BB30055: Genes & Genomes, 2004-05
Molecular basis of genome evolution
1.1 What is the molecular basis for genome evolution?
Genomes are dynamic entities showing a high degree of plasticity resulting in changes in both genome size
and complexity. At the molecular level, DNA alterations due to mutations form the basis of genomic
evolution.
Mutations: The main classes of mutations include
Deletions or Insertions: 1bp to several Mb
Single base substitutions
Missense mutations: replace one amino acid codon with another
Nonsense mutations: replace amino acid codon with stop codon
Splice site mutations: create or remove exon-intron boundaries
Frameshift mutations: alter the ORF due to base substitutions
Dynamic mutations: changes in the length of tandem repeat elements
Effect of mutations:
Neutral mutations are unaffected by agents of selection
Deleterious mutations will disappear from a population by selection against the allele
Rare mutations increase fitness
Changes in genome size are brought about through repeated duplications, as a result of recombination
(unequal crossing over) or transposition (insertion of a DNA sequence into another without any sequence
homology). Genetic drift and mutations can turn duplications into pseudogenes or diversification of a
duplicated gene followed by selection can produce a new gene.
Genome size increases through duplication can be broadly divided into 4 levels
1) exon duplication/shuffling: Genes may elongate by
duplication of exons to generate tandem exons that
determine tandem functional domains e.g., antibody
molecule. Exon shuffling may give rise to new genes
e.g., tissue plasminogen activator (TPA)
2) gene duplication to create multigene families
(tandem / dispersed)
3) Gene families duplicate to create gene superfamilies:
Unequal crossing over can expand and contract gene
numbers in multigene families. Intergenic gene
conversion can increase variation among members of
a multigene family (One gene is changed, the other is
not)
4) Entire genome duplication
Fig. 21.10 - Hartwell
GENE FAMILIES
Set of genes descended by duplication / variation from
some common ancestral gene is called a gene family. Its members may be clustered together or dispersed
on different chromosomes. Duplicated genes, accumulate mutations, get more specialised and eventually
diverge. E.g in highly evolved mammals, multigene variants of almost every gene exist like different types
of actin, opsin, globin, collagen etc. Gene clusters are where 2 or more adjacent related genes lie
tandemly.
Sequence divergence as a result of duplications is the basis for evolution of species. They allow us to
study evolutionary forces over larger regions of genome instead of single genes. The globin gene family is
a particularly good example because unmistakable homologies in amino acid sequence & structure of the
present day globin genes indicate that they must all derive from a common ancestral gene, even though
they are now occupy completely different loci in the mammalian genome.
An Example: The globin gene family
MV Hejmadi (bssmvh@bath.ac.uk)
BB30055: Genes & Genomes, 2004-05
Evolution of the globin gene family shows how random DNA duplications contribute to the evolution of
organisms. E.g. Haemoglobin.
Functional globin genes all have the same structure. Hb –
major constituent of RBC is globin tetramer associated with
heme made of .
Several different variants expressed at different stages of
development e.g. in humans, it is made of the embryonic, foetal
& adult stages.
-like chains - 
-like chains – 
Adult human made of
1.1 Fig 33-35:Voet
 – 97%;
&Voet
 - ~2%;
 - ~1% (fetal persistence)
globin gene expression also controlled by location
– embryonic yolk sac; – yolk sac & fetal liver;
  – adult bone marrow
Evolution: we can now trace evolution of present globin clusters from a single ancestral globin gene
Fig 21.16: Hartwell
References:
Genetics by Hartwell et al Chapter 21
Genes VII by B Levin pgs 89 – 100
Optional reading
Metabolic basis of inherited disease (6th ed) by DJ Weatherall et al (CR Scriver et al Editors) The
hemoglobinopathies pp 2281-2339
MV Hejmadi (bssmvh@bath.ac.uk)
0055: Genes & Genomes
RECOMBINATION AND TRANSPOSITION
Recombination (larger scale chromosome rearrangements)
Recombination is an integral part of evolution which allows favourable & unfavourable mutations to be
separated by shuffling the genes. It occurs usually between corresponding sequences
There are 4 basic types of recombination, all of which have a common characteristic of a physical exchange of
DNA fragments but differ mechanistically by the circumstances under which the exchange takes place.
2 homologous / generalised recombination
 exchange between homologous DNA sequences; accomplished by a set of enzymes
 function: meiosisI of eukaryotic cell division, double-strand break repair, telomere maintenance
 replication is an integral part of the reaction, allowing reformation of functional replication forks after any
fork blocking event
HOMOLOGOUS RECOMBINATION
TRANSPOSITION - Transposable elements (TE)
What are transposable elements
Discrete sequences in the genome that have the ability to translocate or copy itself across to other parts of the
genome without any requirement for sequence homology.
Transposition can occur using either a
RNA intermediate: Class I TEs - retrotransposons and retroposons- which transpose by an RNA intermediate.
Retroposons are structurally similar to mRNA; retrotransposons are structurally similar to retroviruses
and are bound by long terminal repeats (LTR).
DNA intermediate: e.g. Class II TE (IS elements and transposons) – transpose via a DNA intermediate
catalysed by the enzyme transposase. They are bounded by terminal inverted repeats (TIR). Prokaryotic
IS elements (e.g. IS10, Ac/Ds, mariner) encode only transposase sequences whereas eukaryotic
transposons encode additional genes such as antibiotic resistance genes.
TYPES: Transposons are now classified into 5 families, on the basis of their transposase proteins (the enzyme
responsible for the catalysis of transposition)
1) DDE-transposases
4) Serine (S) transposases
2) Rolling circle (RC) or Y2 transposases
5) RT/En (reverse transcriptase/endonuclease)
3) Tyrosine (Y) transposases
transposases
MV Hejmadi (bssmvh@bath.ac.uk)
0055: Genes & Genomes
Fig from Nature Rev Mol. Cell Biol (Nov2003) 4(11):865
Common mechanism of transposition
In most cases, transposase is the only requirement for transposition.
Regulation of expression of this protein controls
transposition.
The catalytic domain of the transposase is involved in
the transphosphorylation step that initiates DNA
cleavage & strand transfer.
The process involves 2 sequential steps
 Site specific cleavage of of DNA at the end of TE
 Complex of transposase-element ends brought to
DNA target where strand transfer is carried out by
covalent joining of 3’end of TE to target DNA.
Recombinational reading:
1) GenesVII by B. Lewin pgs 415-430 OR
5) Nature Reviews Mol Cell Biol (June2003) Molecular views of recombinational proteins and their control
4(6):435-445 by SC West.
Transposable reading:
1) Genetics by Hartwell pgs 460-465
2) Curcio MJ and Derbyshire KM. The outs and ins of transposition: From mu to kangaroo (Nature
Reviews Mol Cell Biol, Nov 2003) Vol 4 (11): 865-877
3) LAM Bram & WS Reznikoff (www.els.net) DNA transposition: classes & mechanisms pgs 1-8
MV Hejmadi (bssmvh@bath.ac.uk)