lecture 21 slides

8/12/2019 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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