Human Population Genetics Bisc403-Nordborg_Variation

8/6/2019 Human Population Genetics Bisc403-Nordborg_Variation

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Human population genetics

Rough outline of human evolution What makes us human?

Variation in modern humans

Relevance to human health


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Relationship to other primates


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Our closest living relative appears to be thechimpanzees. . .

Pan troglodytes (chimpanzee) Pan paniscus (bonobo)


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Humans, chimps, and gorillas

Chen & Li1

sequenced 53 regions randomly chosen shortregions from humans, chimps, and gorillas. They thenestimated 53 phylogenetic trees. . .

H C G H G C C G H

31 10 12

1

Am. J. Hum. Genet. 2001


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Gene trees and species trees

If species are separated byenough time for gene lineagesto coalesce within species,then gene trees will reectspecies trees.

Coalescence times withinspecies depend on pop-ulation sizes, geographicstructure, etc .


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Gene trees and species trees

If species are not sepa-rated by enough time forgene lineages to coalescewithin species, then gene

trees will often not reectspecies trees.

The human-chimp split is

borderline: coalescence timeswithin the species seem tolie between 0.5 and 1 Myr;the species may only be sep-arated by 45 Myr. A B C


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Perspective on polymorphism

two human genomes differ from each other aboutonce every 1,000 base pairs

chimps differ from each other once every 200 basepairs

fruit ies differ from each other once every 100 basepairs

Californian intertidal copepods (Suzanne Edmands)may differ from each other every 10 bp

a human and a chimp genome differ from each otherabout once every 100 base pairs


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Most differences have no effect

There is no direct relationship between the amounts of genetic and phenotypic differentiation. Of the 109 10 3 = 10 6 differences between two humans, mostmean nothing!


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Aside: The Neutral Theory

Formulated in the late 1960s in response to thepolymorphism data that was then becombing available:

Protein sequencing revealed an approximately linear

relationship between divergence times and sequencedivergence: the molecular clock (Zuckerkandl &Pauling, 1965)

Protein electrophoresis (Lewontin & Hubby, 1966)revealed substantial variation within species: 1550%of enzyme-coding genes were polymorphic with morethan one common allele


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The molecular clock


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The Neutral Theory of Molecular Evolution

Kimura (1968):

most mutations are deleterious and are rapidlyeliminated

a very small number of mutations are favorable andare rapidly xed

most of the variation that we observe within species

is selectively neutral, and is governed by the interplayof mutation and genetic drift

by extension, most of the differences between speciesare simply due to the random xation of mutations


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Synonymous and nonsynonymous sites


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Evidence for the Neutral Theory


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Further evidence for the Neutral Theory


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The importance of gene regulation

The low level of differention between humans andchimps on the amino-acid level led King & Wilson2 topropose that most of the differences were regulatory

We still know next to nothing about the geneticdifferences between chimps and humans

Recently, Bailey et al. 3 found that there are moregenetic differences than previously believed in terms

of segmental duplications. . .

2 Science 19753

Science 2002


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Types of mutations

single base-pair substitutions

insertions and deletions

inversions

translocations

duplications


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How can we nd the differences that matter?

A geneticist would either:

make some crosses, or;

carry out a mutational screen (for the chimpmutation...)

The former makes a lot more sense than the latter, butneither is feasible. Instead, we have to rely on indirectevidence traces of selection in the pattern of polymorphism and divergence either in candidate loci orin genome-wide screens


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Traces of selection

Selection can leave traces two main different ways4 :

rapid selection for a new function that requires manyfunctional changes can result in a detectable excess

of functional changes whenever an allele is swept through a population by

selection, linked neutral polymorphisms hitch-hikealong possibly leaving a detectable trace in theregional pattern of overall polymorphism

4 Reviewed by Kreitman, Annu. Rev. Genomics & Hum. Genet.

2000, vol. 1


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Example: very rapid evolution of reproductive proteins

The per-site rate of non-synonymous substitution(K a ) is typically much lower than the per-site rate of synonymous substitution ( K s )

K a /K s > 1 is a sure sign of directional selection (butis an extremely conservative test)

Examples:

sea-urchin sperm binding protein and lysin, Drosophila male reproductive proteins female reproductive proteins in mammals also various resistance alleles


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The McDonald-Kreitman test

A more powerful test would utilize within-speciespolymorphism as well. A very simple test that does this isthe McDonald-Kreitman test, which utilizes the fact that,under neutrality, polymorphism and divergence are bothproportional to u, the neutral mutation probability.

Consider, for example, G6pd from D. melanogaster and D.simulans :

type of differencetype of change xed polymorphicnon-synonymous 21 2synonymous 26 36


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Selective sweeps

The methods mentioned will detect neither simpleamino-acid substitutions nor regulatory changes

To detect these, we need to look for the footprint of selection in the overall pattern of polymorphism

Advantageous variant

Selection


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Teosinte to corn: < 10,000 years; ve genes?

teosinte maize maize with tb1 mutation


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A sweep in the tb1 promotor region?


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Gene trees reect the sweep

a) tree based on the 1,729-bptranscribed region

b) tree based on the 1,143-bp5' non-transcribed region

l h l l


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Selective sweeps are the Holy Grail

No successes in humans yet

We can only expect to detect sweeps that were recentenough and strong enough to change the localgenealogical structure

H l d ?


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How related are we?

Lets compare you to your brother or sister. . .

about 50% of your genomes will be identical bydescent from mom or dad

for the rest, you may well be more closely related tosomeone from Africa (or Sweden, or the Brazilian rainforest) than to each other

on average, you will be slightly more closely related

to someone from your ethnic group on average, the time back to a common ancestor is

800,000-1,000,000 years the level of polymorphismreects this. . .

W ll b l l l d f


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We may all be more closely related for someloci

0 5 10 15 20 25position Mb

0

0.0005

0.001

0.0015

p

selective sweep?

A f l ?


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A gene for language?

The ability to to develop articulate speech relies oncapabilities, such as ne control of the larynx andmouth, that are absent in chimpanzees and othergreat apes

FOXP2 is the rst gene relevant to the human abilityto develop language

Mutations in FOXP2 appear to cause a (dominant)disorder characterized by severe articulationdifficulties accompanied by linguistic and grammaticalimpairment

E d l 5 di d i i FOXP2 i hi


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Enard et al. 5 studied variation at FOXP2 withinhumans, and also sequenced it in several primates

The pattern of substitutions suggests recent selection

5 Nature 2002

Th l i f l ti i th tt f


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There are also signs of selection in the pattern of polymorphism overall diversity is not decreased,but:

there is an excess of rare alleles there are too many non-ancestral alleles at high

frequency

It has been suggested (in particular by Richard Klein, ananthropologist at Stanford University) that somethingdramatic happened in human evolution about 50,000 yearsago, possibly due to improved communication, and thatthis could be due to a single mutation. . .

(I nd the notion of a single gene for culture ridiculouslysimplistic)

How many genes?


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How many genes?

Early hominid evolution


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Early hominid evolution

bipedal, with small brains and large protruding faces

with large canines fossils are all found in Southern or Eastern Africa, and

are assigned to Ardipithecus and Australopithecus

start appearing about 4.4 mya the famous Lucy(Australopithecus afarensis ) is perhaps 3 million yearsold

between 3 and 2.5 mya, there appears to be manyspecies, some robust, some gracile

robust forms disappear roughly 1 mya; some gracilespecies gives rise to. . .

The genus Homo


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The genus Homo

Fragmentary fossils as early as 2.5 mya; also rstevidence of manufactured stone tools

Several species around 2 mya in East Africa: H.habilis , H. rudolfensis , and H. erectus

H. erectus appears to have been completely bipedal,and was about the size of a modern human, but witha smaller brain

H. erectus is found world-wide: Indonesia 1.61.8mya; China 1.11.9 mya; Georgia 1.7 mya

H. erectus appears to have been much morecarnivorous than other hominids

But


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But...

This summer, Brunet et al. 6 , reported a remarkable 6million year old fossil from Chad:Sahelanthropus tchadensis

looks like a chimp from behind, but. . .

a 1.75 million year old australopith from the front. . .

This nding wreaks havoc with many tidy scenarios forhominid evolution. . .

6 Nature 2002


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Too many stories too little data


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Too many stories, too little data. . .

It is important to recognize that:

whereas all living things have ancestors, not all fossilshave descendants

only a small fraction of all species that ever existedwill have left fossils

Tavare et al. 7 estimated that only 7% of all primate speciesthat ever existed have left fossils. They also estimated thatactual divergence times between species will typically be at70% older than the age of the oldest known fossil. . .

7 Nature2002

Speciation model


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Speciation model

Conclusion


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Conclusion

Things are probably far more complex than suspected

Famous fossils like Lucy are probably not ancestral tous (almost certainly not in the genetic sense)

I suspect the same will be true for modern humanorigins. . .

The origin of modern humans


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g

Archaic H. sapiens start appearing 400,000-500,000years ago: they generally have brain sizes similar tomodern humans, but rather more robust skulls

Neanderthals are an example of archaic humans

How modern humans evolved from H. erectus isextremely controversial. . .

Israel, 90,000 years ago


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, , y g

France, 23,00027,000 years ago


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, , , y g

Australia, 9,00013,000 years ago


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y g

Out of Africa


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Mitochondrial Eve


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Africa Europe Asia

Africa

Africa Europe Asia

Africa

Africa Europe Asia

Africa

a) Out-of-AfricaModel

b) MultiregionalModel

c) CandelabraModel

millionyears ago

1

0

0.5

migration

Africans

Schematic version ofthe human mtDNA

tree

non-Africans

A single gene tree does not tell us much. . .

Variation in modern humans


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Humans have less polymorphism than other primates

There is typically more variation in African samples(exceptions seem to involve selection)

There is typically less LD in African samples

Race


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Next time you hear or read There is no biological basis for

race, please ask what no basis means. . .

Race, in the sense of genetically based phenotypicdifferences between humans that are not

geographically randomly distributed, clearly exist Race, in the sense of pure lines, certainly does not

In terms of genetic markers, there is much more

variation within groups than between groups . . . however, this may not be all that relevant

Human variation is continuous. . .

What is going on?


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A biased selection of current topics:

The Human Haplotype Map Project

Common Disease Common Variant?

Predicting drug response: GenaissancePharmaceuticals

Should ethnicity be taken into account?

Genotyping Iceland: deCode Genetics


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The Human

HapMapProject

A genome-wide screen for disease association


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is too expensive

There are plenty of markers: 1.8 million SNPs areavailable from the private/public SNP Consortium 8

However, typing a SNP currently costs $0.30. . .

...so typing a single individual for half a millionSNPs would cost $150,000. . .

. . . and a typical epidemiological study involveshundreds or thousands of individuals

8 http://snp.cshl.org/


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Population geneticsto the rescue?

As seen here in thechromosome 21 datadiscussed earlier, the patternof LD is blocky: this isexpected under the standardcoalescent model, but theeffect is probably enhanced

by heterogeneity in therecombination rate alongthe chromosomes.

The HapMap Project


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If we knew the pattern of LD, it may be possiblechoose markers intelligently

Many unanswered questions:

Will markers chosen in one sample work inanother?

Are genome-wide screens a waste in any case?

$100 million have been allocated to nding out9 . . .

9 http://www.nhgri.nih.gov/About NHGRI/Der/variat.htm

Common Disease Common Variant?


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Genome-wide screens for association are unlikely to

work unless there are major allelesalleles thatexplain a large fraction of the variation in thepopulation

Mendelian diseases are typically rare: the target iscommon diseases

Are common diseases due to common alleles, or arethey due to many alleles (each of which has a tiny

effect)? If there are many alleles, are there also many loci?

If there are many loci, do they interact epistatically?

Predicting drug response


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A very large number of drugs fail testing not because

they dont work, but because they have signicantside effects in a small subset of the population

It may well be that this often has a relatively simplegenetic basis

Genaissance Pharmaceuticals 10 is trying to identifyhaplotype markers short fragments containingseveral SNPs that can be used to predict drug

response They are completely sequencing the coding regions of

10,000 genes in a sample of 96 individuals10 http://www.genaissance.com


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Preliminary results from313 genes were publishedby Stephens et al. a

The distribution of variation among ethnicgroups agree with otherresults.

a Science 2001

Genes, Race, and Disease


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A recent debate concerned the use of race inepidemiology:

Wilson et al. 11 published a study showing that drugresponse was better predicted by genetic markersthan by ethnicity. In other words, let the markersdecide the grouping, and ignore what you thinkpeople are, or what they say they are.

Risch et al.12

replied that this was completenonsense:11 Nature Genet. 200112 Genome Biology , 2002

the results in question was an artifact of lumpingNew Guineans and Chinese as Asians with


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New Guineans and Chinese as Asians withbetter samples and more markers, markers and

self-proclaimed ethnicity are likely to agreemuch better ( cf . Noahs results) in any case, self-proclaimed ethnicity should

always be taken into account, because it is likely

to reect the environment race is not onlya matter of genes

deCode Genetics


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A different approach to common diseases is taken by

deCode Genetics13

. They argue that the Devil is in theDetails:

The common diseases public health problems such

as stroke, heart disease, and Alzheimers resultfrom the interplay of multiple genes andenvironmental and health factors

Unraveling this complexity requires the ability togather and correlate detailed information on diseaseand genetic variations across as large a group of people as possible: a population.

13 http://www.decode.com

To do this efficiently it is also critical to haveaccurate and comprehensive genealogical records the


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accurate and comprehensive genealogical records, theonly means for tracing how the genetic components

of disease travel between generations of vastextended families.

A population with all three kinds of data genetic,

disease, and genealogical is needed. . .

Genotyping Iceland


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Iceland was founded by Norwegian vikings (and

probably Celtic slaves) about 1100 years ago.Islendingabok The Book of Icelanders contains more than 95% of all those who have livedin Iceland since the rst census in 1703, and stretchesback to the 9th century. In all, it contains more thanhalf of all Icelanders who have ever lived.

Iceland has a well-functioning national health service,with excellent records

DNA samples and disease data are being collectedfrom approximately 80,000 volunteers: 1/3 of theadult population is participating in deCodes projects,as are more than 90% of those over 65.

Controversial stuff


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deCODE holds a license from the government of Iceland

to build and commercialize the Icelandic Health SectorDatabase (IHD). Now under construction, the IHD willassemble anonymized, encrypted data from patient recordsfrom Icelands national health service in a secure computer

system. The IHD will enable users, including doctors inIcelands national health system, to conduct populationanalyses of longitudinal healthcare data and trends on, forexample, clinical measurements and basic lifestyleinformation, disease diagnoses, treatments and outcomes.deCODE believes that this system will provide valuableresource for better understanding the environmentalcomponents that, along with genetic factors, lie behind theonset of common diseases.

Publications 2002


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PRINTABLE PAGE 2002-12-06 09:32:01 -0800

ht tp : //www.decode.com/main/view. jsp?branch=19134&e196OriginBranchID=3627&e196Colnumber=2&e196Rownumber=4&oldbranch=3627 Page 1

2002

AA Hicks, et al.A susceptibility gene for late-onset idiopathic Parkinson's diseaseAnnals of Neurology (Vol. 52 No. 5)

Gislason T, et al.Familial Predisposition and Cosegregation Analysis of Adult ObstructiveSleep Apnea and the Sudden Infant Death SyndromeAmerican Journal of Respiratory and Critical Care Medicine (Vol. 166)

Stefansson H, et al.Neuregulin 1 and Susceptibility to Schizophrenia.American Journal of Human Genetics (Vol. 71 No. 4)

Hakonarson H, et al.A Major Susceptibility Gene for Asthma Maps to Chromosome 14q24.American Journal of Human Genetics (Vol. 71 No. 3)

Gudbjartsson T et al.A population-based familial aggregation analysis indicates geneticcontribution in a majority of renal cell carcinomas.International Journal of Cancer (Vol. 100 No. 4)

Kong A, et al.A high-resolution recombination map of the human genomeNature Genetics (Vol. 33 No. 3)

Kristjansson K, Manolescu A, Kristinsson A, Hardarson T, Knudsen H,Ingason S, Thorleifsson G, Frigge ML, Kong A, Gulcher JR, Stefansson K.Linkage of essential hypertension to chromosome 18q.Hypertension (Vol. 39 No. 6)

Gretarsdottir S et al.Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12.American Journal of Human Genetics (Vol. 70 No. 3)

Gudmundsson G et al.Localization of a Gene for Peripheral Arterial Occlusive Disease toChromosome 1p31.American Journal of Human Genetics (Vol. 70 No. 3)

Stefansson H, Geirsson RT, Steinthorsdottir V, Jonsson H, Manolescu A,Kong A, Ingadottir G, Gulcher J, Stefansson K.Genetic factors contribute to the risk of developing endometriosis.Human Reproduction (Vol. 17 No. 3)

Gudjonsson JE, Karason A, Antonsdottir AA, Runarsdottir EH, Gulcher JR,Stefansson K, Valdimarsson H.HLA-Cw6-Positive and HLA-Cw6-Negative Patients with Psoriasis Vulgarishave Distinct Clinical Features.The Journal of investigative dermatology (Vol. 118 No. 2).

Copyright deCODE genetics, Inc. 1995-2002

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Human Population Genetics Bisc403-Nordborg_Variation