Transcript Lecture PPT - Carol Lee Lab

Origin of Animals
1
Evolution of Development:
Evolution of Animal Body Plans as an Example
Or, another way to conceptualize
today’s lecture:
Evolution of Gene
Regulatory Networks:
Evolution of Development as an Example
• What is an Animal?
• What makes them different from
other organisms?
• When did they Evolve?
• How did they Evolve?
What is an Animal?
Multicellular (metazoan)
Heterotrophic (eat, not photo or chemosynthetic)
Eukaryote
No Cell Walls, have collagen
Nervous tissue, muscle tissue
Particular Life History-developmental patterns
(this lecture)
• http://www.wimp.com/planktonlife/
Are there differences between plant
and animal evolution?
• Greater diversity in sexual systems in plants
– Abundant asexuality
• More chemistry less behavior in plants
• Development is less rigid and regulated in
plants: perhaps allowing for more evolution
by “hopeful monsters,” as developmental
abnormalities are more tolerable in plants
• Polyploidy is tolerated more readily and
common in plants
Outline
• Today: Bigger picture on how radical changes
in body plan come about
• Evolution of Development
• Evolution of Developmental Gene Regulatory
Networks (GRNs)
• Hierarchy in Evolution of GRNs
• Evolution of GRNs leading to evolution of
major phylogenetic breaks in Earth History
Outline
• Next Lectures: Human Evolution… a great
example of Evolution of Development
• Most differences between humans and other
primates are due to evolutionary changes at a
few developmental genes
Review concepts from previous lectures:
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cis- and trans-regulation
Transcription factors
Pleiotropy
Cambrian Explosion
Phylogeny
Evolution of Development:
• What is it?
• How can it lead to evolution of radical changes
in body plan?
• How can different types of developmental
changes (mutations at different developmental stages)
lead to different hierarchical evolutionary changes
(that distinguish phylum, class, order, family, genus,
species)?
Ontogeny Recapitulates Phylogeny
Ernst Haeckel (1834-1919)
• Ontogeny is the course of development of an organism from
fertilized egg to adult; phylogeny is the evolutionary history of a
group of organisms.
• Haeckel observed that as embryos of vertebrates developed, they
passed through stages that resembled the adult phase of more
ancestral (“primitive”) organisms. For example, at one point each
human embryo has gills and resembles a tadpole.
• Haeckel’s idea was that a species’ biological
development, or ontogeny, parallels and summarizes
the species’ evolutionary history, or phylogeny
Ontogeny Recapitulates Phylogeny
Ernst Haeckel (1834-1919)
• Some of his analogies have been discredited (in favor
of Von Baer’s ideas)
• However, Haeckel's general concept, that the
developmental process reveals some clues about
evolutionary history, appears to hold for the evolution
of developmental genes.
Romanes's 1892 copy of Ernst
Haeckel’s embryonic drawings
The Cambrian Explosion
65 mya: Cretaceous Extinction
(dinosaurs go extinct)
230 mya: Permian Extinction
570 mya: Cambrian Explosion
Evolution of Animal Body Plans
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True Tissues
Tissue Layers (Diplo vs Triploblasts)
Body Symmetry
Evolution of body cavity (Coelom)
Evolution of Development
Cambrian
Explosion
How could this happen?
(genetic mechanism?)
The Evolution of Development
(Freeman& Herron, Chapter 19)
• The tremendous increase in diversity during the
Cambrian explosion appears to have been caused
by evolution of developmental genes
• Changes in developmental genes can result in
radically new morphological forms
• Developmental genes control the rate, timing, and
spatial pattern of changes in an organism’s form as
it develops into an adult
• The discovery of Hox genes
– Not the “most important” dev genes
– Not the only developmental genes
– But, among the first studied
Hox genes are types of Homeotic genes, which are genes that
control the patterns and order of development in plants and
animals. For example, homeotic genes are involved in
determining where, when, and how body segments develop in
organisms.
Examples of Homeotic genes: Hox genes, paraHox genes,
MADS-box containing genes, etc.
Changes in a few regulatory genes
could have big impacts
• Most new features of multicellular
organisms arise when preexisting cell types
appear at new locations or new times in
the embryo.
• Changes in the specification of cell fates are
a major mechanism for the evolution of
different organismal forms.
• For example, small changes in gene regulation
could cause changes in timing of
developmental events (heterochrony), which
could then lead to dramatic changes in
morphology
• Stephan Jay Gould in 1977 proposed this as a
mechanism for evolutionary change
So, what happened during the
Cambrian Explosion?
(1) Precambrian-Paleozoic
Boundary (~570 MYA)
All major Animal
Phyla (different body
plans) evolved within
a relatively narrow
window of time
Cambrian Explosion
Agnatha
Gnathostomata
200
Echinodermata
0
Annelida
Arthropoda
Mollusca
Million Years Ago
Cambrian
“Cambrian Explosion”
800
1000
1200
1400
Precambrian
600
Based on phylogeny of
animals based on DNA
sequence data, the
radiation of animals
predates the geological
record of the Cambrian
Explosion
Wray et al. 1996
The Grand Mystery
How can different types of
developmental changes lead to
different hierarchical evolutionary
changes (that distinguish phylum,
class, order, family, genus, species)
The Grand Mystery
Why has there has been so little
change in animal body plans since
the Cambrian Explosion???
Davidson & Erwin. 2006. Gene Regulatory Networks and the Evolution
of Animal Body Plans. Science. 311: 796-800.
Big phylogeny
“Kernels”
“Gene Batteries”
Different Hierarchical Components of Gene Regulatory Networks
1. ‘‘Kernels’’ of the GRN: Evolutionarily inflexible subcircuits (of
regulatory genes) that perform essential upstream functions in
building given body parts  main differences among phyla
2. ‘‘Plug-ins’’ of the GRN: Certain small subcircuits (of regulatory
genes), that have been repeatedly co-opted for diverse
developmental purposes
3. Input/Output (I/O) devices within the GRN: Switches that allow
or disallow developmental subcircuits to function in a given
context (e.g. Hox genes)
4. Differentiation Gene Batteries: Consist of groups of proteincoding genes under common regulatory control, the products of
which execute cell type–specific functions  Species differences
First, Basics on Developmental
Gene Regulatory Networks
Developmental Gene Regulatory Network
• The binding of transcription factors to
regulatory DNA sequences controls the spatial
and temporal expression of genes in the
developing organism
• Because each transcription factor regulates the
expression of multiple genes, regulatory gene
interactions form a network.
S. Sinha
Developmental Gene Regulatory Network
• The binding of transcription factors to
regulatory DNA sequences controls the spatial
and temporal expression of genes in the
developing organism
• Because each transcription factor regulates
the expression of multiple genes, regulatory
gene interactions form a network.
Developmental Gene Regulatory Network
Example shown for neural development
Developmental Gene Regulatory Networks (GRNs)
• Development is controlled directly by progressive changes in
the regulatory state in the spatial domains of the developing
organism.
• As regulatory genes regulate one another as well as other
genes, and because every regulatory gene responds to
multiple inputs while regulating multiple other genes, the total
map of their interactions has the form of a network.
• Gene Regulatory Networks consist of:
• Regulatory genes, which encode transcription factors
• Signaling genes, which encode ligands and receptors for
intercellular communication
What kind of evolutionary changes
(i.e. mutations) lead to the evolution
of Gene Regulatory Networks?
Evolutionary Changes within the Gene Regulatory
Networks
• Developmental Biologists have hypothesized that most
changes within regulatory networks would be cisregulatory (e.g. promoter, enhancer at the gene)
• The reason is that cis-regulatory changes would only
change the expression of one gene
• On the other hand, Trans-regulatory changes are often
overly pleiotropic, and thus don’t occur as often. But,
when they occur, they have profound effects.
• So, developmental evolutionary changes have been
assumed to be mostly cis-regulatory.
Developmental Gene Regulatory Networks (GRNs)
• Comparative developmental evidence indicates
that reorganizations in developmental gene
regulatory networks (GRNs) underlie evolutionary
changes in animal morphology, including body
plans.
• The nature of the evolutionary alterations that
arise from regulatory changes depends on the
hierarchical position of the change within a GRN.
Developmental Gene Regulatory Networks (GRNs)
• GRNs are hierarchical, so that the portions
controlling the initial stages of development are
at the top of the hierarchy (early in
development), the portions controlling
intermediate processes of spatial subdivision or
the formation of future morphological pattern
are in the middle, and the portions controlling
the detailed functions of cell differentiation and
morphogenesis are at the periphery.
Developmental Gene Regulatory Network
Example shown for neural development
The fundamental differences
“Kernels”
“Gene Batteries”
Development occurs through a sequence of events
• During Development, regulation of gene expression is
critical for determining the differential fate of
genetically identical cells
• Morphological patterning during the course of
development: General  more detailed
• Developmental changes lead to divergence at different
hierarchical levels from the more upstream “kernels”
early in development, to the more peripheral “gene
batteries”
• Ontogeny recapitulates phylogeny:
Christiane Nüsslein-Volhard and Sean Carroll
Ontogeny Recapitulates Phylogeny
Ernst Haeckel (1834-1919)
• Haeckel’s idea was that a species’ biological
development, or ontogeny, parallels and summarizes
the species’ evolutionary history, or phylogeny
• Haeckel's general concept, that the developmental
process reveals some clues about evolutionary history,
might generally hold for the evolution of developmental
genes.
Christiane Nüsslein-Volhard and Sean Carroll
Architectural changes in animal body plans
might have been produced over the past 600
million years by changes in GRNs (gene
regulatory networks) of multiple classes, with
extremely different developmental
consequences and rates of occurrence.
Evolution of GRNs
• The modular sub-circuits of developmental GRNs differ
in evolutionary lability.
• The most slowly changing components — called
kernels — consist of highly conserved regulatory
interactions that establish the progenitor field of a
developing structure.
• The evolutionary stability (constraint) of kernels
contrasts with the lability (evolvability) of other GRN
sub-circuits.
Different Hierarchical Components of Gene Regulatory Networks
1. ‘‘Kernels’’ of the GRN: Evolutionarily inflexible subcircuits (of
regulatory genes) that perform essential upstream functions in
building given body parts  main differences among phyla
2. ‘‘Plug-ins’’ of the GRN: Certain small subcircuits (of regulatory
genes), that have been repeatedly co-opted for diverse
developmental purposes
3. Input/Output (I/O) devices within the GRN: Switches that allow
or disallow developmental subcircuits to function in a given
context (e.g. Hox genes)
4. Differentiation Gene Batteries: Consist of groups of proteincoding genes under common regulatory control, the products of
which execute cell type–specific functions  Species differences
Different Components of Gene Regulatory Networks
1. ‘‘Kernels’’ of the GRN: Evolutionarily inflexible (constrained)
subcircuits that perform essential upstream functions in
building given body parts
•
•
•
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Often dedicated to major formation of body parts
Often sub-circuit of interacting transcription factors
Often highly constrained by pleiotropy
Often cannot undergo evolutionary change without
catastrophic effects
•
Examples in next four slides. Other possible Examples : anterior to
posterior and midline to lateral specification of the nervous system (in
deuterostomes and possibly across Bilateria); eyefield specification [in
arthropods]; gut regionalization [in chordates]; development of
immune systems [across Bilateria]; and regionalization of the
hindbrain and specification of neural crest [in chordates]
‘‘Kernels’’ of the GRN
• Kernels are sub-circuits composed of recursively wired
regulatory genes (that is, they share inputs through multiple cisregulatory interactions), which operate during the initial phase
of regional pattern formation for a particular body part.
• If any of the genes in the sub-circuit are prevented from
functioning, the body part fails to develop.
• A kernel interacts with regional regulatory state sub-circuits,
which in turn activate or repress the activity of differentiation
gene batteries at the periphery of the GRN (next figures).
• The conserved structure of developmental GRN kernels might
be responsible for the phenotypic stability of animal body plans
that has persisted at least since the Early Cambrian period, 520
million years ago.
Endomesoderm specification
kernel, common to sea urchin
and starfish, the last common
ancestor of which lived about
half a billion years ago.
Five of the six genes in the kernel (all
except delta) encode DNA-recognizing
transcription factors
The linkages are highly recursive. The
cis-regulatory module of the otx gene
receives input from three of the five
genes; the foxa gene, from three of the
five; and the gatae, foxa, and bra
genes from two of the same five genes
Possible heart
specification kernels;
assembled from many
literature sources.
Dashed lines show
possible interactions.
These networks are also
highly recursive
General Model for Heart Specification Kernel
A core set of regulatory
genes are used in
common and are linked in
a similar way in a
conserved subcircuit of
the gene network
architecture (grey boxes)
Zebrafish endoderm
kernel (subcircuit)
Photo shows gene
expression of 4
transcription factors
that are part of this
kernel
Tseng et al. 2011
Different Hierarchical Components of Gene Regulatory Networks
1.
blank
2. ‘‘Plug-ins’’ of the GRN: Certain small subcircuits that have
been repeatedly co-opted for diverse developmental purposes
• Not dedicated to formation of body parts. Instead, they are
inserted in many different networks where they provide inputs
into a great variety of regulatory apparatus.
• Often expressed differentially in the (species-specific) terminal
phases of development
• Their connections into the network are evolutionarily very labile
(evolvable)
• Examples: signal transduction systems, Wnt, transforming
growth factor–b (TGF-b), fibroblast growth factor, Hedgehog,
Notch, and epidermal growth factor
Sonic Hedgehog signaling pathway:
Key role in regulating vertebrate organogenesis, such as in the
growth of digits on limbs and organization of the brain.
Sonic Hedgehog (yellow) signaling controlling neuronal identity in the developing spinal cord
Different Hierarchical Components of Gene Regulatory Networks
3. Input/Output (I/O) devices within the GRN:
Switches that allow or disallow developmental subcircuits to
function in a given context
•
Permit or prohibit the operation of the regulatory subcircuits, and signals between the regulatory sub-circuits
•
They can act to permit or prohibit patterning subcircuits
from acting in given regions of an animal.
•
Examples: regulation of size of homologous body parts.
regulation of fate of segments in animals
hox genes, Ubx, pitx2
Hox Genes
• Hox genes are examples of “Input/Output Devices”…
that is, operate like “on/off” switches
• If they are “on” within an animal region, they will
dictate the fate of that segment
• Hox genes are transcription factors, which regulate
genes that in turn regulate large networks of other
genes
Hox Clusters
• Gene family formed by gene duplication events
• Hox gene products are transcription factors, regulatory proteins
that bind to DNA and control the transcription of other genes
• Hox genes determine the identity of segmental regions along the
anterio-posterior axis of animals during early embryonic
development (e.g. legs, antennae, and wings in fruit flies or the
different vertebrate ribs in humans)
Hox Genes
• Hox genes are a class of homeotic genes that
provide positional information during development
• If Hox genes are expressed in the wrong location,
body parts can be produced in the wrong location
• For example, in crustaceans, a swimming
appendage can be produced in a segment instead
of a feeding appendage
Mutations in a
Hox gene
causing legs to
grow out of the
head
In this case,
the identity of
one head
segment has
been changed
to that of a
thoracic
segment.
Hox genes in Drosophila
Hox genes tend to be
clustered along a
chromosome in the order
that they are expressed in
many taxa (flies and
vertebrates), but not all
taxa
P.Z. Myers
Evolution of Hox clusters
• HOX-clusters undergo essential
rearrangements in evolution of main taxa
• Duplication, deletion, divergence of the genes
lead to differentiation in body plans
• Other regulatory genes/gene families are also
important
Animal body plans
Evolutionary changes in Hox Genes
• New morphological forms likely come from gene
duplication events that produce new
developmental genes
• A possible mechanism for the evolution of sixlegged insects from a many-legged crustacean
ancestor has been demonstrated in lab
experiments
• Specific changes in the Ubx gene have been
identified that can “turn off” leg development
Hox gene 6
Hox gene 7
Hox gene 8
Ubx
About 400 mya
Drosophila
Artemia
Differences in Hox gene
expression distinguish
the various arthropod
segmentation patterns
Evolution of Vertebrates (Phylum Chordata)
• Evolution of vertebrates from invertebrate animals
was associated with alterations in Hox genes
• Two duplications of Hox genes are thought to have
occurred in the vertebrate lineage
• These duplications may have been important in the
evolution of new vertebrate characteristics
• Polyploidization is
probably the single
most important
mechanism for the
evolution of major
lineages and for
speciation in plants
Multiple rounds of
polyploidization might
have occurred during
the early evolution of
vertebrates
Hypothetical vertebrate
ancestor (invertebrate)
with a single Hox clusterFirst Hox
duplication
Hypothetical early
vertebrates (jawless)
with two Hox clusters
Vertebrates (with jaws)
with four Hox clusters
Second Hox
duplication
Different Hierarchical Components of Gene Regulatory Networks
4. Differentiation Gene Batteries:
Consist of groups of functionally linked protein-coding
genes under common regulatory control, the products
of which execute cell type–specific functions and are
major determinant of cell specialization in metazoans
They are expressed in the final stages of given
developmental processes.
Different Hierarchical Components of Gene Regulatory Networks
4. Differentiation Gene Batteries: Consist of groups of
functionally linked protein-coding genes under common regulatory
control, the products of which execute cell type–specific functions
and are major determinant of cell specialization in metazoans
• Reside at the periphery of developmental GRNs, and are
expressed in the final stages of given developmental processes
• They do not regulate other genes (in contrast to kernels and
plug-ins, which are entirely regulatory)
• They do not control the progressive formation of spatial patterns
of gene expression that underlies the building of the body plan;
in short, they do not make body parts.
• Differentiation gene batteries build muscle cells and make
skeletal biominerals, skin, synaptic transmission systems, etc.
Evolution within Developmental Gene Regulatory Networks
So.... Kernels of the network:
• Kernels specify the domain for each body part in the spatial
coordinate system of the postgastrular embryo
•
• Highly pleiotropically constrained
o
internal recursive wiring—many linkages
o
position high in the developmental network hierarchy
When sufficient comparative network data are available, it is likely
that conserved network kernels will be found to program the initial
stages of development of every phylum-specific body part and
perhaps of superphylum and pan-bilaterian body parts as well.
Evolution within Developmental Gene Regulatory Networks
In contrast, peripheral regions of the GRN (i.e.
differentiation gene batteries) are less pleiotropically
constrained, and more likely to evolve.
There are no downstream consequences in changes at
this level.
Examples: many cases of speciation, many cases of
adaptation to the environment
So, not all mutations are equal:
Mutations that are retained
that affect the earlier stages of
development (e.g. kernels) will
have more profound effects on
animal body plans than
mutations that affect the
terminal steps of development
(e.g. gene batteries)
So then, why did massive diversification of major
body forms (evolutionary changes in the
pleiotropic kernels) occur at the time of the
“Cambrian Explosion”
And why did such changes not occur after that?
The kernels would have formed through the same processes of
evolution that affect the other components (while new lineages
were forming during the late Pre-Cambrian-early Cambrian),
But, once formed and operating to specify particular body parts,
kernel structure would have become refractory (resistant) to
subsequent change (because of the catastrophic costs of altering
fundamental structures—because the developmental pathways
had already been laid out).
Molecular phylogeny places this evolutionary stage in the late
Neoproterozoic when Bilateria begin to appear in the fossil
record, between the end of the Marinoan glaciation at about
630 million years ago and the beginning of the Cambrian.
Therefore the mechanistic explanation for the surprising fact
that essentially no major new phylum-level body parts have
evolved since the Cambrian may lie in the internal structural
and functional properties of GRN kernels: Once they were
assembled, they could not be disassembled or basically
rewired, only built upon.
Diverse kinds of change in
GRNs and their diverse
evolutionary consequences
Fig. 3. The left column
shows changes in network
components; the right
column shows evolutionary
consequences expected,
which differ in their
taxonomic level (red).
Big phylogeny
“Kernals”
“Gene Batteries”
Sample Exam Questions
1. Which of the following is FALSE regarding hox Genes?
(a) They serve the role of defining segmental regions along the anterior to
posterior axis during development
(b) Their functions have diversified through gene duplications followed by
differentiation (e.g. subfunctionalization), leading to differentiation of
segmental regions in animals
(c) They encode transcription factors that perform trans-regulatory functions
(d) They are responsible for the major differences among animal phyla
(e) They function by allowing or disallowing developmental subcircuits to
function within segmental regions (like an "on/off" switch)
2. Which of the following would be most
evolutionary constrained?
(a) Plug-ins of the GRN
(b) Kernels of the GRN
(c) Input/Output devices
(d) Gene batteries
(e) Hox genes
3. Changes at which below are most likely to be
responsible for the radiation of animal phyla?
(a) Plug-ins of the GRN
(b) Sonic Hedgehog
(c) Input/Output devices
(d) Gene batteries
(e) Kernels of the GRN
4. What are hox genes within an individual
animal?
(a) Orthologs
(b) Paralogs
(c) Homologs
(d) Xenologs
(e) None of the above
5. Developmental evolutionary differences
between humans and chimpanzees are most
likely to be at the level of
(a) Plug-ins of the GRN
(b) hox genes
(c) Input/Output devices
(d) Gene batteries
(e) Kernels
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1D
2B
3E
4B
5D
• Optional Slides (for your own interest)
Different subcircuits within
Gene Regulatory
Networks
Don’t need to know
this, just showing as
an example
Changes that can affect cis-regulatory modules (CRMs)
(can review lecture notes on cis-regulatory evolution)
• Internal changes that affect the function of a pre-existing CRM
o Single base-pair mutation can cause gain of new binding sites, loss of sites, or
strengthening or weakening of binding to sites.
o Insertions and deletions can change the distance between interacting sites, cause gain
or loss of sites, or an increase in the copy number of given sites.
o Insertion of mobile element carrying regulatory sequences can cause gain or potential
loss of site, change in the distance between interacting sites and increase in copy
number, as well as alter the strength of binding at the site.
• Changes that alter CRM repertoire of pre-existing genes
o Insertion of CRMs from elsewhere: carried by mobile elements, by inversions, by
translocations, or by intronic retrotranspositions can cause gain of developmental
functions without loss of the gene.
o Loss of a CRM: by translocation, large deletion, inversion breakage or insertion of
mobile element can cause loss of specific developmental function without loss of gene.
• Large-scale rearrangements that produce novel gene–CRM complexes
o Regional duplications can result in subfunctionalization and neofunctionalization.
o Translocations can bring new genes into large regulatory domains.