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4: Genome evolution
Why should we care about genome evolution?
Comparing the human and the chimp genomes
Genome evolution – why is it interesting?
The first working draft of the Human genome was
released in 2000. (The first paper was published in the 15
february 2001 in Nature)
September 01, 2005: the full genome of the Chimpanzee
is published in Nature.
Genome evolution – why is it interesting?
The biggest question for molecular evolutionists:
WHAT MAKES US HUMAN?
By comparing the human and chimp
genomes we can search for the genetic
differences responsible for the
human characteristics such as
•Large cranial capacity
•Bipedalism
•Developed brain
Types of differences – at the molecular level
What are the kind of differences between the genomes?
•Single-nucleotide substitutions
•Insertions and deletions (indels)
•Genes and genomes (partial) duplications
•Rearrangements
Types of differences – at the molecular level
Human are Chimp are both 3 billion (3,000,000,000)
nucleotides long.
There are about:
35,000,000 nucleotide differences (~1.2%)
5,000,000 indels (insertions and deletions)
Many chromosomal rearrangements
Most of these differences are probably neutral.
The challenge: find the few that are meaningful!
Known differences 1: Diseases/Pathogens
HIV progression to AIDS is common in humans and very
rare in great apes.
Humans are susceptible to Plasmodium falciparum
malaria. Great apes are resistant
Carcinomas (epithelial cancer) is common in humans and
rare in great apes.
Known differences 2: Karyotype
Human karyotype
Karyotype
All members of
Hominidae except
humans have 24
chromosomes.
Humans have
only 23
chromosomes.
Karyotype: fusion
Human chromosome
2 is widely accepted
to be a result of an
end-to-end fusion of
two ancestral
chromosomes.
from Yunis, J. J., Prakash, O., The origin of man: a
chromosomal pictorial legacy. Science, Vol 215, 19
March 1982, pp. 1525 - 1530
Karyotype: invertion
There are large
inversions on human
chromosomes 4 and 5
relative to the chimp.
There are hundreds of
invertions of smaller
size
Known differences 2: Karyotype
Chimps have an additional chromosome compared to
human because the genetic material on human
chromosome 2 is split between chimpanzee chromosomes
12 and 13.
There are large inversions on human chromosomes 1, 4, 5
and 18 relative to the chimp.
The heterochromatic genome segments are distributed
differently on several chromosomes in the two species
(heterochromatin is the part of the genome that is not
transcribed, and has a structural rather than functional
role).
Known differences 3: Gene expression
Transthyretin is a protein responsible for transporting
thyroid hormones in the blood. (Thyroid hormones effect
metabolic rate and have an effect on embryonic brain
development).
It was found that humans have lower levels of transthyretin
expression compared to chimpanzees.
Studying expression differences between human and
chimps is problematic because of the huge potential for
artifacts in such studies (e.g., rate of tissues deterioration
after death).
3 theories
Protein evolution: Most meaningful changes are due to
amino-acid replacements in proteins.
Gene regulatory evolution: Most meaningful changes are
in non-coding regions that are responsible for gene
regulation.
Less is more hypothesis: Most meaningful changes are due
to deletions, stop codons in coding proteins (loss of coding
regions) and deletions of entire genes.
4: Genome evolution
An example of “protein evolution” in the
lineage leading to humans:
The story of FOXP2:
a speech and language related gene
Humans can talk
Why can humans talk and chimps cannot?
Two possible explanations
1.Culture
2.Genetics
Because chimps that are raised in human environments do
not acquire human linguistic competence, even with
intensive tuition, we believe there is a strong genetic
background underlying this difference.
Humans can talk
From the anatomical point of view:
Humans have a
longer oral
cavity and a
lower larynx
than other
primates.
This is crucial
for modern
human speech.
Humans can talk
It is expected that there are genetic differences that have
impact on neurological development, for example:
•The ability to control the articulators (one of the organs of
speech, such as the lips or tongue).
•Higher order of cognitive processing involved in language
acquisition.
Source: Marcus GF, and Simon EF. 2003. TRENDS in Cognitive Sciences 7:257-261.
The KE family
This is a unique family, 3 generations, in which 15 out of
24 members suffer from severe speech and language
difficulties. Remaining relatives are unaffected.
The gene is found
The single gene was found by correlating the distribution
of the disorder among members of the KE family with a set
of DNA markers (gene hunt!)
The gene is found
The gene is in human chromosome 7 and is a transcription
factor. The name is FOXP2. It works in a dominant
fashion.
The gene: a FOX transcription factor
The FOXP2 is a transcription factor: it activates genes in
specific tissues and/or specific physiological conditions.
What’s the phenotype – a debated issue
1990. Hurst et al. Problematic verbal development (verbal
dyspraxia).
1990,1991. Miriam Gopnik. More specifically, the problem
is in grammar: tenses, gender, numbers, and such. (Big
splash, a gene for grammar).
1995. Faaneh-Vargha-Khadem et al. Not only grammar.
Also problems in face and mouth movements which
impede their speech. (Maybe this is a motor problem?)
2002. Watkins et al. Against the motor problem. They also
have problems in writing and in understanding.
The gene: a FOX transcription factor
The name FOX is for “forkhead” as mutations in the first
gene from this family that was studied in the fruit fly had
unusual spiked-head structures in the embryo.
All FOX proteins share a 80-100 amino-acid motif (the
forkhead box) responsible for DNA binding.
In the KE family, the mutation is in this forkhead box.
FOX are found only in animals and fungi. Yeasts have 4
FOX genes, nematode 15, fruit flies 20, and 40 in humans.
This increase is suggested to be correlated with body-plan
complexity.
FOXP2
It is currently unknown:
•Which genes is FOXP2 activating or repressing?
•Which genes activate/repress FOXP2?
•Which genes work with FOXP2?
FOXP2 – where is it expressed?
FOXP2 is expressed in the brain, lung, gut, and heart.
Many transcription factors have multiple jobs, sometimes
at diverse time points during development.
Why do we only see speech problems in the KE family?
Maybe because other mutations are recessive.
FOXP2 – evolutionary perspective
FOXP2 is also found in mouse.
There are almost no differences in the amino-acid
sequence between mouse FOXP2 and human
FOXP2 (3 aa differences, p-distance for nucleotides
= 0.065).
•Mice don’t talk.
?
Conclusion: FOXP2 is finally not related with
speech…
FOXP2 – evolutionary perspective
Francois Jacob: evolution is like molecular
tinkering… Uses what it can find around...
There are 3 aa differences between human and mouse
but two of them occurred after the divergence of
chimpanzee.
FOXP2 – evolutionary perspective
Comparing a model of Ka/Ks in which this ratio is
the same in all lineages versus a model in which the
branch to humans evolves with a different Ka/Ks
ratio, showed that there was a change in selection
pressure in the lineage leading to modern human
Source: Enard W. et al (Svante Paabo group). 2002. Nature 418:869-872.
Conclusions
A classical example of “Protein Evolution”- the first
source of variation that can explain why species A
is different from species B…
In genomic scale, it could be interesting to detect
all proteins with positive Darwinian selection in the
lineage leading to human (and to a lesser extant, in
other organisms).
A remark
Although this was a classical example of “Protein
Evolution”- it is also an example of “Gene
Regulatory Evolution”, because it involves
transcription factors. These two theories have a lot
in common, if protein evolution acts mainly on
transcription factors…
More on FoxP2
In 1972 it was discovered that rodents produce
noise at ultrasonic frequencies (that human ears
cannot hear).
Mice do not talk but they sing…
FOXP2 – evolutionary perspective
FOXP2 – evolutionary perspective
Knockout mice
with only one
functional copy of
the FOXP2 gene
have significantly
reduced
vocalizations as
pups.
[Shu W. et al. (2005). "Altered ultrasonic vocalization in mice with a
disruption in the Foxp2 gene“ Proc Natl Acad Sci U S A 102 (27): 9643–8]
FOXP2 – evolutionary perspective
Bird also sing…
Songbirds also require a properly functioning
FoxP2 gene if they are to sing their song accurately
and completely
[Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, et al. (2007) Incomplete
and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal
Ganglia Nucleus Area X. PLoS Biol 5(12): e321. ]
Haesler S, et al. (2007) Incomplete and Inaccurate
Vocal Imitation after Knockdown of FoxP2
in Songbird Basal Ganglia Nucleus Area X
PLoS Biol 5(12): e321
• In bird, FoxP2 is up-regulated in Area
X, a brain region important for song
plasticity. In the paper they reduced
FoxP2 levels in Area X before zebra
finches started to learn their song,
using virus-mediated RNA
interference.
short interfering hairpin RNA (shRNA)
Haesler S, et al. (2007) Incomplete and Inaccurate
Vocal Imitation after Knockdown of FoxP2
in Songbird Basal Ganglia Nucleus Area X
PLoS Biol 5(12): e321
• Birds with experimentally lowered
levels of FoxP2 imitated their tutor's
song imprecisely and sang more
variably than controls. FoxP2 thus
appears to be critical for proper song
development.
More on FoxP2
• There have been many studies on FoxP2
in the last 5 years.
– FoxP2 of bat (do animal that use echolocation
use FoxP2?)
– FoxP2 of Neandertal (were they talking?)
– And many more….
4: Genome evolution
Story 3: The “less is more” hypothesis.
The theory
The claim is that loss-of-function mutations are
important in recently evolved novel lineages such
as humans.
This theory is counter-intuitive as it suggests that
humans are “degenerate apes”.
The theory
The theory was first suggested by MV Olson in
1999.
Points in favor
Deleterious mutations are very common.
In yeast, 85% of the genes are not essential (knock
out experiments). In some cases, knocking out a
gene increased growth relative to the w.t.
Points in favor
Loss of function mutations can protect against
pathogens. For example, human with double
mutant to CCR5 are immune to HIV-1.
The frequency of the CCR5 deleterious allele is
~15% in certain area of northern Europe, but
1.It is probably not the result of HIV-1 which is a
new emerging pathogen.
2.It is difficult to separate “founder effect” from
“selective advantage”.
Human vs. other primates
Degenerative phenotypes in humans compared to
chimpanzees are:
•Delayed postnatal development
•Loss of muscle
•Loss of strength of hair
A molecular example
Humans, unlike great apes cannot synthesize a
form of the cell-surface sialic acid.
A molecular example
Specifically, humans cannot synthesize the sialic
acid N-glycolyl-neuraminic acid (Neu5Gc).
This results in an excess of the precursor Neu5Ac.
The “problem” in humans is that the enzyme that
catalyzes the reaction: Neu5Gc → Neu5Ac does
not function.
Neu5Ac
Neu5Gc
A molecular example
The defective enzyme is CMAH (it hydroxylates
CMP-Neu5Ac).
In humans, it is inactivated by a 920bp deletion that
occurred in the lineage leading to humans after the
divergence from chimpanzees.
Neu5Ac
Neu5Gc
A molecular example
Molecular dating shows that this mutation might
have occurred 2.5-3 millions years ago.
Knowledge of the biological functions of this
specific sialic acid is, as yet, insufficient to relate
this change to any particular human-specific
characteristics.
Other molecular examples
•Loss of the V10 variable gene of the human T-cellreceptor gamma locus
•Loss of the olfactory receptor gene OR921-93
•Loss of the type I hair-keratin gene
Common to all these losses, is that the genes are
part of a multi-gene family. Thus, there is a backup
for most of these genes…