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The Human Genome and Human Evolution Y Chromosome

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Title: The Human Genome and Human Evolution Y Chromosome


1
The Human Genome and Human EvolutionY Chromosome
  • Dr Derakhshandeh, PhD

2
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

3
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

4
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5
  • But small changes (called polymorphisms) do occur
  • passed down from generation to generation

6
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

7
  • 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)

8
  • 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

9
  • 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

10
  • 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

11
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

12
  • 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

13
the evolutionary clock
  • the UEPs as the hour hand
  • the microsatellite polymorphisms as the minute
    hand
  • the minisatellites as a sweep second hand

14
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

15
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

16
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
17
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

18
  • 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

19
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

20
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

21
The amelogenin gene
  • is a single copy gene
  • homologues of which are located on
  • Xp22.1-Xp22.3
  • and Yp 11.2

22
  • 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.

23
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

24
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

25
Who are our closest living relatives?
Chen FC Li WH (2001) Am. J. Hum. Genet. 68
444-456
26
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
27
Chimpanzee-human divergence
6-8 million years
Hominids or hominins
Chimpanzees
Humans
28
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
29
Hominid fossil summary
Found only in Africa
Found both in Africa and outside, or only outside
Africa
30
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
31
Additional migrations out of Africa
  • First known Europeans date to 800 KYA
  • Ascribed to H. heidelbergensis

Atapueca 5, Spain, 300 KYA
32
Origins of modern humans (1)
  • Anatomically modern humans in Africa 130 KYA
  • In Israel by 90 KYA

Omo I, Ethiopia, 130 KYA
33
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
34
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
35
the Upper Paleolithic period
  • In the Upper Paleolithic period
  • Neanderthal man disappears
  • and is replaced by a variety of Homo sapiens

36
Routes of migration?archaeological evidence
Upper Paleolithic
130 KYA
Middle Stone Age
37
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

14
38
Mixing or replacement?
39
Human genetic diversity is low
40
Human genetic diversity is evenly distributed
Most variation between populations
Most variation within populations
Templeton (1999) Am. J. Anthropol. 100, 632-650
41
Phylogenetic trees commonly indicate a recent
origin in Africa
Y chromosome
42
Modern human mtDNA is distinct from Neanderthal
mtDNA
Krings et al. (1997) Cell 90, 19-30
43
Classical marker studies
Based on 120 protein-coding genes in 1,915
populations Cavalli-Sforza Feldman (2003)
Nature Genet. 33, 266-275
44
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

45
Phylogenetic trees commonly indicate a recent
origin in Africa
Y chromosome
46
Y haplogroup distribution
Jobling Tyler-Smith (2003) Nature Rev. Genet.
4, 598-612
47
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48
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49
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50
An African origin
51
SE Y haplogroups
52
NW Y haplogroups
53
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?

54
Fluctuations in climate
Ice ages
Antarctic ice core data
Greenland ice core data
55
Possible reasons for genetic change
  • Adaptation to new environments
  • Food production new diets
  • Population increase new diseases

56
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

57
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

58
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)

59
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)

60
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
61
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

62
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

63
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
64
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

65
AZF
66
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

67
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

68
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

69
Selection in the human genome
time
Negative (Purifying, Background)
Positive (Directional)
Neutral
Balancing
Bamshad Wooding (2003) Nature Rev. Genet. 4,
99-111
70
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

71
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

72
Demographic changes
  • Population has expanded in range and numbers

73
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

74
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

75
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

76
Effect of positive selection
Neutral
Selection
Derived allele of SNP
77
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

78
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

79
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

80
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
81
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

82
Mutation and evolution of the FOXP2 gene
Chr 7
7q31
Nucleotide substitutions
FOXP2 gene
silent
replacement
Enard et al. (2002) Nature 418, 869-872
83
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
84
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
85
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
86
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

87
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
88
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
89
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
90
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

91
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)

92
CCR5 and Its Allele ( del32 CCR5)
monocyte/macrophage (M),
T-cell line (Tl)
a circulating T-cell (T)
93
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
94
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
95
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

96
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
97
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
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