EVOLUSI GENOM

OLEH :
ANDRE
IAN IMANUEL FIDHATAMI

GENOMe EVOLUTION ?
Evolusi genom

Its really happens ?

Change of
genome

Berkembang

Why ?
Kurang/bertambah/
hilangnya beberapa
gen

Banyak Faktor

Example
Homeosis
the vertebrate ancestor
hypothesis

Mutasi
(Duplikasi)
Kompleks hox

Manusia : kromosom 7
dan 17
Tikus rumah : kromosom
6,9,11,5 ..
Drosophila sp. : 3R.

Rancangan dasar
tubuh/
perkembangan
pengaturan
spesial organorgan tubuh.

Gen Hox

Mekanisme Evolusi Genom

(Symbiogenesis)
Genom
Prokaryote

Proteobacteria

Mitokondria

Transfer Gen

Genom Eukaryote

Chloroplas

Cyanobacteri
um

The Truth is Unkown .. But ... ?

Genome
Chloroplas

copies of
mitochondrial
DNA

Genom inti

Genom Mitokondria

Superoxide dismutase
(Chromosome 6)

2. Genome evolution introduction

In the course of a human lifetime, the genome is used, damaged, repaired, copied and handed down to
offspring cells dozens of times. In the process, the genome is changed. This change is called a mutation.
At first this involves just a single individual. If the change is has no phenotypic consequence, no selection
acts against (or for) the mutation, and chance determines whether the individuals offspring will carry the
mutation, and so on. The process by which the frequency of the mutation changes in the population is
called (random) genetic drift.
Of all neutral mutations in a population of 2N haploid genomes, a fraction 1/2N will eventually spread
through the entire population. The mutation is said to have gone to fixation. Mutations that have a
beneficial effect have a (much) larger probability of getting fixed (once they reach a non-negligible
population frequency), while deleterious mutations have almost no chance of going to fixation.
Mutations that have become fixed in the population are called substitutions.
(Note: substitutions usually refer to single nucleotide substitutions, but the term indel substitution is also
used.)
When comparing genomes from different species, what you see are all the fixed mutations (substitutions)
that have occurred since the two species split. Mutations that are reside in either of the two individuals
whose genomes were sequenced are called polymorphisms, and will also be included. Usually these
form a small proportion and the distinction is ignored (but note that polymorphisms may well be
deleterious, while substitutions rarely are).

2. Genome evolution nucleotide

substitutions
Basically two causes: damage, and copy errors during
replication.
The two causes can be teased apart by comparing
species with different generation times. More
generations per unit of time mean more copying
errors, while the rate of damage might stay relatively
constant.
Errors are recognized and repaired by specific and highly
efficient repair mechanisms.
-8 per nucleotide per
Resulting error rate is low: about 3x10-8
generation in humans.

The repair mechanism is extremely important: damage to

this system increases the likelihood of getting cancer.
The rate of mutagenesis is higher in males than in
females (see e.g. Berlin et al., J Molec Evol 62(2) 226233), probably due to more cell divisions in the male
germline. This results in low mutation rates on the X,
and high mutation rates on the Y chromosome.
In mammals, the rate of transitions (pyrimidine-topyrimidine or purine-to-purine) is about twice higher
than the rate of transversions (pyrimidine-to-purine
or vice versa).

2. Genome evolution CpG

mutation rate
Methylation of Cytosine (mC) involves adding a methyl
group (CH3) on to the C5 carbon.
Accidental de-amination of the C4 carbon turns a mC into
a normal Thymine.
This results in a mismatch, but the wrong base cannot
be identified, since both are in the alphabet.
Result: substitution rate on CpG dinucleotides is about
15x higher than for ordinary Cs or Gs.
(The same process on the reverse-strand mC causes a
high mutation rate on the G).
Over time, this causes CpGs to be about 4x
underrepresented compared to the expectation based
on C and G frequencies.
For sequences that are not methylated (in the germline),
this mechanism does not apply, resulting in high
(i.e. normal) levels of CpG in so-called CpG islands.
These are often promoters of ubiquitously expressed
genes.

2. Genome evolution
Transcription-coupled repair

When RNA polymerase II

encounters a mutated nucleotide,
it stops. This triggers the TCR
pathway which repairs the
mutation.

Failure of TCR leads to Cockayne

syndrome, extreme form of
accelerated aging.

TCR is strand-asymmetric
(mutations in the untranscribed
strand are not corrected by TCR),
and leads to asymmetric mutation
rates in transcribed regions.

2. Genome evolution Indels

CGACATTAA--ATAGGCATAGCAGGACCAGATACCAGATCAAAGGCTTCAGGCGCA
CGACGTTAACGATTGGC---GCAGTATCAGATACCCGATCAAAG----CAGACGCA
Indel

Indel

Indel

When the ancestral sequence is not known, insertions and deletions

cannot be distinguished, and are often referred to as indels.
Indels form an important source of sequence change more on this
later.
Most small indels are in fact deletions (by a factor 3 in human).
Indels can have any size, up to several Mb. The majority are 1 nt
indels.

2. Genome evolution Indel

mechanisms
During replication, the template and
copy can become separated.
If this happens in a tandem-repetitive
region, there is a possibility of
incorrect re-pairing (slippage)
This can lead to both short insertions
and deletions.
Long stretches of short-period tandem
repeats (microsatellites) are
particularly prone to slippage.
This is the reason behind the fast
evolution of microsatellite length.
The gene encoding for huntingtin
contains a repeat region of CAG
triplets. Expansion of the number
of CAG units beyond 36 causes
Huntingtons disease.

http://www.sci.sdsu.edu/~smaloy/

2. Genome evolution indel

mechanisms
Recombination between direct repeats
in a single chromosome leads to a
(potentially Mb size) deletion.
Recombination requires (near)
sequence identity over fairly large
region (100s nt?), so these
deletions are mostly not very small.
Unequal recombination (involving
similar or identical regions at
different chromosomal locations)
can also lead to insertions
(segmental duplications).
In the picture, unequal recombination
between sister chromatids at
replication is shown. The same
process may also happen between
parental (homologous)
chromosomes.
http://www.sci.sdsu.edu/~smaloy/

2. Genome evolution
Recombination
Mechanism of recombination:
1. Double-stranded break (DSB) formation
2. Broken ends get digested
3. Single strands invade region with
high sequence similarity
4. Repair and re-synthesis Holliday junction
5. Holliday junction resolution:
Crossing over (black arrows), or
NO crossing over (grey arrows)
Gabriel Marais, Trends Genet, 19(6)2003

2. Genome evolution - types of

recombination

Double-stranded breaks appear:

Accidentally (somatic & germ cells)
Repair recombination
Deliberately (germ cells at meiosis)
Sexual (or meiotic) recombination

Different (but overlapping) pathways

Preference for:
sister chromatid in repair recombination
parental chromosome in sexual
recombination

Recombination is obligatory during meiosis.

Rate of recombination is >1 per generation per
chromosome.

2. Genome evolution Gene

conversion

Gene conversion = copying of one stretch

of DNA into another

Single-stranded DNA can invade sister chromatid

Identical DNA, so no mutations

If single strand invades parental chromosome:

Without crossing over: gene conversion
With crossing over: gene conversion +
recombination

When the nicked strand invades a non-homologous

but sequence-similar region (as in unequal
recombination), gene conversion causes sideways
copying of genetic material. Causes similarities to
increase / persist.

The effect of gene conversion (without recombination)

on the genome sequence is equivalent to two
recombination events happening close to each other

2. Genome evolution
Biased Gene Conversion
Mutation bias for GC as a side effect of gene
conversion

Two repair mechanisms:

Base Excision Repair (BER)
Targets hetero-mismatches, AG, TG, AC, TC
Efficient; replaces just one base
Favours GC
Nucleotide Excision Repair (NER)
Targets AA, CC, TT, GG mismatches
Digests ~1kb, resynthesizes
Favours unbroken strand, no nucleotide bias

Second source of biased gene conversion

AT sites seem to be target for DSBs in sexual
recombination
DSB strand gets digested, copied back from other allele
Result: bias towards GC

2. Genome evolution Recombination hotspots

Rate of recombination is measured in centiMorgans

(cM). Two genetic loci are 1 cM apart if 1 recombination
per 100 generations occurs between them.

Recombination rate not uniform:

Background rate ~0.04 cM/Mb
Average rate ~1 cM/Mb
0.5% of genome >15 cM/Mb

Recombination hotspot = gene conversion hotspot

Cause of hotspots not known:

CCTCCCT motif?
Bias for high GC

One mutation can change hotspot activity

DNA2 locus in MHC region,
CT suppresses hotspot

Perhaps differences in recombination rates have, over

time, caused the current isochore structure through
biased gene conversion.

Myers, Bottolo, Freeman, McVean,

Donnelly, Science 310 Oct 2005

2. Genome evolution
double stranded break repair
Accidental breaks are also
repaired through the nonhomologous end joining (NHEJ)
pathway. Does not require
homologous sequence.
Evolutionary very old pathway:
yeast and some bacterial
species have NHEJ.
Repairs most breaks correctly, but
is also able to induce
translocations (chromosome
rearrangements).
Gill and Fast BMC Molecular Biology 2007 8:24
doi:10.1186/1471-2199-8-24

2. Genome evolution
chromosomal rearrangements

Mouse chromosomes (1-19 and X) coloured according to homology with human

chromosomes (1-22 and X). In the about 2 x 80 million years that separate humans
and mice, many chromosomal rearrangements have occurred.

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