Chimp and us

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Chimp and us
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ID _PANTR
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ID _PANPA
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Complete chimp (PANTR) genome publication
Nature, sept 2005 - Genome derived from one
individual Clint (male from west Africa) -
Inter vs intra (polymorphism) species differences
!!!
- Individual human genome variation 1bp/1000 -
Individual chimp genome variation 1bp/250
(estimation Varki (2000)
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Cheeta has been recognized by the Guinness Book
of World Records as the world's oldest chimp.
Chimps rarely live past the age of 40 in the
wild, but can reach 60 in captivity.
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• The chimpanzee genome was sequenced to
  approximately four-fold coverage (error rate lt
  10-4)
• WGS sequencing approach (-gt problem for the
  assembly of region with segmental duplication)
  22.5 millions of sequence reads to assemble.
• ? 2 assembly approaches (PCAP and ARACHNE)
• - In one of the 2 approaches, contigs were
  assembled using the human genome as a guide ?
  "humanized" in their construction.
• ? some sequences, such as insertions, deletions,
  and gene duplications, may not be accurately
  represented by the current chimpanzee assembly.

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chromosomal fusion in the human lineage ?
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• NCBI has adopted the NEW chimpanzee chromosome
  naming system as proposed by McConkey, 2004
• - The UCSC-Genome browser currently uses the
  original chimpanzee chromosome naming system.

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• Humanness
• - Bipedalism
• - Large cranial capacity (Brain size)
• - Advance brain development (langage capability)
• A long generation time
• and some other biomedical differences.

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Chimps expressed apoE4 allele
Chimps no acne, rhinitis but no asthma, no
rheumatoid arthritis
Olson et al., (2002)
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• The last common acestor of humans and chimp is
  believed to have walked on 4 legs.
• The oldest fossils that resemble bipedal human
  are 6 to 7 millions years old.
• - DNA sequence analyses suggest the 2 lineages
  separated about 5.4 millions years ago.

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Short time since human-chimp split it is likely
that a few mutations of large effects are
responsible for part of the differences.
Comparative genomic analysis Human vs mouse,
chick focus on similarities Human vs chimp
focus on differences
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Hypothesis to account for the evolution of
humanness traits
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Quantifying the sequence divergence Single
nucleotide subtitutions 1.23 (1, 78 for
chromosome Y) (0.8 in protein coding
region) Indels 1.5 Transposable elements 3
Recent duplication of DNA segments 2.7
35 mo nucleotides differences 5 mo
indels Many chromosomal rearrangements Human
3.4 109 bp Chimp 3.6 109 bp
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35 mo nucleotides differences Since we
apparently diverged from a common ancestor 6
million years ago, that is roughly 6 mutations
per year that get fixed within the genome (or 3
per year if you divide them equally amongst the 2
branching species). Given a conservative estimate
of average generational time of 10 years, this
means that 30 new mutations had to be fixed
within the population every generation. The
current human mutation rate is around 3 or 4
mutations per organism. http//www.uncommon
descent.com/index.php/archives/875
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At the genome level 1) Structural variations
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chromosomal fusion in the human lineage ?
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A genome-wide survey of structural variation
between human and chimpanzee (Newman et al.,
(2005)) - Approach Mapping chimp fosmid
against human reference sequence and identifying
discordant regions by size and orientation -
Limitations The human genome is not complete The
chimp genome 1 individual (! Inter/intraspecific
differences !)
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• Identification of 651 regions of putative
  structural variation between the human genome
  assembly and the single chimp individual (293
  chimp deletions, 184 chimp insertions and 174
  inversions/duplicative transpositions).
• Chromosome Y is the most rearranged chromosome
  between human and chimp (! Repetitive regions !)

- They have identified 245 (RefSeq) genes that
may be affected by the structural differences
between chimp and human (drug detoxification,
receptors, reproduction)
(Newman et al., (2005))
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• At the genome level
• Structural variations
• 2) Segmental duplication

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• Segmental duplication (impact 2.7 )
• Longer than 20 kilobases (-gt 300 kb), greater
  than 94 sequence identity
• 33 of human duplicated segments are human
  specific
• - 17 of chimp duplication are chimp specific.
• Half of the genes in the human specific
  duplicated regions exhibit significant
  differences in gene expression relative to chimp
  and are most often upregulated.
• Cheng et al., Nature (2005)

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About 300 region were identified where the human
genome showed significant increase in copy number
when compared to chimp. Only 92 regions where
the chimp genome showed an increase in copy
number compared to human (but with higher rate of
duplication)
Cheng et al., Nature (2005)
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Example 4 human regions represented 400 x in
chimp genome (99.2 identity)
Cheng et al., Nature (2005)
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• At the genome level
• Structural variations
• 2) Segmental duplication
• 3) Interspersed/Transposable repeats

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• The human genome is composed of 45 of
  interspersed elements
• Including
• Long interspersed elements (LINEs) these encode
  a reverse transcriptase
• Short interspersed elements (SINEs) these
  include Alu repeats
• -The human genome contains about 1,000,000 Alu
  elements.

- Found only in primates .
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Interspersed/Transposable element insertions
(impact 3 )

• endogenous mutagens which can alter genes,
  promote genomic rearrangements
• may help to drive the speciation of organisms

• Particular interest in recently mobilized
  transposons
• - The transposons that inserted into human or
  chimp genome during the passed 6 mo years would
  be expected to be present in only one of the 2
  genome.

• 11000 recent transposons copies that are
  differentially present in human/chimp
• 73 found in human and 27 found in chimp

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Interspersed/Transposable element insertions
Endogenous retrovirus
Mills et al., Am. J. Hum. Genet., 78671-679,
2006
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Interspersed /Transposable element insertions

• Alu, L1 and SVA insertions accounted for gt 95
  of the insertion in both species
• - Human and chimp have amplified different
  subfamilies of these elements.

SVA composite element (1.5-2.5 kb) (2 Alu, a
tandem repeat and a region derived form HERV-k)
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Human have supported higher levels of
transposition than chimp during the past several
million years (butnot the case for the baboo
which shows an activity 1.6 fold higher than
human -gt general decline in Alu activity in chimp)
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Blat human DNA vs chimp DNA AJ271736 Xq
pseudoautosomal
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Interspersed /Transposable element insertions

• 34 of the insertions were located within known
  genes during the evolution of human and chimp

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Interspersed /Transposable element insertions -
conclusions
- The original set of transposons in the common
ancestor of human and chimp behaved differently
during the subsequent evolution of the 2
organisms - Human received at least 4800
additional transposon insertions compared to
chimp -gt impact of transposon mutagenesis is
likely to be greatest in human during the past
several million years. - Human and chimp have
amplified different subfamilies of these
elements. - Factors such as differences in
population size may also have influence the
pattern of transposon insertion.
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At the sequence level (coding sequence level)
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Nucleotide divergence 1.23 14-22 of these
differences are due to polymorphism -gt fixed
divergence rate 1.06 Chromosome X 0.94
Chromosome Y 1.9 Higher mutation rate in
the male compared with female germ line (higher
number of cell division (5 to 6 fold))
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At the gene level 13454 pair of orthologous
genes (507 Swiss-Prot, 1134 TrEMBL 1641) (NCBI
3111) - 29 are 100 identical - 5 with
in-frame indel (mainly in repetitive region)
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A classical measure of the overall evolutionary
constraint on a gene KA non-synonymous
substitution rate in coding sequence KB or Ks
synonymous substitution rate in coding
sequence Kl substitution rate in non-coding
sequence KA/KB ltlt 1 typical of most proteins
where change is detrimental (negative
selection) KA/KB gt 1 for the rare protein
for which it is a positive selection
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About 500 genes with a KA/KB gt 1 Most of the
genes with a KA/KB gt 1 are not involved in
process related to supposed humanness. Genes
with highest KA/KB ratio are mostly related to
host-pathogen interaction, immunity and
reproduction (pattern also found in other mammals
(cf Valerias work on human/mouse orthologs)
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In fact genes related to brain function and
neuronal activities show lower-than-average KA/KB
ratio - Neural genes, as a group, have much
lower average of KA/KB ratio than genes expressed
outside of the brain. Hypothesis only a small
subset of genes may be the target of positive
selection not visible in such type of
studies. (Hill, Walsh (2005))
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• Example 1 FOXP2
• gene relevant for the human ability to develop
  language
• among the 5 most conserved protein
• CC -!- DISEASE Defects in FOXP2 are the cause
  of speech-language
• CC disorder 1 (SPCH1) MIM602081 also
  known as autosomal dominant
• CC speech and language disorder with
  orofacial dyspraxia. Affected
• CC individuals have a severe impairment in
  the selection and
• CC sequencing of fine orofacial movements,
  which are necessary for
• CC articulation. They also show deficits in
  several facets of
• CC language processing (such as the ability
  to break up words into
• CC their constituent phonemes) and
  grammatical skills.

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• Extremely conserved among mammals
• - Acquired 2 aa changes in the human lineage
  (T303N and N325S),
• including one potential/functional
  phosphorylation site (N325S)
• Estimation fixation of these mutations occurs
  during the last 200000 years of human history,
  concomitant with of subsequent to the emergence
  of anatomically modern humans.
• Enard et al., Nature (2002)

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• BUT
• no aa substitution are shared between
  song-learning birds, vocal learning whales,
  dolphins and bats, and human,
• AND
• during times of song plasticity, FoxP2 is
  upregulated in a striatal region esssential for
  song learning.
• selection acted on large non-coding regulatory
  regions of FoxP2 ???
• - duplication of the chromosomal region (27 genes
  including FoxP2) may be another cause of speech
  and language disturbance ???

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Less-is-more hypothesis Loss of function changes
(lack of body hair, preservation of juvenile
traits, expansion of the cranium) could be caused
by non-synonymous substitutions, indels, loss of
coding regions and deletions of entire genes. -gt
53 human genes with disruptive indels in the
coding regions (compared to chimp)
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Well documented examples of human specific
pseudogenization - MYH16, CMAH, CASP12, ELN,
T2R62P (bitter taste receptor), MBL1 -
Microcephalin (MCPH1) Challenge dating the
event !
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MYH16 Myosin gene mutation (MYH16) correlates
with anatomical changes in the human lineage
inactivated by a frameshifting mutation after the
lineages leading to humans and chimpanzees
diverged (2.4 Myr). The gene is transcribed (-gt
the coding sequence deletion was not preceeded by
a mutation in a transcriptional control domain).
Expressed only in masticatory muscles in other
mammals. Loss of this protein isoform is
associated with marked size reductions in
individual muscle fibres and entire masticatory
muscles. Nature 428, 415-418 (2004)
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Phylogenetic reconstruction for all human
sarcomeric myosin genes (heavy chain), showing
early divergence of MYH16 from others.
Nature 428, 415-418 (2004)
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Aligned DNA sequences for MYH16 exon 18
representing seven non-human primate species and
six geographically dispersed human populations,
revealing the effect of frameshift on reading
frame and deduced amino acid sequence. Note stop
codon at position 72-74.
Nature 428, 415-418 (2004)
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The findings on the age of the inactivating
mutation in the MYH16 gene raise the intriguing
possibility that the decrement in masticatory
muscle size removed an evolutionary constraint on
encephalization, as suggested by the anatomy of
the muscle attachments relative to the sutures -gt
marked increase in cranial capacity.
Nature 428, 415-418 (2004)
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But Human encephalization -gt obstetric
constraints associated with pelvic dimensions for
bipedality Importance of the genes that control
the development of brain size in mammals ASPM,
MCPH1, CASP3 Have undergone accelerated rates
of protein evolution Strong positive selection
at several loci McCollum et al., (2006), J.
of Human Evolution, 50, 232-236
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MCPH locus (microcephalin) MCPH1 -gt
MCPH6 MCPH5/ASPM locus (abnormal spindle
microcephaly)

• High KA/KB ratio
• Patients with loss-of-function in microcephalin
  have cranial capacities about 4 SD below the mean
  at birth and 1/3 of the size as adult.
• May control the proliferation and/or
  differenciation of neuroblasts during
  neurogenesis.
• Continues its trend to adaptive evolution
• Ex APSM acquires an advantageous aa change
  every 350000 years.

Evans et al., Nature 2005
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Pseudogenization
CMAH Alu-mediated sequence replacement -gt
inactivation of the enzyme CMP-N_acetylneuraminic
acid hydrolase in human This mutation occurred
after our last common ancestor with bonobos and
chimpanzees, and before the origin of present-day
humans (2.8 mya ) -gt susceptibility or
resistance to certain microbial pathogens (host
receptors).
Chou et al., 2005
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Pseudogenization
CASP12 Functional gene in all mammals except
human. Mediator of apoptosis in response to
perturbed calcium homeostasis -gt loss of this
gene in mice increases resistance in to
amyloid-induced neuronal apoptosis (-gt Alzheimer
in human ?) -gt loss of this gene seems also to
confer resistance to severe sepsis
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Last but not least
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Nature (2005)
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• Comparative analysis of cancer genes in the human
  and chimpanzee genomes
• - The incidence of cancer in non-human primates
  is very low.
• All examined human cancer genes (n333) are
  present in chimpanzee, contain intact open
  reading frames and show a high degree of
  conservation between both species (99.38)
• Sequencing of the BRCA1 gene has shown an 8 Kb
  deletion in the chimpanzee sequence that
  prematurely truncates the co-regulated NBR2 gene.

Blat of P53_Human vs chimp
Ex Pro-72 is polymorphic only in human
Puente et al., (2006)
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Transcriptome evolution (and epigenetics
events) Changes in gene usage may be a primary
contributor to the differences in chimp and human
brains. 10 of all genes expressed in the
brain differ in their expression levels between
humans and chimpsbut no causative connection
found Several studies, but none with
convincing results
Heissig et al., 2005 Khaitovich et al., 2005
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Swiss-Prot annotation
Existence of orthologs DEF7_PANTR
MISCELLANEOUS The human orthologous protein
seems not to exist, its coding region does not
have a start codon. Pseudogenization (when
documented) T2R64_PANPA MISCELLANEOUS The human
and chimpanzee orthologous proteins do not exist,
their genes are pseudogenes.
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Thats all folk !