The Human Genome and Human Evolution Y Chromosome

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The Human Genome and Human EvolutionY Chromosome

• Dr Derakhshandeh, PhD

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Outline

• Information from fossils and archaeology
• Neutral (or assumed-to-be-neutral) genetic
  markers
• Classical markers
• Y chromosome
• Genes under selection
• Balancing selection
• Balancing selection can arise by the
  heterozygotes having a selective advantage, as in
  the case of sickle cell anemia
• It can also arise in cases where rare alleles
  have a selective advantage
• Positive selection

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Why Y?

• "Adam passed a copy of his Y chromosome to his
  sons
• The Y chromosome is paternally inherited
• the Y chromosome a father passes to his son is,
  in large measure, an unchanged copy of his own

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• But small changes (called polymorphisms) do occur
  
• passed down from generation to generation

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CHROMOSOME CHANGES

• indels
• insertions into or deletions of the DNA at
  particular locations on the chromosome
• YAP
• which stands for Y chromosome alu polymorphism
• Alu is a sequence of approximately 300 letters
  (base pairs) which has inserted itself into a
  particular region of the DNA

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• Snips
• "single nucleotide polymorphisms
• Stable indels and snips are relatively rare
• so infrequent
• they have occurred at any particular position in
  the genome only once in the course of human
  evolution
• Snips and stable alus have been termed "unique
  event polymorphisms" (UEPs)

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• microsatellites
• short sequences of nucleotides (such as GATA)
• repeated over and over again a variable number of
  times in tandem
• The specific number of repeats in a particular
  variant (or allele) usually remains unchanged
  from generation to generation
• but changes do sometimes occur and the number of
  repeats may increase or decrease

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• increases or decreases in the number of repeats
  take place in single steps
• for instance from nine repeats to ten
• whether decreases in number are as common as
  increases has not been established

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• Changes in microsatellite length occur much more
  frequently than new UEPs arise
• while we can reasonably assume that a UEP has
  arisen only once
• the number of repeat units in a microsatellite
  may have changed many times along a paternal
  lineage

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The microsatellite data

• can facilitate the estimation of population
  divergence times
• which can then be compared (and contrasted) with
  estimated mutational ages of the polymorphic
  markers
• the combination of these two kinds of data
• offers a powerful tool with which to assess
  patterns of migration, admixture, and ancestry

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• minisatellites
• 10-60 base pairs long
• the number of repeats often extends to several
  dozen
• Changes during the copying process take place
  more frequently in minisatellites than in
  microsatellites

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the evolutionary clock

• the UEPs as the hour hand
• the microsatellite polymorphisms as the minute
  hand
• the minisatellites as a sweep second hand

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a further benefit of using Y chromosome to
study evolution

• most of the Y chromosome does not exchange DNA
  with a partner
• all the markers are joined one to another along
  its entire length
• linkage of markers

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The human Y chromosome

• can also be used to draw evolutionary trees
• the relationships of the Y chromosomes of other
  primates
• The different polymorphic loci are distinguished
  from each other by their chain lengths
• it can be measured using an automatic DNA
  sequencer

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Gene scan output of microsatellite DNA analysis
from a single individual The microsatellite
peaks are sorted by size, the different colors
representing different microsatellites. The small
red peaks are size markers
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new UEP arises in a certain man

• As the new UEP is copied from generation to
  generation
• The UEP does not change but, albeit not very
  often
• increasing
• decreasing in length
• The longer the time since the UEP arose
• the greater will be the number of different UEP
  allele

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• Such a process
• differentiates one population from another
• the more closely two populations
• display common haplotype frequencies
• the more closely related is their biological
  history likely to be

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IN ANCIENT TIMES

• only the analysis of DNA obtained from our
  contemporaries
• suggested ways in which we might deduce past
  history from an interpretation of those data
• DNA can be extracted from ancient remains

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amelogenin gene

• exists in two forms
• the one on the X chromosome being different in
  length from the one on Y
• Small portions of
• cranial bones
• and teeth
• were crushed to powder and decalcified

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The amelogenin gene

• is a single copy gene
• homologues of which are located on
• Xp22.1-Xp22.3
• and Yp 11.2

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• DNA was purified
• copied by PCR using primers flanking the region
• the size of the products was measured by agarose
  gel electrophoresis
• Since Y chromosomes yield fragments 218 base
  pairs long
• while X chromosome products contain 330 base
  pairs
• they should be clearly distinguishable
• if the specimen yields the shorter gene, it must
  come from a Y chromosome fragment and thus from a
  male.

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Disadvantages

• DNA is often degraded
• so that continuous fragments are no longer
  present
• cannot be copied
• substances may be present
• inhibit both purification and amplification

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The first two human Y chromosome marker

• studies appeared in 1985 (Casanova et al. 1985
  Lucotte and Ngo 1985)
• It was not until almost a decade later that
  Torroni and co-workers (1994a) published the
  first Y chromosome data on Native Americans
• Numerous surveys of variation on the
  non-recombining portion of the Y chromosome (NRY)
  devoted primarily to Amerind speakers quickly
  followed

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Who are our closest living relatives?
Chen FC Li WH (2001) Am. J. Hum. Genet. 68
444-456
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Phenotypic differences between humans and other
apes

development of an individual from the moment the
egg is fertilized up till adulthood Carroll
(2003) Nature 422, 849-857
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Chimpanzee-human divergence
6-8 million years
Hominids or hominins
Chimpanzees
Humans
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Origins of hominids

• Sahelanthropus tchadensis
• Chad (Central Africa)
• Dated to 6 7 million years ago
• Posture uncertain, but slightly later hominids
  were bipedal

Toumai, Chad, 6-7 MYA
Brunet et al. (2002) Nature 418, 145-151
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Hominid fossil summary
Found only in Africa
Found both in Africa and outside, or only outside
Africa
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Origins of the genus Homo

• Homo erectus/ergaster 1.9 million years ago in
  Africa
• Use of stone tools
• H. erectus in Java 1.8 million years ago

Nariokatome boy, Kenya, 1.6 MYA
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Additional migrations out of Africa

• First known Europeans date to 800 KYA
• Ascribed to H. heidelbergensis

Atapueca 5, Spain, 300 KYA
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Origins of modern humans (1)

• Anatomically modern humans in Africa 130 KYA
• In Israel by 90 KYA

Omo I, Ethiopia, 130 KYA
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Origins of modern humans (2)

• Modern human behaviour starts to develop in
  Africa after 80 KYA
• By 50 KYA, features such as complex tools and
  long-distance trading are established in Africa

The first art? Inscribed ochre, South Africa, 77
KYA
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Expansions of fully modern humans

• Two expansions
• Middle Stone Age technology in Australia 50 KYA
• Upper Palaeolithic technology in Israel 47 KYA

Lake Mungo 3, Australia, 40 KYA
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the Upper Paleolithic period

• In the Upper Paleolithic period
• Neanderthal man disappears
• and is replaced by a variety of Homo sapiens

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Routes of migration?archaeological evidence
Upper Paleolithic
130 KYA
Middle Stone Age
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Strengths and weaknesses of the
fossil/archaeological records

• Major source of information for most of the time
  period
• Only source for extinct species
• Dates can be reliable and precise
• need suitable material, C calibration required

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Mixing or replacement?
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Human genetic diversity is low
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Human genetic diversity is evenly distributed
Most variation between populations
Most variation within populations
Templeton (1999) Am. J. Anthropol. 100, 632-650
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Phylogenetic trees commonly indicate a recent
origin in Africa
Y chromosome
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Modern human mtDNA is distinct from Neanderthal
mtDNA
Krings et al. (1997) Cell 90, 19-30
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Classical marker studies
Based on 120 protein-coding genes in 1,915
populations Cavalli-Sforza Feldman (2003)
Nature Genet. 33, 266-275
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Phylogeographic studies

• Analysis of the geographical distributions of
  lineages within a phylogeny
• Nodes or mutations within the phylogeny may be
  dated
• Extensive studies of mtDNA and the Y chromosome

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Phylogenetic trees commonly indicate a recent
origin in Africa
Y chromosome
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Y haplogroup distribution
Jobling Tyler-Smith (2003) Nature Rev. Genet.
4, 598-612
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An African origin
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SE Y haplogroups
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NW Y haplogroups
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Did both migrations leave descendants?

• General SE/NW genetic distinction fits
  two-migration model
• Basic genetic pattern established by initial
  colonisation
• All humans outside Africa share same subset of
  African diversity (e.g. Y M168, mtDNA L3)
• Large-scale replacement, or migrations were
  dependent
• How much subsequent change?

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Fluctuations in climate
Ice ages
Antarctic ice core data
Greenland ice core data
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Possible reasons for genetic change

• Adaptation to new environments
• Food production new diets
• Population increase new diseases

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Debate about the Paleolithic-Neolithic transition

• Major changes in food production, lifestyle,
  technology, population density
• Were these mainly due to movement of people or
  movement of ideas?
• Strong focus on Europe

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Estimates of the Neolithic Y contribution in
Europe

• 22 (Eu4, 9, 10, 11) Semino et al. (2000)
  Science 290, 1155-1159
• gt70 (assuming Basques Paleolithic and
  Turks/Lebanese/ Syrians Neolithic populations)
  Chikhi et al. (2002) Proc. Natl. Acad. Sci. USA
  99, 11008-11013

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The genetic legacy of Paleolithic Homo sapiens
sapiens in extant Europeans a Y chromosome
perspective (1)

• It was derived from 22 markers of the
  nonrecombining Y chromosome (NRY)
• Ten lineages account for gt95 of the 1007
  European Y chromosomes
• Geographic distribution and age estimates of
  alleles are compatible with two Paleolithic and
  one Neolithic migratory episode (Semino et al.
  (2000)

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The genetic legacy of Paleolithic Homo sapiens
sapiens in extant Europeans a Y chromosome
perspective (2)

• that have contributed to the modern European gene
  pool
• A significant correlation between the NRY
  haplotype data and principal components based on
  95 protein markers was observed
• indicating the effectiveness of NRY polymorphisms
  in the characterization of human population
  composition and history
• (Semino et al. (2000)

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More recent reshaping of diversity

• Star cluster Y haplotype originated in/near
  Mongolia 1,000 (700-1,300) years ago
• Now carried by 8 of men in Central/East
  Asia, 0.5 of men worldwide
• Suggested association with Genghis Khan

Zerjal et al. (2003) Am. J. Hum. Genet. 72,
717-721
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Mongolia (1)(Zerjal et al. (2003) Am. J. Hum.
Genet. 72, 717-721)

• It was found in 16 populations
• throughout a large region of Asia
• stretching from the Pacific to the Caspian Sea
• present at high frequency
• 8 of the men in this region carry it
• 0.5 of the world total
• behavior

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Mongolia (2)(Zerjal et al. (2003) Am. J. Hum.
Genet. 72, 717-721)

• The pattern of variation within the lineage
• it originated in Mongolia 1,000 years ago
• Such a rapid spread cannot have occurred by
  chance
• it must have been a result of selection
• The lineage is carried by likely male-line
  descendants of Genghis Khan
• propose that it has spread by a novel form of
  social selection

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Is the Y a neutral marker?

• Recurrent partial deletions of a region required
  for spermatogenesis
• Possible negative selection on multiple (14/43)
  lineages

Repping et al. (2003) Nature Genet. 35, 247-251
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1.6-Mb deletion (1)

• Polymorphism for a 1.6-Mb deletion of the human Y
  chromosome
• persists through balance between
• recurrent mutation
• and haploid selection
• Repping et al. (2003) Nature Genet. 35, 247-251

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AZF
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1.6-Mb deletion (2)

• Many human Y-chromosomal deletions
• severely impair reproductive fitness
• precludes their transmission to the next
  generation
• ensures their rarity in the population
• Repping et al. (2003) Nature Genet. 35, 247-251

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1.6-Mb deletion (3)

• 1.6-Mb deletion that persists over generations
• It is sufficiently common to be considered a
  polymorphism
• They hypothesized that this deletion might affect
  spermatogenesis
• because it removes almost half of the Y
  chromosome's AZFc region (1.6 Mb)
• a gene-rich segment that is critical for sperm
  production1

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gr/gr deletion Y chromosomes

• lower penetrance with respect to spermatogenic
  failure than previously characterized
  Y-chromosomal deletions
• it is often transmitted from father to son
• the existence of this deletion
• as a polymorphism
• reflects a balance between haploid selection
• and homologous recombination
• which continues to generate new gr/gr deletions
• Repping et al. (2003) Nature Genet. 35, 247-251

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Selection in the human genome
time
Negative (Purifying, Background)
Positive (Directional)
Neutral
Balancing
Bamshad Wooding (2003) Nature Rev. Genet. 4,
99-111
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Selection in the human genome (1)

• Natural selection leaves signatures in our genome
  that can be used to identify the genes that might
  underlie variation in disease resistance or drug
  metabolism
• Evidence of positive selection acting on genes is
  beginning to accumulate

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Selection in the human genome (2)

• Demographic processes should affect all loci in a
  similar way, whereas the effects of selection
  should be restricted to specific loci

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Demographic changes

• Population has expanded in range and numbers

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The Prion protein gene and human disease

• Prion protein gene PRNP linked to protein-only
  diseases e.g. CJD, kuru
• A common polymorphism, M129V, influences the
  course of these diseases
• the MV heterozygous genotype is protective
• Kuru acquired from ritual cannibalism was
  reported (1950s) in the Fore people of Papua New
  Guinea, where it caused up to 1 annual mortality

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Creutzfeldt-Jakob Disease (CJD)

• a neurodegenerative disease called Kuru
• found in cannibalistic Pacific Islanders
• a disorder diagnosed in one person per million
• common symptoms
• gait disorders
• jerky movements
• dementia that lead to death months after the
  first appearance of symptoms

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Balancing selection at PRNP

• Deep division between the M and V lineages,
  estimated at 500,000 years
• Kuru imposed strong balancing selection on the
  Fore
• essentially eliminating PRNP 129 homozygotes
• Worldwide PRNP haplotype diversity and coding
  allele frequencies
• strong balancing selection at this locus
• during the evolution of modern humans

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Effect of positive selection
Neutral
Selection
Derived allele of SNP
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What changes do we expect?

• New genes
• Changes in amino-acid sequence
• Changes in gene expression (e.g. level, timing or
  location)
• Changes in copy number

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How do we find such changes?

• Chance
• fhHaA type I hair keratin gene inactivation in
  humans
• Identify phenotypic changes, investigate genetic
  basis
• Identify genetic changes, investigate functional
  consequences

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Human type I hair keratin pseudogene fhHaA

• This mutant protein is unable to activate hair
  keratin gene expression
• the nude phenotype
• has functional orthologs in the chimpanzee and
  gorilla
• evidence for recent inactivation of the human
  gene after the Pan-Homo divergence
• 5. 5 million years ago

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Inheritance of a language/speech defect in the KE
family
Autosomal dominant inheritance pattern
Lai et al. (2000) Am. J. Hum. Genet. 67, 357-367
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A forkhead-domain gene is mutated in a severe
speech and language disorder

• the gene FOXP2
• encodes a putative transcription factor
• Containing
• a polyglutamine tract
• a forkhead DNA-binding domain
• disrupted by the translocation or point mutation
• the KE family that alters an invariant amino-acid
  residue in the forkhead domain

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Mutation and evolution of the FOXP2 gene
Chr 7
7q31
Nucleotide substitutions
FOXP2 gene
silent
replacement
Enard et al. (2002) Nature 418, 869-872
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Positive selection at the FOXP2 gene
Constant rate of amino-acid replacements?
Positive selection in humans?

• Resequence 14 kb of DNA adjacent to the
  amino-acid changes in 20 diverse humans, two
  chimpanzees and one orang-utan

replacement (non-synonymous) dN
silent (synonymous) dS
Orang
Gorilla
Chimp
Human
Human-specific increase in dN/dS ratio (Plt0.001)
Enard et al. (2002) Nature 418, 869-872
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A gene affecting brain size

• Microcephaly (MCPH)
• Small (430 cc v 1,400 cc) but otherwise normal
  brain, only mild mental retardation
• MCPH5 shows Mendelian autosomal recessive
  inheritance
• Due to loss of activity of the ASPM gene

ASPM-/ASPM-
control
Bond et al. (2002) Nature Genet. 32, 316-320
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Evolution of the ASPM gene (1)
Summary dN/dS values
Sliding-window dN/dS analysis
0.62
0.52
0.53
1.44
0.56
0.56
Orang
Gorilla
Chimp
Human
Human-specific increase in dN/dS ratio (Plt0.03)
Evans et al. (2004) Hum. Mol. Genet. 13, 489-494
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What changes?

• The Drosophila homolog of ASPM codes for a
  microtubule-binding protein that influences
  spindle orientation and the number of neurons

• Subtle changes to the function of well-conserved
  genes

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Genome-wide search for protein sequence evolution

• 7645 human-chimp-mouse gene compared
• Most significant categories showing positive
  selection include
• Olfaction sense of smell
• Development e.g. skeletal
• Hearing for speech perception
• brain size IQ

Clark et al. (2003) Science 302, 1960-1963
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Gene expression differences in human and
chimpanzee cerebral cortex

• Affymetrix oligonuclotide array (10,000) genes
• 91 show human-specific changes, 90 increases

Caceres et al. (2003) Proc. Natl. Acad. Sci. USA
100, 13030-13035
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Copy number differences between human and
chimpanzee genomic DNA
Human male reference genomic DNA hybridised with
female chimpanzee genomic DNA
Locke et al. (2003) Genome Res. 13, 347-357
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Selection at the CCR5 locus

• CCR5?32/CCR5?32 homozygotes are resistant to HIV
  and AIDS

• The high frequency and wide distribution of the
  ?32 allele suggest past selection by an unknown
  agent

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The Role of the Chemokine Receptor Gene CCR5 and
Its Allele ( del32 CCR5)

• Since the late 1970s
• 8.4 million people worldwide
• including 1.7 million children, have died of AIDS
• an estimated 22 million people are infected with
  human immunodeficiency virus (HIV)

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CCR5 and Its Allele ( del32 CCR5)
monocyte/macrophage (M),
T-cell line (Tl)
a circulating T-cell (T)
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Lactase persistence

• All infants have high lactase enzyme activity to
  digest the sugar lactose in milk
• In most humans, activity declines after weaning,
  but in some it persists

LCTP
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Molecular basis of lactase persistence

• Lactase level is controlled by a cis-acting
  element
• Linkage studies show association of lactase
  persistence with the T allele of a T/C
  polymorphism 14 kb upstream of the lactase gene

Enattah et al. (2002) Nature Genet. 30, 233-237
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The lactase-persistence haplotype

• The persistence-associated T allele occurs on a
  haplotype (A) showing over gt 1 Mb

• Association of lactase persistence and the A
  haplotype is less clear outside Europe

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Selection at the G6PD gene by malaria

• Reduced G6PD enzyme activity (e.g. A allele)
  confers some resistance to falciparum malaria

Extended haplotype homozygosity at the A allele
Sabeti et al. (2002) Nature 419, 832-837
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Final words

• Is there a genetic continuum between us and our
• ancestors and the great apes?
• If there is, then we can say that
• these i.e. microevolutionary processes are
• genetically sufficient to fully account for human
  
• uniqueness