the human genome and human evolution y chromosome dr derakhshandeh, phd

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

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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 (Snips and stable Alus : "unique event polymorphisms)

• 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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Yp 11.2Yp 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)

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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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• selected 53 autosomal / Y Ch intergenic nonrepetitive DNA segments from the

• human genome and sequenced them in a human, a chimpanzee, a gorilla, and an orangutan.

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The average sequence

• divergence was only 1.24% +/- 0.07% for the human-chimpanzee pair

• 1.62% +/- 0.08% for the human-gorilla Pair

• and 1.63% +/- 0.08% for the chimpanzee-gorilla pair

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• Taking the orangutan speciation date as 12 to 16 million years ago

• an estimate of 4.6 to 6.2 million years for the Homo-Pan divergence

• an estimate of 6.2 to 8.4 million years for the gorilla speciation date

• gorilla lineage branched off 1.6 to 2.2 million years earlier than did the human-chimpanzee divergence

12 to 16 million

4.6 to 6.2 million

6.2 to 8.4 million

1.6 to 2.2 million

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Phenotypic differences between humans and other apes

*Carroll (2003) Nature 422, 849-857

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Chimpanzee-human divergence

Chimpanzees Humans

6-8millionyears

Hominids or hominins

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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 MYABrunet 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

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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

50 KYA

47 KYA40 KYA

39 KYA

MiddleStone Age

Upper Paleolithic

~130KYA

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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

14

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Mixing or replacement?

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Human genetic diversity is low

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Modern human mtDNA is distinct from Neanderthal mtDNA

Krings et al. (1997) Cell 90, 19-30

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Nature Genetics 33, 266 - 275 (2003)

The application of molecular genetic approaches to the study of

human evolution

L. Luca Cavalli-Sforza1 & Marcus W. Feldman2

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• Haploid markers from mitochondrial DNA and the Y chromosome have proven invaluable for generating a standard model for evolution of modern humans

• earlier research on protein polymorphisms

• Co-evolution of genes with language and some slowly evolving cultural traits, together with the genetic evolution

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Evolutionary events affecting genomic variation (1)

• All genetic variation is caused by mutations

• The most common and most useful for many purposes are SNPs

• which can be detected by DNA sequencing

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• Allelic frequencies change in populations owing to two factors:– natural selection:– population variation among individual genotypes in

their probabilities of survival and/or reproduction, random genetic drift

– next generation– Both natural selection and genetic drift can ultimately

lead to the elimination or fixation of a particular allele• In the presence of mutation and in the absence of

selection:– neutral conditions:

• the rate of neutral evolution of a finite population is equal to the mutation rate!

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• The earliest evidence of selection :

– heterozygotes of the hemoglobin A/S

• polymorphism have greater resistance to malaria than do AA or SS homozygotes

– G6PD locus:

• resistance to malaria

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• Strong directional selection : for FOXP2

– a two amino-acid difference between the human protein and in primates

– selectively important for the evolution of speech and language in modern humans

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• the agent of selection is not at all obvious:

– the CCR5 gene seems :

• related to HIV resistance

– mutations in the BRCA1 gene:

• produce an increased risk of female breast cancer

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Migration is another important factor in human evolution that can

profoundly affect genomic variation within a population

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Summary tree of world populations.Phylogenetic tree based on polymorphisms of 120 protein genes in 1,915

populations

Cavalli-Sforza & Feldman (2003) Nature Genet. 33, 266-275

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For populations that are geographically close, genetic and geographic distances are

often highly correlated


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Dating the origin of our species using genetic data (1)

• The mutation rate of the NRY is comparable to that of nuclear DNA

• polymorphisms are more difficult to find but genealogies are easier to reconstruct

• The greater length of DNA on the NRY (perhaps 30 million bases of euchromatic DNA) lower mutation rate

• Even though the NRY behaves effectively as a single locus• usually insufficient for evolutionary analyses• it has provided results that are consistent across many

studies and in agreement with many archeological findings

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High resolution history using haploid markers

• SNPs on the NRY and mtDNA :– higher resolution of population history

through the reconstruction of the phylogenetic relationships of extant Y chromosomes and mtDNA

• the Y Chromosome Consortium:– the first two haplogroups (A and B) are

almost completely African and even today represent mostly their descendants

57NRY

SiberiaSiberia

India

Eskimo

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The migration of modern Homo sapiens.begins with a radiation from East Africa to the rest of Africa about 100 kya and from the same area to Asia, southern and northern between 60 and 40 kya. Oceania, Europe and America were settled from Asia in

that order.


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NRY

• Slow growth is indicated by the accumulation of many mutations within a branch, as in most descendants of haplogroup A and B

• and in those of the earliest branches of haplogroups C, D, E and F

•

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NRY

• By contrast, when there are many branches (called a starburst) after a specific mutation or group of mutations, we can infer rapid growth

• The major expansions are those of haplogoup F (seven branches) after an initial lag in population growth, and even more remarkable is the later expansion of haplogroup K (nine branches).

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haplogroup K (nine branches)

• These began in the last 40 kya and led to the major settlement of all continents from Africa, first to Asia, and from Asia to the other three continents.

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mtDNA

• The tree of mtDNA is more bushy, but there are more haplogroups because of the higher mutation rate!

63mtDNA

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mtDNA• The earliest branches all remain in Africa• in both trees they clearly refer to the

slowly growing hunter-gatherers• In both trees the major growth in Africa

is due to a late branch, taking place in the second part of the last 100,000 years and clearly connected with the expansion to Asia

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Language families of the world

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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

A B C D E F* G H I J K* L M N O P* Q R

10

20

30

40

60

50

70

90

80

0

KYA

90 (50 - 130) KYA, Hammer and Zegura59 (40 - 140) KYA, Thomson et al.

69 (56 - 81) KYA, Hammer and Zegura40 (35 - 89) KYA, Thomson et al.

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?

76

Fluctuations in climate

Ice ages

Antarcticice 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

78

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

• >70% (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 >95% 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

86

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


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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


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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


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Selection in the human genome

time

NeutralNegative

(Purifying,Background)

BalancingPositive

(Directional)

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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Neutral Selection

Derived allele of SNP

Effect of positive selection

99

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– φhHaA 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 φhHaA

• 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

Lai et al. (2000) Am. J. Hum. Genet. 67, 357-367

Autosomal dominant inheritance pattern

103

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 77q31

FOXP2 gene

Nucleotide substitutions

silent replacement

Enard et al. (2002) Nature 418, 869-872

105

Positive selection at the FOXP2 gene

• Resequence ~14 kb of DNA adjacent to the amino-acid changes in 20 diverse humans, two chimpanzees and one orang-utanOrang Gorilla Chimp Human

silent(synonymous)

dS

replacement(non-synonymous)

dN

Human-specific increase in dN/dS ratio (P<0.001)

Constant rate of amino-acid replacements? Positive selection in humans?

Enard et al. (2002) Nature 418, 869-872

106

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

Orang Gorilla Chimp Human

Human-specific increase in dN/dS ratio (P<0.03)

1.44

0.560.56

0.53

0.52

0.62

Sliding-window dN/dS analysis

Evans et al. (2004) Hum. Mol. Genet. 13, 489-494

108

What changes?• The Drosophila homolog of ASPM codes for a

microtubule-binding protein that influences spindle orientation and the number of neurons

do Carmo Avides and Glover (1999) Science 283, 1773-1735

DNA

Microtubules

asp

• 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

110

Gene expression differences in human and chimpanzee cerebral cortex

Increased expression Decreased expression

Caceres et al. (2003) Proc. Natl. Acad. Sci. USA 100, 13030-13035

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

111

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

112

Selection at the CCR5 locus• CCR532/CCR532 homozygotes are resistant to

HIV and AIDS

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

113

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)

114

CCR5 and Its Allele ( del32 CCR5)

T-cell line (Tl)

monocyte/macrophage (M),

a circulating T-cell (T)

115

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:

LCT*P

116

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

117

The lactase-persistence haplotype

• The persistence-associated T allele occurs on a haplotype (‘A’) showing over > 1 Mb

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

118

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

119

Final wordsIs 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

the human genome and human evolution y chromosome dr derakhshandeh, phd

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