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Medicine in the light of evolution
Yong Edward Zhang
Computational & Evolutionary Genomics Group
Key Laboratory of Zoological Systematics and Evolution
Institute of Zoology, CAS
http://zhanglab.ioz.ac.cn
Peking University
2013/11/26
Preface
First, we must insist that evolution is much more than just a topic in biology –
it is the foundation of the entire discipline. Biology without evolution is like
physics without gravity.
Carroll, S, et al (2005)
In 1973, Dobzhansky penned a short commentary titled “ Nothing in biology
makes sense except in the light of evolution. ” ……Given the central position
of evolutionary thought in biology, it is sadly ironic that evolutionary
perspectives outside the sciences have often been neglected, misunderstood, or
purposefully misrepresented.
Ayala, F, et al (2012)
Outline
1. Basic concepts of molecular evolution
2. Evolutionary theory of human disease
3. Application of evolutionary strategy in medicine
1. Basic concepts of molecular evolution
1.1 Speciation and tree
1.2 Ortholog and paralog
1.3 Mutation
1.4 Polymorphism and divergence
1.5 Selection
1.1 Speciation and tree
Darwin, C. (1837)
From tree of life to web of life
Adapted from Eugene V. Koonin (2009) Nucleic Acids Res.
Is it time to redefine evolutionary biology?
1.2 Ortholog and paralog
Gene
duplication
a Hemoglobin
b Hemoglobin
Speciation
Mouse
a Hb
Rat
a Hb
Paralogs
Mouse
b Hb
Rat
b Hb
Orthologs
By David Pollock
Detection of orthologs
We can perform BLAST all-against-all search and pull out one-to-one best
hits. A more convinient way is to download Ensembl pre-computed
annotation.
http://www.ensembl.org
Detection of orthologs (continued)
http://genome.ucsc.edu
Orthologs may not be functionally more
similar between each other
“It is widely assumed that orthologs share similar
functions, whereas paralogs are expected to diverge
more from each other. But does this assumption hold up
on further examination? We present evidence that
orthologs and paralogs are not so different in either their
evolutionary rates or their mechanisms of divergence.“
Studer, R. et al. (2009) Trends in Genet.
1.3 Mutation: single nucleotide
polymorphism (SNP)
From Wikipedia
Types of SNP
Purines:
Transitions
A
G
Transversions
Pyrimidines:
C
T
David Pollock (2011)
SNP in coding regions
Cys Arg Lys
UGU/AGA/AAG
Silent
Nonsense
Missense
UGU/CGA/AAG
Cys Arg Lys
UGU/GGA/AAG
Cys Gly Lys
Cys STOP Lys
First position: 4% of all changes silent
Second position: no changes silent
Third position: 70% of all changes silent (wobble position)
David Pollock (2011)
Indels
…TGTACAAAG…
Insertion
Deletion
…TGTAAAAG…
…TGTTACAAAG…
Adapted from David Pollock (2011)
Indels may increase the local substitution rate
Tian, D. et al (2008) Nature
Structural variation
Sharp, A., Cheng, Z. & Eichler, E.E. (2006) Annu. Rev. Genomics Hum. Genet.
1.4 Polymorphism and divergence
Innan, H & Kondrashov, F (2010) Nature Rev. Genet.
Population genetics and molecular evolution is intrinsically
interconnected. Conventionally, the key question for evolutionary
biologists is to infer the evolutionary history of DNAs and the
underlying evolutionary forces.
1.5 Positive or adaptive Selection
From Wikipedia
Negative or purifying selection
In natural selection, negative selection or purifying
selection is the selective removal of alleles that are
deleterious.
From Wikipedia
Ka/Ks
The Ka/Ks ratio (or ω, dN/dS), is the ratio of the
number of non-synonymous substitutions per nonsynonymous site (Ka) to the number of synonymous
substitutions per synonymous site (Ks).
Ka/Ks > 1, positive selection
Ka/Ks = 1, neutral evolution
Ka/Ks < 1, negative selection
http://abacus.gene.ucl.ac.uk/software/paml.html
Outline
1. Basic concepts of molecular evolution
2. Evolutionary theory of human disease
3. Application of evolutionary strategy in medicine
Evolutionary root of human disease
Evolutionary root of human disease (continued)
Adaptive landscape
Sewall Wright
Evolutionary root of human disease (continued)
Randolph M. Nesse & Stephen C. Stearns (2008)
Genetic basis for Mendelian diseases and
common diseases is different
Bernard J. Crespi (2011)
Mismatch theory suggests common disease allele may follow the
ancestral susceptibility (AS) model or the thrifty model
Anna Di Rienzo (2006)
Cardiovascular disease may be a
representative case following AS model.
Mitochondria is subject to a shift of
selection
Douglas C. Wallace (2005)
Mitochondria is subject to a shift of
selection (continued)
Raj S Bhopal & Snorri B Rafnsson (2009)
Genes underlying Coronary Heart Disease are often
subject to recent adaptive selection
Keyue Ding & Iftikhar J. Kullo (2009)
Outline
1. Basic concepts of molecular evolution
2. Evolutionary theory of human disease
3. Application of evolutionary strategy in medicine
3. Application of evolutionary strategy in medicine
3.1 Conservation guided practice
3.2 Evolution guided practice
3.3 Opportunities with next generation
sequencing (NGS)
3.1 Conservation guided practice
The central dogma of Evo devo
Hedgehog is important for the cuticle
development
Tool kit gene classification
Hox
Hedgehog
Hedgehog as a demo case of biomedicine
study
Conservation as a proxy of disease gene
3.2 Evolution guided practice
Paradigm shift: deal with lineage-specific
trait, for example, human brain
Complexity of human brain
Johnson, M. et al. (2009) Neuron
Expansion of human brain
Rakic, P. et al. (2009) Nature Rev. Neurosci.
Regulatory changes drives brain expansion
“Their macromolecules are so alike that regulatory mutations may
account for their biological differences.”
King, M. et al. (1975) Science
“Promoter regions of many neural- and nutrition-related genes have
experienced positive selection during human evolution.”
Haygood, R., et al. (2007) Nature Genet.
Torgerson, D., et al. (2009) PLoS Genet.
Accelerated evolution of brain genes in human
Dorus, S., et al. (2004) Cell
Brain genes are generally constrained
“We suggest that such abundant and complex transcription
may increase gene–gene interactions and constrain CDS
evolution.”
Wang, H., et al. (2007) PLoS Bio.
Protein-level evolution appears generally
irrelevant with brain evolution. Is it true?
How about new gene origination?
Brain preferentially recruited new genes in
human lineage relative to other organ/tissues
Zhang, Y. E., Landback, P., Vibranovski, M. D.& Long, M. (2011) PLoS Biology
This excess is mainly contributed by fetal
brain
Developing neocortex contributes to most
excess
New genes upregulated in developing neocortex is highly
enriched with primate-specific transcription factors
New gene origination parallels the
morphological evolution of brain
Conclusion: the uniqueness of human
brain is at least partially contributed by
new gene origination
Broad impact
Human-specific genes are indeed involved in
brain development
Charrier, C. et al.(2012) Cell
3.3 Opportunities with next generation
sequencing (NGS)
“We have learned nothing from the genome”
Venter, C.
HGP is dead. Long live HGP!
Rapidly decreased cost enabled by next
generation sequencing (NGS) techniques
Our journey is to the ocean of stars.
Things previously impossible become
possible
1. GWAS-like disease allele hunting
2. Searching for loci underlying population differentiation
3. Cancer evolution
4. Meta-genomics
1. Disease allele hunting
Ng, S. et al. (2009) Nature Genet.
2. Searching for loci underlying population differentiation
Yi, X., et al. (2010) Science
MacLnnis, M., et al. (2011) High Alt. Med. & Biol.
PCSK9 as a demo case
3. Search cancer-causing mutations by
phylogenetic reconstruction
Tao, Y et al. (2011) PNAS
On timing of cancer progress
“A quantitative analysis of the timing of the genetic
evolution of pancreatic cancer was performed, indicating
at least a decade between the occurrence of the initiating
mutation and the birth of the parental, non-metastatic
founder cell.”
Yachida, S. et al. (2010) Nature
4. Meta-genomics
Coghlan, M.L. et al. (2012) PLoS Genet.
4. Meta-genomics (continued)
Qin, J. et al. (2012) Nature
It is time to play, 
Many thanks. Any question is welcome!
Email: [email protected]