Transcript Question

IUPS President’s Lecture
(Sponsored by Wiley)
17:30 - 18:30, Sunday 21 July Hall 1 (The ICC)
Physiology moves back onto centre stage:
a new synthesis with evolutionary biology
Denis Noble
University of Oxford, United Kingdom
Evolution: a brief history
1809 Jean-Baptiste Lamarck published Zoologie
Philosophique. Established transformation of species;
assumed inheritance of acquired characteristics
1859 Charles Darwin published The Origin of
Species. Proposed theory of natural selection, but had
no theory of heredity. Also assumed inheritance of
acquired characteristics
1900 approx. Neo-Darwinism: incorporation of
Mendelian discrete inheritance. Weismann barrier:
exclusion of inheritance of acquired characteristics
1940 approx. The Modern Synthesis: Julian Huxley, R
A Fisher, J B S Haldane, Sewell Wright
Evolution: the Modern Synthesis
often called Neo-Darwinism
Popularised by The Selfish Gene (1976)
Gene-centred view of natural selection
(slow accumulation of ‘random’ mutations, followed by selection)
Impossibility of inheritance of acquired characteristics
(mis-called ‘Larmarckism’)
Distinction between replicator (genes) and vehicle (phenotype)
Buttressed by [mis-interpretations of] The Central Dogma of
Molecular Biology (Crick)
Shapiro, 2011: Evolution. A view from the 21st Century

Are mutations random?

“It is difficult (if not impossible) to find a
genome change operator that is truly random in
its action within the DNA of the cell where it
works. All careful studies of mutagenesis find
statistically significant non-random patterns of
change.” (page 82)
Random?

The question is not just whether changes are random, but
whether they are functionally relevant.

“I will use the definition that the changes are assumed to be
random with respect to physiological function and could not
therefore be influenced by such function or by functional
changes in response to the environment. This is the
assumption that excludes the phenotype from in any way
influencing or guiding genetic change.” (Noble 2013)

That assumption is now insecure since some genome changes
are related to physiological function.

Example of targeted genome insertion

P element homing in fruit flies. These are DNA transposons that
insert into the genome in a functionally significant way,
depending on the added DNA. There is up to 50% greater
insertion into regions of the genome that are related functionally.

Possible explanation: donor element and target site may be
brought close together in the nucleus, i.e. organisation of the
genome is important. This kind of information is also therefore
‘genetic’.
Hama, Ali, and Kornberg 1990 Genes Dev 4: 1079–1093
Are mutations random?
Are gradual accumulations of mutations
the cause of speciation?
“The 2001 Nature report of the draft human genome contained two
important figures illustrating what genome sequencing had taught
us about protein evolution. Using transcription factors and
chromatin binding proteins as examples, the figures showed that
these classes of protein did not evolve one amino acid at a time.
Instead, the two classes of protein “shuffled” and “accreted”
copies of functional protein segments called domains…...”
Shapiro, 2011, page 95
Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium
Nature 2001, 409, 860-921
Domain accretion in chromatin proteins
Domain accretion in yeast (Y), worm (W), fly (F), vertebrates, (V)
Human (H) shown by stars,
First conclusion
Proteins did not all evolve via gradual
accumulation of mutations
Some other forms of genome reorganisation
must have occurred
What was wrong with neo-darwinism?
The errors are both
philosophical (conceptual and linguistic)
and
scientific (empirical, experimental)
Selfish gene:
Metaphor or empirical science?
in reply to Midgley (1979):
“that was no metaphor. I believe it is the literal truth,
provided certain key words are defined in the
particular ways favoured by biologists” (Dawkins,
1981).
But a metaphor does not cease to be a metaphor simply
because one defines a word to mean something other
than its normal meaning. Indeed, it is the function of
metaphor to do precisely this. (Noble, J Physiol, 2011)
Noble D. (2011). Neo-Darwinism, the Modern Synthesis, and Selfish Genes:
are they of use in physiology? Journal of Physiology 589, 1007-1015.
Conclusion
The selfish gene idea is not falsifiable
Further details in
Noble D. (2011). Neo-Darwinism, the Modern Synthesis, and Selfish Genes:
are they of use in physiology? Journal of Physiology 589, 1007-1015.
“selfishness cannot be defined as an intrinsic property of nucleotide
sequences independently of gene frequency. It is a strange hypothesis
that uses its own definition of its postulated entity as its only prediction”.
Are mutations random?
Are gradual accumulations of mutations
the cause of speciation?
“It is important to note that selection has never led to
formation of a new species. Selection operates as a
purifying but not creative force.”
(Shapiro, 2011, page 144)
Thousands of years of domestic selection produced new
varieties not new species
By contrast, hybridisation in plants does achieve speciation
Second conclusion
‘Selfishness’ is not a testable hypothesis
Question
Has the concept of a gene changed?
Environment
Phenotype
X
Biological
Networks
signalling
pathways, filters,
conditioners
‘determinants of phenotype’
≡
original concept of ‘gene’
incubators that
enable and
restrict reactions
molecular biology notion:
gene = DNA sequence
DNA
Kohl P, Crampin E, Quinn TA & Noble D. (2010).
Systems Biology: an approach. Clinical Pharmacology and Therapeutics 88, 25-33.
Environment
Phenotype
Biological
Networks
signalling
pathways, filters,
conditioners
‘determinants of phenotype’
≡
original concept of ‘gene’
incubators that
enable and
restrict reactions
molecular biology notion:
gene = DNA sequence
DNA
Most knock-outs and mutations
are buffered by the networks
Most knock-outs and mutations
are buffered by the networks
Some examples
Model of sinus node – ibNa & if
Example of ‘gene knock-out’
Em
If
Hyperpolarization
Activates if
IbNa
20%
40%
60%
80% 100%
Noble, D., J. C. Denyer, H.F. Brown. & D DiFrancesco (1992). Proc Royal Society B 250: 199-207.
Genetic buffering:
How extensive is it?
Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, Lee W,
Proctor M, St Onge RP, Tyers M, Koller D, Altman RB, Davis RW,
Nislow C & Giaever G. (2008). The chemical genomic portrait of yeast:
uncovering a phenotype for all genes. Science 320, 362-365.
Why should a physiologist be concerned
about evolutionary theory?
The modern synthesis is a
gene-centred theory of evolution
Yet organisms are very good
at ‘immunising’ themselves from their genomes
Noble D, Differential and integral views of genetics in computational systems
Biology, 2011, Interface Focus 1, 7-15
Conclusion:
Knockouts do not reveal regulators
Davies, J. 2009 Regulation, necessity, and the misinterpretation
of knockouts. Bioessays 31, 826–830.
Origin of the problem:
Downward causation
The reductionist causal chain
I know one approach that will fail,
created
bodyproteins
and mind
whichThey
is to [genes]
start with
genes,us,make
from them
Richard
Dawkins,
1976
and to
try to build
things
bottom-up
Sydney Brenner, 2001
organism
organ
tissue
cellular
sub-cellular
pathways
protein
gene
NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.
Unravelling complexity
Need to work in an integrative way at all levels:
Systems level
triggers of
cell signalling
Epigenetic
marking by
all levels
organism
organ
tissue
cellular
sub-cellular
pathways
protein
gene
Systems level
controls of
gene expression
Protein machinery
reads and corrects genes
There are feed-downs as well as upward between all these levels
Origin of the problem:
Downward causation
Royal Society journal Interface Focus
Focused issue, 2012
(Editors: Ellis, Noble, O’Connor)
Some principles of Systems Biology
Second principle
Transmission of information is NOT one-way
So, the ‘central dogma’ of biology is insufficient or even incorrect!
(Shapiro, J. A. 2009 Revisiting the Central Dogma in the 21st Century.
Annals of the New York Academy of Sciences 1178, 6-28
Shapiro, J.A. 2011 Evolution. A view from the 21st Century, FT Press Science)
There is ‘downward causation’ from all levels
This influences gene expression, and gene marking
(epigenetic inheritance)
“Lamarckism is not so obviously false as is sometimes made out”
(John Maynard Smith, Evolutionary Genetics, OUP, 1998)
Some principles of Systems Biology
Third principle
DNA is NOT the sole transmitter of inheritance
We all inherit a complete egg cell
DNA marking – methylation, histone marking and other processes
(maternal factors can transmit through generations)
Epigenetic marking can also be transmitted through sperm line
(via RNAs)
We should invert the usual question:
What prevents inheritance of acquired characteristics?
Jablonka & Lamb (1995) Epigenetic inheritance and Evolution (OUP)
Examples of Inheritance of epigenetic information
Weaver, I. C. G.,. 2009
Life at the interface between a dynamic environment and a fixed genome
Mammalian Brain Development (Ed Janigro) 17-40.
Anway, M. D., Leathers, C. & Skinner, M. K. 2006
Endocrine disruptor vinclozolin induced epigenetic
transgenerational adult-onset disease. Endocrinology 147, 5515-5523.
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding
J & ALSPAC_study_team. (2006). Sex-specific, male-line transgenerational
responses in humans. European Journal of Human Genetics 14, 159-166.
Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. 2005
Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from
Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish
(Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, 510-515.
Rechavi, O, Minevish, G, Hobert, O. 2011 Transgenerational Inheritance of an
Acquired Small RNA-Based Antiviral Response in C. elegans. Cell, 147, 1248-1256.
The Guardian, 14 February 2007
ARE
Weaver et al
The Journal of Neuroscience, February 14,
2007 • 27(7):1756 –1768
Inheritance of epigenetic information
Anway, M. D., Leathers, C. & Skinner, M. K. 2006
Endocrine disruptor vinclozolin induced epigenetic
transgenerational adult-onset disease. Endocrinology 147, 5515-5523.
An endocrine disruptor) can induce transgenerational
(four generations were followed) disease states or
abnormalities, and this suggests a potential epigenetic
etiology and molecular basis of adult onset disease.
Sharma, A. & Singh, Priyanka. 2006
Detection of transgenerational spermatogenic inheritance of adult male acquired
CNS gene expression characteristics using a Drosophila systems model.
PLoS one 4, e5763.
Chronic PTZ treatment of adult males changes CNS
transcriptome. This is inherited. First demonstration of
spermatogenic inheritance of an adult-induced characteristic.
Third conclusion
Environmentally-induced changes can be inherited
Question
What happens in cross-species clones?
Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. (2005)
Inheritance of epigenetic (cytoplasmic) information
Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. Goldfish
(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish
Derived from Transgenic Common Carp (Cyprinus carpio)
Nuclei and Goldfish (Carassius auratus) Enucleated Eggs.
Biology of Reproduction 72, 510-515.
Carp 33
26
Carp nucleus in Goldfish egg 28
?
Inheritance of epigenetic (cytoplasmic) information
Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y.
(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish
Derived from Transgenic Common Carp (Cyprinus carpio)
Nuclei and Goldfish (Carassius auratus) Enucleated Eggs.
Biology of Reproduction 72, 510-515.
Carp 33
Goldfish 26
Carp nucleus in Goldfish egg 28
X-ray photographs showed that the vertebral number of six cloned fish was of the
enucleated egg providing goldfish type, ranging from 26 to 28. In contrast, the
vertebral number of nuclear-donor common carp was 33–36. These data suggest
that the goldfish egg cytoplasm plays an important role in regulating the somite
development and vertebral number in the nuclear transplants.
McClintock, Barbara. 1984
The significance of responses
of the genome to challenge.
Science 226, 792-801.
And Nobel Prize Lecture, 1983
In the future attention undoubtedly will be centered on the genome, and
with greater appreciation of its significance as a highly sensitive organ of the
cell, monitoring genomic activities and correcting common errors, sensing the
unusual and unexpected events, and responding to them, often by restructuring
the genome. We know about the components of genomes that could be made
available for such restructuring. We know nothing, however, about how the cell
senses danger and instigates responses to it.
A genome consists largely of semistable genetic elements that may be rearranged
or even moved around in the genome thus modifying the information content of DNA.
(Beurton et al 2008)
Fourth conclusion
Cytoplasmic changes can be inherited
Question
Possible mechanisms?
Rechavi, O, Minevish, G, Hobert, O. 2011 Transgenerational
Inheritance of an Acquired Small RNA-Based Antiviral Response
in C. elegans. Cell, 147, 1248-1256.
• Viral replication triggers an RNAi-dependent viral silencing response
• The acquired silencing response is transgenerationally transmitted
• Transgenerational transmittance is non-Mendelian
• involves small antiviral RNAs
• Inheritance is robust
• for over 100 generations
Stop press: from Joe Nadeau’s lab
Nelson, V. R., Heaney, J. D., Tesar, P. J., Davidson, N. O., & Nadeau, J. H.
(2012). Transgenerational epigenetic effects of Apobec1 deficiency on
testicular germ cell tumor susceptibility and embryonic viability.
Proceedings of the National Academy of Sciences, 109, E2766–E2773
these [epigenetic] effects persist for many generations
and are as strong as conventional genetic inheritance
The heritable epigenetic changes persisted for multiple
generations and were fully reversed after consecutive crosses
through the alternative germ-lineage
“the belief that the soma and germline do not communicate
is patently incorrect.” PNAS Commentary article
Sixth conclusion
Environmentally-induced changes can be inherited
The inheritance is robust,
can carry through many generations
and the molecular mechanisms are known in some cases
Question
If gradual mutations is not the answer,
what is responsible for re-organisation of genomes?
THE NETWORK OF LIFE

“Contrary to traditional theories, it is now well
documented that all prokaryotes and many
eukaryotes acquire novel genomic segments and
biochemical functions from other, often
unrelated cells rather than exclusively by vertical
inheritance from progenitors”
Shapiro: Evolution. A view from the 21st Century p 91
Beurton PJ, Falk R & Rheinberger H-J, ed. (2008).
The Concept of the Gene in Development and Evolution:
Historical and Epistemological Perspectives.
Cambridge University Press, Cambridge.
“it seems that a cell’s enzymes are capable of actively manipulating
DNA to do this or that. A genome consists largely of semistable
genetic elements that may be rearranged or even moved around in
the genome thus modifying the information content of DNA.”
Genes “begin to look like hardly definable temporary products
of a cell’s physiology”
Final conclusion
If functional changes in the adult can be inherited,
and therefore a target for natural selection,
then physiology – the analysis of function –
IS highly relevant to evolution.
“It is hard to think of a more fundamental change
for physiology and for the
conceptual foundations of biology in general”
(Noble Exp Physiol 2013)
Evolution & physiology: towards a new Synthesis
Gene-centred view of natural selection
Selection is multi-level
Impossibility of inheritance of acquired characteristics
Acquired characters can be inherited
Distinction between replicator (genes) and vehicle (phenotype)
The genome is an ‘organ of the cell’ not its dictator. Control is
distributed.
The Central Dogma of Molecular Biology
Genomes are not isolated from organism & environment
Evolution & physiology: towards a new Synthesis
Evolution & physiology: towards a new Synthesis
Questions page
http://musicoflife.co.uk/pdfs/Answers.pdf
Further reading
Does the Modern Synthesis need
extending or replacing?
Pigliucci, M., & Müller, GB. (2010). Evolution - The
extended synthesis. Cambridge, Mass: MIT Press.
Gissis, SB., & Jablonka, E. (Eds.). (2011).
Transformations of Lamarckism. From Subtle Fluids
to Molecular Biology. Cambridge, Mass: MIT Press
Shapiro, J. (2011) Evolution: a view from the 21st
Century FT Press
Beurton, PJ, Falk, R. & Rheinberger, H-J. (2008) The
concept of the gene in development and evolution:
historical and epistemological perspectives. CUP.
Noble, D. (2006) The Music of Life, OUP.