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Molecular Evolution
Sylvia Nagl
Sequence-structure-function paradigm
•Relationships between
CGCCAGCTGGACGGGCAC
ACCATGAGGCTGCTGACC
CTCCTGGGCCTTCTG…
TDQAAFDTNIVTLTRFVM
EQGRKARGTGEMTQLLNS
LCTAVKAISTAVRKAGIA
HLYGIAGSTNVTGDQVKK
LDVLSNDLVINVLKSSFA
TCVLVTEEDKNAIIVEPE
KRGKYVVCFDPLDGSSNI
DCLVSIGTIFGIYRKNST
DEPSEKDALQPGRNLVAA
GYALYGSATML
DNA or amino acid
sequence
3D structure
protein functions
•Use of this knowledge for prediction of function,
molecular modelling, and design (e.g., new therapies)
A novel sequence or structure
Prediction based on “similarity”
= evolutionary relatedness
Evolution as an algorithmic process
Random mutation (genotype) “mutate”
‘cumulative’
Selection (phenotype)
“select”
Differential reproduction
“replicate”
The term algorithm denotes a certain kind of formal process
consisting of simple steps that are executed repetitively in a
defined sequential order and will reliably produce a definite kind
of result whenever the algorithm is run or ‘instantiated.’
•Cumulative selection will work on almost anything that can yield similar,
but non-identical, copies of itself through some replication process.
•It depends on a medium that stores information and can be passed on to
the next generation - DNA or RNA (virus) in terrestrial life forms.
•Most genetic mutations are deleterious - proofreading and error
correction mechanisms - negative selection
•Whenever positive selection acts, it can be thought of as selecting DNA
with particular phenotypic effects over others with different effects.
•Advantageous mutations may confer a survival and reproductive
advantage on individuals who will then, on average, pass on more copies
of their genetic material because they will tend to have a larger number
of offspring.
•Over many generations, the accumulation of small changes can result in
the evolution of DNA sequences with new associated phenotypic effects.
Roadmap of the human genome
Noncoding
DNA
810Mb
Genes and generelated sequences
900Mb
Coding
DNA
90Mb
Pseudogenes
Gene fragments
Introns, leaders, trailers
Single-copy genes
Tandemly
repeated
Multi-gene families
Dispersed
Regulatory sequences
Repetitive DNA
420Mb
Non-coding
tandem
repeats
Genomewide
interspersed
repeats
Extragenic DNA
2100Mb
Satellite DNA
Minisatellites
Microsatellites
DNA transposons
LTR elements
LINEs
SINEs
Unique and low-copy
number
1680Mb
Multi-gene families: Evolution by gene duplication
•Gene duplication is the most important mechanism for
generating new genes and new biochemical processes.
This mechanism has facilitated the evolution of complex
organisms:
•In the genomes of eukaryotes, internal duplications of gene
segments have occurred frequently. Many complex genes
might have evolved from small primordial genes through
internal duplication and subsequent modification.
•Vertebrate genomes contain many gene families absent in
invertebrates.
•Many gene duplications have occurred in the early
evolution of animals (“Biology’s Big Bang”, “Cambrian
explosion”, ~570-505 million year ago).
Types of duplication events
A duplication may involve
•a single gene (complete gene duplication)
•part of a gene (internal or partial gene duplication)
•part of a chromosome (partial polysomy)
•an entire chromosome (aneuploidy or polysomy)
•the whole genome (polyploidy)
Gene duplication: Mechanisms
Unequal sister chromatid exchange at meiosis
Unequal crossing-over at meiosis
Gene duplication: Mechanisms
Transposition via an RNA intermediate
transcription
RNA
reverse
transcription
reintegration
cDNA
DNA transposons
transposon
replication
Homology: Paralogy, orthology and xenology
a
duplication
‘Redundant copy’
a
paralogous
b
speciation
a
b
species 1
a
b
species 2
orthologous
Duplication – mutation in ‘redundant copy’ – paralogy - new
function
Random mutation (genotype) “mutate”
Selection (phenotype)
“select”
Differential reproduction
“replicate”
Complete gene duplication
deleterious
mutations
invariant repeats
pseudogene
(silent)
variant repeats
“tandem arrays”
sequence divergence
increased gene product
HOX/HOM genes
Examples:
function or regulation may
differ
large quantities of
specific rRNAs or
tRNAs, histone proteins
amplified esterase gene
in Culex mosquito
Dayhoff (1978):
at least 50% identity: gene
family
>35% identity: homologous
(super)family
Evolution of Hox and HOM gene clusters by gene duplication
mouse
gene
duplication
Amphioxus
hypothetical
ancestor
Drosophila
Antennapedia
Bithorax
Internal gene duplication: Domain duplication
•Duplicated gene segments often correspond to functional or
structural domains.
A domain is a well-defined region within a protein that either performs a
specific function or constitutes a stable structural unit.
•Domain duplication is a form of internal duplication.
This mechanism may
•increase number of active sites
•enable acquisition of a new function by modifying
the redundant segment.
Domain duplication increases the functional complexity of
genes in evolution.
Internal repeats in the apolipoprotein genes
The structural and functional module: a 22-mer repeat
In exon 4 of the genes belonging to this family, this 22-mer is repeated 1 to ~15 times.
The presence of many copies lead to the evolution of new functions:
apoE now plays a role in neural regeneration, immunoregulation, growth and
differentiation, via interactions with low-density lipoprotein receptors and apoE
receptors.
Gene evolution by domain shuffling
1. Internal duplication
Duplication of one or more domains
2. Domain insertion
Structural or functional domains are exchanged between
proteins or inserted into a protein
“Mosaic or chimeric proteins”
Examples: Two common domains
Kringle domain from
plasminogen protein
EGF-like domain from
coagulation factor X
Domain insertion: “Mosaic proteins”
Structural modules:
Domain origins:
plasminogen kringle domain
EGF domain
fibronectin finger domain
epidermal
growth factor
(EGF)
fibronectin
vit. K-dependent calciumbinding domain (osteocalcin)
trypsin-like serine protease
Mosaic proteins
tissue plasminogen activator
urokinase
prothrombin
plasminogen