human polymorphisms and genetic anthropology

C. Mulligan, Copyright 2011All rights reserved

Human Polymorphisms and Genetic Anthropology

Prof. Connie J. MulliganProf. Connie J. Mulligan

Department of AnthropologyDepartment of Anthropology

September 20, 2012September 20, 2012


Molecular geneticsMolecular genetics

• GeneticsGenetics is the study of is the study of heredity and variation of heredity and variation of organismsorganisms– Classical, Mendelian genetics Classical, Mendelian genetics

traces the inheritance of traces the inheritance of particular traits, or phenotypesparticular traits, or phenotypes

• Molecular geneticsMolecular genetics is the study is the study of heredity and variation using of heredity and variation using molecules, such as DNAmolecules, such as DNA– Traces the inheritance of genes Traces the inheritance of genes

or genetic variantsor genetic variants

Human karyotype


A little terminologyA little terminology

• A gene is a piece of DNA A gene is a piece of DNA that is responsible for the that is responsible for the inheritance of a specific inheritance of a specific characteristiccharacteristic– eye coloreye color– ability to process lactate ability to process lactate

(drink milk)(drink milk)

• Gene Gene protein protein

Human chromosomes, Genetics, Hartl and Jones, 2000


A little terminologyA little terminology

• A gene is a piece of DNA A gene is a piece of DNA that is responsible for the that is responsible for the inheritance of a specific inheritance of a specific characteristiccharacteristic– eye coloreye color– ability to process lactate ability to process lactate

(drink milk)(drink milk)

• Gene Gene protein protein– Coding = genes (~3%)Coding = genes (~3%)– Non-coding (~97%)Non-coding (~97%)

Human chromosomes, Genetics, Hartl and Jones, 2000


DNA = Deoxyribonucleic acidDNA = Deoxyribonucleic acid

• DNADNA is represented as is represented as a sequence of letters a sequence of letters (nucleotide bases)(nucleotide bases)– Adenosine = AAdenosine = A– Guanine = GGuanine = G– Cytosine = CCytosine = C– Thymine = TThymine = T– A-T and G-C pairsA-T and G-C pairs

• DNADNA is a blueprint to is a blueprint to direct the synthesis of direct the synthesis of proteinsproteins

Genetics, 2001, Hartl and Jones, Jones and Bartlett Publishers, Inc

TGTG


Genetic variantsGenetic variants are changes in DNA are changes in DNA sequence between individualssequence between individuals

(A C-to-T variant is depicted in the DNA sequence below)(A C-to-T variant is depicted in the DNA sequence below)


TerminologyTerminology

• Genetic variantGenetic variant• Genetic markerGenetic marker• MutationMutation• PolymorphismPolymorphism• SNP (single nucleotide polymorphism)SNP (single nucleotide polymorphism)• Biallelic markerBiallelic marker• All of these terms are used to refer to genetic All of these terms are used to refer to genetic

differences between individuals or populationsdifferences between individuals or populations


A little more terminologyA little more terminology

• PhenotypePhenotype– Physical characteristics of an individualPhysical characteristics of an individual

• GenotypeGenotype– An individual’s DNA sequence or set of An individual’s DNA sequence or set of

genetic markersgenetic markers

• An individual’s genotype is responsible An individual’s genotype is responsible for an individual’s phenotypefor an individual’s phenotype


How do you interpret a genetic How do you interpret a genetic variant?variant?

• What does a C-to-T What does a C-to-T change mean?change mean?

• Smarter, prettier, Smarter, prettier, faster, stronger???faster, stronger???– No, just differentNo, just different

• Most variants are Most variants are neutral = no effectneutral = no effect– Genes make up only Genes make up only

~3% of genome and ~3% of genome and genes make our genes make our phenotypephenotype


GeneticGenetic anthropology anthropologyTypes of studiesTypes of studies

Modified from Balaresque et al. 2007

Expansion out of Africa

Peopling of the Americas

Domestication of the donkey

Origin and expansion of Semitic speakers

Genetic and cultural components to ethnicity and health

• Population historyPopulation history– OriginsOrigins– RelationshipsRelationships

• Populat’n movementsPopulat’n movements– Migrations/colonizationMigrations/colonization– Fission/fusionFission/fusion

• Ancient DNAAncient DNA– Link ancestral and Link ancestral and

descendant popsdescendant pops

• DiseaseDisease– Origin of diseaseOrigin of disease– Genetic basis of diseaseGenetic basis of disease


How do we interpret genetic variants How do we interpret genetic variants to ask anthropological questions?to ask anthropological questions?

• Look at the patterns of genetic variationLook at the patterns of genetic variation

• What has created the patterns of genetic variation?What has created the patterns of genetic variation?– Evolutionary history of humansEvolutionary history of humans

Shriver and Kittles, 2004


~ 200 kya

Slides by Ryan Raaum


100-200 kya


by 80 kya


~ 60 kya


45-60 kya


by 45 kya


40-50 kya


~ 35 kya

Thanks, Ryan


Human evolution encompasses both Human evolution encompasses both demographic history and adaptationdemographic history and adaptation

• Demographic historyDemographic history– Neutral markersNeutral markers

• Not subject to natural Not subject to natural selectionselection

– Non-coding, ~97%Non-coding, ~97%• Origin of anatomically Origin of anatomically

modern humansmodern humans• Neanderthal geneticsNeanderthal genetics

• AdaptationAdaptation– Non-neutral markersNon-neutral markers

• Subject to natural Subject to natural selectionselection

– Genes, ~3% genomeGenes, ~3% genome• Skin color, eye color, Skin color, eye color,

facial morphology, facial morphology, racerace


Genetic evidence for the origin of Genetic evidence for the origin of modern humansmodern humans

• H. sapiensH. sapiens are are characterized by very little characterized by very little genetic variation relative to genetic variation relative to other primatesother primates– What does this suggest?What does this suggest?

Jobling et al. 2003



• H. sapiensH. sapiens are characterized by very little genetic are characterized by very little genetic variation relative to other primatesvariation relative to other primates– What does this suggest?What does this suggest?

• Relatively recent evolutionRelatively recent evolution• SelectionSelection• Or, more recent research suggests it might relate to Or, more recent research suggests it might relate to

generation timegeneration time– Longer generation time in humans Longer generation time in humans → fewer opportunities for germ line → fewer opportunities for germ line

mutations → slower mutation rate → less variation/shallower time mutations → slower mutation rate → less variation/shallower time depthdepth

– Mutation rate follows generation timeMutation rate follows generation time• Humans < chimpsHumans < chimps• hominoids < Old World monkeyshominoids < Old World monkeys• Old World monkeys < marmosetsOld World monkeys < marmosets



• Greatest genetic diversity is in Greatest genetic diversity is in African populationsAfrican populations– Consistent w/ out-of-Africa theory Consistent w/ out-of-Africa theory

of human originof human origin

• Most genetic variation in Most genetic variation in humans is within populations, humans is within populations, not between populationsnot between populations– ~85% w/i pops~85% w/i pops– ~5% b/t pops on same continent~5% b/t pops on same continent– ~10% b/t pops on different ~10% b/t pops on different

continents, i.e. racescontinents, i.e. races


Types of DNATypes of DNA• Mitochondrial (mtDNA)Mitochondrial (mtDNA)

– no recombinationno recombination

– high copy number (but high copy number (but haploid)haploid)

– maternal inheritancematernal inheritance

– high mutation ratehigh mutation rate

– studied firststudied first

– large comprehensive large comprehensive databasedatabase

• Nuclear DNA (nDNA = Nuclear DNA (nDNA = autosomes + sex autosomes + sex chromosomes)chromosomes)– homologous recombinationhomologous recombination

– single genome/diploid cellsingle genome/diploid cell

– biparental inheritancebiparental inheritance

– variable mutation ratevariable mutation rate

– studied more recentlystudied more recently

– multiple studied loci make multiple studied loci make comparisons more difficultcomparisons more difficult

Holland & Huffine 2001


Mitochondrial EveMitochondrial Eve- the mother of us all- the mother of us all

• What is the What is the mitochondrial mitochondrial Eve theory?Eve theory?



• What is the What is the mitochondrial mitochondrial Eve theory?Eve theory?– The idea that we The idea that we

all trace back to all trace back to a single womana single woman

• How can this How can this be?be?



• What is the What is the mitochondrial Eve mitochondrial Eve theory?theory?– The idea that we all The idea that we all

trace back to a trace back to a single womansingle woman

• How can this be?How can this be?– B/c mitochondrial B/c mitochondrial

DNA does not DNA does not recombinerecombine

– We have infinite We have infinite nuclear ancestors nuclear ancestors b/c nuclear DNA b/c nuclear DNA does recombinedoes recombine


If we can all trace our maternal lineage If we can all trace our maternal lineage back to a single women, then why back to a single women, then why

don’t we all have the same mtDNA?don’t we all have the same mtDNA?


If we can all trace our maternal lineage If we can all trace our maternal lineage back to a single women, then why back to a single women, then why

don’t we all have the same mtDNA?don’t we all have the same mtDNA?

• MUTATION!MUTATION!


RaceRace


Genetics and RaceGenetics and Race

• What can biology/genetics tell us about race?What can biology/genetics tell us about race?

• What can biology/genetics tell us about What can biology/genetics tell us about ourselves?ourselves?


What can genetics tell us about race?What can genetics tell us about race?

• There is no genetic or biological definition for what we There is no genetic or biological definition for what we refer to as ‘race’ in humansrefer to as ‘race’ in humans

• There is no Caucasian gene, no African gene, no Asian There is no Caucasian gene, no African gene, no Asian genegene

• Is there one gene that distinguishes one race from Is there one gene that distinguishes one race from another? No.another? No.


Human evolution and genetic variationHuman evolution and genetic variation

• Anatomically modern humans have been evolving Anatomically modern humans have been evolving for over 200,000 years and we are still evolvingfor over 200,000 years and we are still evolving

• There are no ‘pure’ human stocks and there never There are no ‘pure’ human stocks and there never werewere

• No populations are more highly evolved than No populations are more highly evolved than othersothers

• Human populations are too closely related to be Human populations are too closely related to be considered subspecies considered subspecies

• There is a continuum of genetic variation across There is a continuum of genetic variation across the globethe globe


What genes do we have?What genes do we have?• We have genes for:We have genes for:

– ATP/energy productionATP/energy production– DNA repairDNA repair– Metabolic pathwaysMetabolic pathways– ……

• No one has ever identified a gene for:No one has ever identified a gene for:– IntelligenceIntelligence– AthleticismAthleticism– Musical abilityMusical ability– Language abilityLanguage ability– Work ethicWork ethic– PersonalityPersonality


How do you interpret a genetic How do you interpret a genetic variant?variant?

• What does a C-to-T What does a C-to-T change mean?change mean?

• Smarter, prettier, Smarter, prettier, faster, stronger???faster, stronger???– No, just differentNo, just different

• Most variants are Most variants are neutral = no effectneutral = no effect– Genes make up ~2% of Genes make up ~2% of

genomegenome


But there are different frequencies But there are different frequencies of alleles in different populationsof alleles in different populations

• Alleles differ in frequency between people and Alleles differ in frequency between people and populations, genes don’t differ in frequencypopulations, genes don’t differ in frequency– Gene – DNA sequence that encodes a proteinGene – DNA sequence that encodes a protein– Allele – one of several alternative forms of a DNA sequence Allele – one of several alternative forms of a DNA sequence

(can be coding or non-coding)(can be coding or non-coding)

Human chromosomes, Genetics, Hartl and Jones, 2000 Types of alleles, Genetics, Hartl and Jones, 2000


But differences in allele frequencies But differences in allele frequencies doesn’t mean populations fall into doesn’t mean populations fall into

racial categoriesracial categories

• Most genetic variation among humans Most genetic variation among humans occurs within populations, not between themoccurs within populations, not between them

• Variation in gene frequency is distributed Variation in gene frequency is distributed continuously, or clinally, in response to continuously, or clinally, in response to selection or genetic driftselection or genetic drift


Most genetic variation among humans Most genetic variation among humans occurs within populations, not between occurs within populations, not between

themthem

Total Species(100%)

Between Regional Populations

(10%)

Within Regional Populations

(90%)

Between Local Populations Within

Regional Populations(5%)

Between Individuals Within Local Populations

(85%)


But differences in allele frequencies But differences in allele frequencies doesn’t mean populations fall into doesn’t mean populations fall into

racial categoriesracial categories

• Most genetic variation among humans Most genetic variation among humans occurs within populations, not between themoccurs within populations, not between them

• Variation in gene frequency is distributed Variation in gene frequency is distributed continuously, or clinallycontinuously, or clinally


Variation in skin color in 22 populationsVariation in skin color in 22 populations


• Bad sampling (A) can give the illusion of clusters, Bad sampling (A) can give the illusion of clusters, but good sampling (B) shows a cline in frequenciesbut good sampling (B) shows a cline in frequencies

Serre, D., and S. Paabo. 2004. Genome Research 14:1679-1685.


But we look different!But we look different!

• We can see differences between peopleWe can see differences between people– e.g. dark-skinned, light hair, etce.g. dark-skinned, light hair, etc

• But, only a few genes (out of ~20,000) determine But, only a few genes (out of ~20,000) determine skin color, hair color, etc. so it doesn’t take many skin color, hair color, etc. so it doesn’t take many variants to make us look differentvariants to make us look different– The differences are literally only ‘skin deep’The differences are literally only ‘skin deep’– Skin color is controlled by levels of melaninSkin color is controlled by levels of melanin– Three main genes for melanin productionThree main genes for melanin production


What can genetics tell us about ourselves?What can genetics tell us about ourselves?

• For a fee, lots of companies will tell you For a fee, lots of companies will tell you something about your ancestors based on a DNA something about your ancestors based on a DNA sample sample – National Genographic, DNA Ancestry Project, DNA National Genographic, DNA Ancestry Project, DNA

Tribes, Ancestral OriginsTribes, Ancestral Origins• https://www.gtldna.net/ancestral-origins-dna-ancestry.html?s

rc=google&gclid=CMaqk6jzv58CFQmdnAodOTr0zw


Neanderthal (+ other archaics) Neanderthal (+ other archaics) geneticsgenetics


First publication of DNA First publication of DNA sequences from a Neanderthalsequences from a Neanderthal

• Sequence data from Neanderthal Sequence data from Neanderthal type specimen, found in Neander type specimen, found in Neander Valley, Germany in late 1800sValley, Germany in late 1800s– Krings et al. 1997 – mtDNA HVRI Krings et al. 1997 – mtDNA HVRI

sequencesequence– Krings et al. 1999 – mtDNA HVRII Krings et al. 1999 – mtDNA HVRII

sequencesequence

Holland & Huffine 2001


Neanderthal geneticsNeanderthal geneticsWhat is the evidence against What is the evidence against interbreeding between Neanderthals interbreeding between Neanderthals and modern humans?and modern humans?

Jobling et al. 2003


Neanderthal geneticsNeanderthal genetics

• Mitochondrial DNA data show that the Mitochondrial DNA data show that the majority of Neanderthal genetic variation majority of Neanderthal genetic variation lays outside modern human genetic lays outside modern human genetic variationvariation

Jobling et al. 2003




• Phylogenies show Neanderthal as an Phylogenies show Neanderthal as an outgroupoutgroup

Jobling et al. 2003

Noonan 2010




• Phylogenies show Neanderthal as an Phylogenies show Neanderthal as an outgroupoutgroup

• MRCA b/t Neanderthal and humans is 4x MRCA b/t Neanderthal and humans is 4x older than MRCA of humansolder than MRCA of humans

Jobling et al. 2003

Noonan 2010



• Means that Neanderthal mtDNA gene pool Means that Neanderthal mtDNA gene pool evolved for a long time, isolated from evolved for a long time, isolated from humans, and there is no support for a humans, and there is no support for a Neanderthal contribution to modern Neanderthal contribution to modern human mtDNAhuman mtDNA

Jobling et al. 2003

Noonan 2010


What about nuclear DNA?What about nuclear DNA?Represents 3 billion bases, not 16 thousandRepresents 3 billion bases, not 16 thousand

• Green et al. (2010) published draft nuclear Green et al. (2010) published draft nuclear genome sequences of 3 Neanderthalsgenome sequences of 3 Neanderthals– Posits 1-4% Neanderthal admixture in Europeans and Posits 1-4% Neanderthal admixture in Europeans and

AsiansAsians– Since it occurred in both Europeans and Asians, Since it occurred in both Europeans and Asians,

likely to have occurred before those groups split, i.e. likely to have occurred before those groups split, i.e. ~50-80 kya~50-80 kya

– No Neanderthal DNA in AfricansNo Neanderthal DNA in Africans– Expected difference between Expected difference between

mitochondrial and nuclear DNAmitochondrial and nuclear DNA


DenisovaDenisova

• In 2008, a hominin bone fragment In 2008, a hominin bone fragment was discovered in the Denisova cave was discovered in the Denisova cave in southern Siberia’s Altai mountains in southern Siberia’s Altai mountains – Child’s finger bone scattered among stone tools Child’s finger bone scattered among stone tools

and bone implements in layer dated to 48-30 kyaand bone implements in layer dated to 48-30 kya

• It was believed that modern humans It was believed that modern humans and Neanderthals were the only and Neanderthals were the only hominins present there at the timehominins present there at the time


Phylogenetic analysisPhylogenetic analysis

• Denisova mtDNA lineage Denisova mtDNA lineage branches much earlier than branches much earlier than human and Neanderthal human and Neanderthal lineageslineages– Most recent common ancestor Most recent common ancestor

(MRCA) between humans and (MRCA) between humans and Denisovans is ~1myaDenisovans is ~1mya

– MRCA is twice as old as MRCA of MRCA is twice as old as MRCA of humans and Neanderthalshumans and Neanderthals


Phylogenetic analysisPhylogenetic analysis

• Denisova mtDNA lineage Denisova mtDNA lineage branches much earlier than branches much earlier than human and Neanderthal human and Neanderthal lineageslineages– Most recent common ancestor Most recent common ancestor

(MRCA) between humans and (MRCA) between humans and Denisovans is ~1myaDenisovans is ~1mya

– MRCA is twice as old as MRCA of MRCA is twice as old as MRCA of humans and Neanderthalshumans and Neanderthals

• Denisova can’t be Denisova can’t be H erectus H erectus b/c b/c H H erectuserectus wasn’t in mainland Asia ~40 wasn’t in mainland Asia ~40 kya and kya and H erectus H erectus left Africa ~2 myaleft Africa ~2 mya– Denisova must have been in Africa ~2 Denisova must have been in Africa ~2

mya to share a common ancestor with mya to share a common ancestor with modern humans and Neanderthalmodern humans and Neanderthal

– New hominin! ID’ed by DNA!!New hominin! ID’ed by DNA!!


What about nuclear DNA?What about nuclear DNA?

• Changes phylogeny – Denisovan closer to Changes phylogeny – Denisovan closer to Neanderthal than modern humansNeanderthal than modern humans


What about nuclear DNA?What about nuclear DNA?

• Changes phylogeny – Denisovan closer to Changes phylogeny – Denisovan closer to Neanderthal than modern humansNeanderthal than modern humans

• 4-6% admixture in Southeast Asians4-6% admixture in Southeast Asians


Major paradigm shiftMajor paradigm shift

• We do have Neanderthal DNA in us!We do have Neanderthal DNA in us!

• And Denisovan, another archaic homininAnd Denisovan, another archaic hominin

• Recent papers propose admixture from possibly Recent papers propose admixture from possibly two more, unidentified archaic homininstwo more, unidentified archaic hominins

• Allele in a gene in our immune system has Allele in a gene in our immune system has recently been identified as coming from recently been identified as coming from Neanderthals and conferring a selective Neanderthals and conferring a selective advantage advantage (Mendez et al. AJHG, 2012)(Mendez et al. AJHG, 2012)


Current statusCurrent status

• Some debate about Some debate about archaic admixture archaic admixture vs vs ancient population substructure ancient population substructure in Africa in Africa (> 100-200kya) that could create signal of (> 100-200kya) that could create signal of archaic admixture but is really just archaic admixture but is really just separate gene pools in Africa, only one of separate gene pools in Africa, only one of which left and gave rise to European and which left and gave rise to European and AsiansAsians


Cro-Magnon, n=2Cro-Magnon, n=2Conclusion -Conclusion - Modern humans clearly group w/ Cro-Magnon and show Modern humans clearly group w/ Cro-Magnon and show

no shared ancestry with Neanderthalno shared ancestry with Neanderthal

Caramelli et al. 2003

Neanderthal

Cro-MagnonMultidimensional scaling of HVRI sequences of 60 modern Europeans (filled squares), 20 modern non-Europeans (filled circles), 4 Neanderthals (open diamonds), Lake Mungo specimen (open circle), and Paglicci specimens (open squares)

human polymorphisms and genetic anthropology

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