute terms, there
is more gene expression
difference betweenH-C liver than between
H-C brain or blood
(not evident from
this figure) (Hsieh,2003).
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Expression profiling in primates reveals rapid evolution
in expression of human transcription factors
(Tissues compared were livers)
Up-regulated just in humans Down-regulated just in humans
human
chimp
orangutan
rhesus monkey
Gilad 2006 Nature 440:242-5
Genes with human-unique expression patterns
Human data point appears first for each gene.
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What possible effect could arise from rapid evolution
of human transcription factors?
Largephenotypic changes could be the result of
changes in a smallnumber of transcription factors.
changes in expression of a transcription factor gene
could cause a transcription factor to be more or less
active, active in different cell types, or active
at different times in development.
changes in the protein sequence of a transcription factor
could change how a transcription factor regulates genes,
or change which genes it regulates
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We now know many genes that differ significantly in
protein sequence and in expression levels
between humans and chimpanzees.
However, in almost all cases,
we do not understand how these genetic differences
translate into phenotypic differences.
This is the challenge for the future.
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The following experiment demonstrates one way
by which we might gain understanding of how
genomic differences lead to phenotypic differences
between chimp & human species.
Getting at Functional Significance of Genes
Case study:
A Regulatory Region of the Androgen Receptor Gene
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