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Relating the evolution of gene content to
tissue specialization
Shiri Freilich
Janet Thornton’s group, EBI
Cambridge University
“...And when he was 93, Grandpa decided that the time had come
for a man-to-man conversation.
(I was 36 at the time, I have been married for 15 years).
‘All my life I am all the time looking at woman, looking and
learning. Nu, and what I learned, I want to learn to you now also.’
‘Woman, in some ways is just like us exactly the same. But in some
other ways a woman is entirely different.’
‘But you know what? In which ways a woman is just like us and in
which ways she is very different –
nu, on this I am still working’.”
(Amos Oz, A Tale of Love and Darkness)
The full genome sequence from various
species can highlight the common versus
unique
What’s new?
The transition from unicellularity to
multicellularity as an interior design challenge
- gene
Overview
• Part 1: Expression pattern of ‘old’ and ‘new’ proteins in mouse
tissues
• Part 2: Expression pattern of singleton and duplicate proteins in
mouse tissues
• Part 3: The evolution of tissue-specific metabolic pathways in
mammals
Part 1:
Relating age and function of a protein to
its expression pattern in mouse tissues
A collaboration with Tom Freeman’s group
(MRC RFCGR)
Freilich et al, Genome Biol. 2005;6(7):R56.
Processing mouse expression and sequence
data
Classification of mouse proteins into
phylogenetic groups
Tissues have a similar composition of functional
classes
enzymes
transporters
signal transduction
Fraction
transcription regul.
Tissue type
Tissues have a similar composition of phylogenetic
classes
universal
eukaryote sp.
metazoan sp.
Fraction
mammalian sp.
Tissue type
Expression distribution of proteins from
different categories
Fraction
• Tissues have almost identical functional/ phylogenetic
composition
• Tissue diversity must be achieved through differences in the
protein composition within each category
• Do proteins from different categories duffer in their expression
pattern?
Number of tissues where protein is expressed
Regulatory proteins are more specifically
expressed
Metabolic
proteins
Regulatory
proteins
enzymes
transporters
signal transduction
Mouse proteins
classified into
functional groups
transcription regul.
Fraction
~1/3
~1/10
Number of tissues where is expressed
Metazoan-specific proteins are more
specifically expressed
Present in a unicellular
ancestor of metazoa
eukaryote sp.
metazoan sp.
mammalian sp.
Fraction
Specific to metzoa
universal
Number of tissues where protein is expressed
Mouse proteins
classified into
phyletic groups
Functional categories overlap with
phylogenetic categories
• Most of the pre-metazoan proteins are metabolic proteins
(transporters and enzymes)
• Most of the metazoan-specific proteins are regulatory
proteins (signal transduction and transcription regulation)
Fraction
Identifying the dominant influence: function or
age
Number of tissues where protein is expressed
• Obvious differences between ‘old’ and ‘new’ proteins, within
the metabolic functional group
• Yet, less than 1/3 of the pre-metazoa proteins are expressed
in all tissues
Still, some of the pre-metazoa proteins are
tissue specific
• Functions occurring in the unicellular cell become tissue-specific
in multicellular species (Ldh example)
• Universal genes that have been duplicated become specific to a
tissue whilst a second copy maintains its original expression
pattern (Pgk-2 example)
Part 2:
Relating duplication events to expression pattern
in mouse tissues
Freilich et al, Genome Biol. 2006;7.
“…duplication events had contributed greatly to
the attainment of the complex body organisation in metazoa,
where cells having identical genetic material can differentiate …
due to the presence of duplicated genes in their genomes”
Ohno S. (1970). Evolution by gene duplication.
The subfunctionalization model
Lynch M & Force A, Genetics. 154 (2000):
The division of expression of an ancestor gene between its daughter
duplicates promotes the retention of a gene in the genome
Microarray expression data provide
support to the subfunctionalization model
• Gu et al: expression divergence between duplicate genes
increases with evolutionary time (differentiation modes in yeast).
Trends Genet. 2002;18: 609-13.
• Makova et al: spatial expression divergence between duplicate
genes increases with evolutionary time (human tissues). Genome Res.
2003;13:1638-45 .
• Huminiecki and Wolfe: a general trend for increased tissuespecificity of expression as family size increase was observed for
mammalian genes. Genome Res. 2004;14:1870-79
.
Project Overview:
The relationship between gene
duplication and breadth of expression
Protein’s perspective:
1.
Does duplication event lead to an increase in tissue specificity?
Time of duplication perspective:
2.
Does the date of duplication event matters? (i.e., do duplication events
occurring in the ancestral unicellular lead to an increase in tissue specificity)
Protein-family perspective:
3.
does a protein family maintain a non-specific expression pattern? (i.e., is a
specific expression of proteins from big families complementary)
(Freilich et al, Genome Biol. 2006;7(10):R89)
Fraction
Singleton proteins are more globally
expressed
Singletons (570)
Duplicate proteins
(1886)
Proteins with many close
homologues (417)
Number of tissues in which protein is expressed
Mean number of tissues
Negative correlation between expression
breadth and number of homologues
Singletons
Duplicate proteins
Groups of proteins, ordered by their number of homologues
Large variation
Number of tissues
Singletons
Correlation
-0.20
Correlation
-0.20
P-value
1.5e-55
P-value 1.5e-55
Duplicate proteins
Mean number of
expressed tissues
Number of homologues proteins
Does the date of duplication event matter?
(i.e., do duplication events occurring in the ancestral unicellular lead to an increase in tissue
specificity)
Increase in
tissue
specificity
?
Global
expression
Identifying ‘old’ and ‘new’ duplications
Only post-multicelullarity duplication
events lead to expression specificity
The protein-family perspective:
Is the specific expression of family
members complementary?
Proteins from big families tend to be more specifically expressed.
Does a protein family maintain a non specific expression pattern?
Complementary
expression
?
Overlapping
expression
Calculating the cumulative tissue
distribution of protein families
Cumulative tissue distribution of protein
families is not correlated with family size
Average tissue-coverage of
protein families
Singletons
Families with any
expression information
Families with >=75%
expression information
Protein families, ordered by size
Complementary expression pattern in protein families:
While a duplication event leads to a tissue specialisation of one or
both copy, the total tissue-distribution of the protein family remains
constant.
The findings support the
subfunctionalization model
Protein’s perspective:
1. Does duplication event lead to an increase in tissue specificity?
Yes
Time of duplication perspective:
2. Does the date of duplication event maters?
only duplication events that that place in a multicellular
species lead to a specific expression
-> suggests that expression divergence, following gene
duplication, promotes the retention of a gene in the genome
Protein-family perspective:
3. Does a protein family maintain a non-specific expression pattern?
Yes
-> suggests the division of expression between family
members
Part 3:
The evolution of the mammalian metabolic
pathways
Some of the tissue-specific pathways are specific to mammals.
Can we understand how tissue-differentiation of animals’
metabolism reflects their evolution?
Freilich et al, BMC evolutionary biology 2008, 8:247.
STEROID HORMONE
METABOLISM
Why studying metabolic networks?
• Metabolic networks’ structure and composition are well defined
• Available metabolic databases
• Genotype is highly related to phenotype
The structure of the KEGG database
STEROID HORMONE METABOLISM
The reactions within a pathway can be
absent/present in a species
Arabidopsis Thaliana
Homo Sapiens
Project overview:
• Identification of pathways absent/present in a
species
• Classification of human pathways according to
their phyletic origin
• Characterization of lineage-specific metabolic
pathways
Phylogenetic classification of human pathways
Universal pathways
All pathways in human (metabolic)
Eukaryota-specific
pathways
Metazoan-specific
pathways
Mammalian-specific
pathways
Phylogenetic classification of human pathways
33 Universal pathways
Metabolic skeleton:
sugars, nucleotides,
some amino-acids, energy
10 Metazoan-specific pathways
Tissue specific activities:
Neuronal guidance,
hormonal activity, digestion
8 Eukaryota-specific pathways
Components of the
Eukaryotic membrane
14 Mammalian-spc. pathways
Tissue specific activities and
intracellular signaling
(blood cell recognition)
(sphingolipids, glycosaminoglycan)
The pathways can be linked to form
a network
The network structure of the metabolic pathways
Universal pathways
Eukaryota-spc. pathways
Metazoan-spc. pathways
Mammalian-spc. pathways
The integration of the steroid biosynthesis pathway into the sterol
biosynthesis pathway
sterol
cholesterol
bile acid
steroid hormone
Universal
Eukaryota
Human
From manually selected examples to a computational
approach
Creating a list of
adjacent reactions:
2.7.4.2 -> 4.1.1.33
4.1.1.33->2.5.1.1
..
2.5.1.1->2.5.1.21
2.5.1.21->1.14.99.7
Using the adjacency list for a large-scale characterization
of the metabolic network
What’s new (metabolic pathways)?
Summary
• ‘New’ genes tend to be more tissue-specific, ‘ancient’ genes tend to
be globally expressed
• Despite this trend, many metazoan genes are ubiquitous and many
universal proteins are tissue specific
• ‘New’ duplications of ‘old’ and ‘new’ proteins lead to a more
specific expression, and therefore can facilitate the evolution of
new, tissue-specific, functions
• The core of metabolic-pathways, inherited from a uniclellular
ancestor, provides a platform for the evolution of mammalianspecific, tissue-specific pathways
Thanks
Thornton Group
Janet Thornton
Tim Massingham
Eric Blanc
Expression data:
Tom Freeman
Sumit Bhattacharyya