Genes and human historyGil McVean, Department of Statistics, Oxford

Contact: mcvean@stats.ox.ac.uk

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• Where does the variation come from?

• How old are the genetic differences between us?

• Are these differences important?

How different are our genomes?

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Serological techniques for detecting variation

Human

Rabbit

A

A O

Anti-A antibodies

B AB

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Blood group systems in humans• 28 known systems

– 39 genes, 643 alleles

System Genes AllelesABO ABO 102

Colton C4A, C4B 7+

Chido-rodgers AQP1 7

Colton DAF 10

Diego SLC4A1 78

Dombrock DO 9

Duffy FY 9

Gerbich GYPC 9

GIL AQP3 2

H/h FUT1, FUT2 27/22

I GCNT2 7

Indian CD44 2

Kell KEL, XK 33/30

Kidd SLC14A1 8

Knops CR1 24+

Landsteiner-Wiener

ICAM4 3

Lewis FUT3, FUT6 14/20

Lutheran LU 16

MNS GYPA,GYPB,GYPE

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OK BSG 2

P-related A4GALT, B3GALT3

14/5

RAPH-MER2 CD151 3

Rh RHCE, RHD, RHAG

129

Scianna ERMAP 4

Xg XG, CD99 -

YT ACHE 4

http://www.bioc.aecom.yu.edu/bgmut/summary.htm

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Protein electroporesis• Changes in mass/charge ratio resulting from amino acid substitutions in proteins

can be detected

• In humans, about 30% of all loci show polymorphism with a 6% chance of a pair of randomly drawn alleles at a locus being different

+++

--- ---

++--- - --- - +

Starch or agar gel

Direction of travel

Lewontin and Hubby (1966)Harris(1966)

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GATAAGACGGTGATACTCACGCGACGGGCTTGGGCGCCGACTCGTTCAGACGGTGACCCAACTTATCCGATCGACCCCGGGTCCCGATTTAGACTCGGTATCATTTCTGGTGATTATCGCCTGCAGGTTCAAGAACACGTTTGCAGCAAGAAGTGAGGGATTTTGTCAGTGATCCCAGTCTACGGAGCCAGTCACCTCTGGTAGTGAAATTTTATTCGTTCATCTTCATATAAGTCGCAGACCGCACGATGGGGGACAGAATACTCGCACAGGAAGAACCGCGATGAACCGAGGTAACCTAACATCCTAAGCCATTCCAACGAGGCTTTCGTAACCAAATCAGTTCTTCCCAGTCCAGATGAGGCGAACGTAGGTGCTGTTGGAACCATGAGTGGCCAACAGAATACTGTGGATGCTAAGCTAATGGAATGTGTTAATCAGACGTTTGCTGATGTGACACATTGGTCGCTGCTCTTTGATGCGGAAATCTATGAGCGGTCAAACCGATACAAACCCGGCTATGTCGTTCGCACAACAGTCGGGTCCCACCCCATTGTTCTTATGAAGGTATTACTGGTCATACGATGCTTTTGCGACGCATCCCTCCCTATGACGAGAGTGCAGTCAGACCCCTCGACCATTTCCCTTAGAAAGACCACCCATCTCTTCAAAGTTATTCTCCGTGACATGCGAACGCTGAAGGATAAGGAGCGGCATGCAGACTTTTATGTGTGCTCTCTGCTGGTCCAGCGGCATCTAAACGTCTCATCACTAGGGCCACGCAGTCGTTTTTAAGAGGCTCTATTTTTACTAATTATTCTTGTCCACCACGACCTCTCAGCGCGGCAGATAGGTTCACAGGCTAGCGTCGGGTAATGCATTGCAGTTTCGTTACTCGTTCAGACAAGACTCGATGCTTTACACTCACGACCCGCAAAGCCTTGGCCTTACAAGGGTATTAGGCCGAACACTTACTTATCGCCGAAGGTACGTCGGCTATTGTAGCCCAAACCCTAGACTGAGCCCTAACCTCTACGCGTATCTTATAGGTTCAGAACGCCGAAGGACTATTCTCACGGCATTCATGGTTAAAAGAGAGTCGAGGCGCCTGCTATATGTGCCGAGTCCCATTAGTCAGTACACTTGCCATCACATTTGTCCTGTTAGGCGGACACTTAGAGTAAGCGTACAACGCCTTACAACGAGACGCAGATCGCTTTTCTAATTGCGCCGCGTCTCTACCATCGTGGCCAGTTCATACTCACACGGAGGTGTGCAACCCGTAACACGAGTGAGTGCTCACTTTATAATAAGTCAGCGTTCAGGACTGAGTGCAACCAATCTACGCCAGGAATCGCAAACAGCGCTCATAAACTTCTTACCTTTCCATAGCGCGCCTTTCGAGTATTATTGACCGTTAGGACTACGATAGGCTTCGACAATAGACCCTATCTGCGCATCATTACCTCTCACCGGGGGAAAGAAATTCCAATCAATCTGTCCAGGGCGCCCGTTTTTTTAAGACCTTAGTGCCCATGAATGAACTGGCTCAAGCAATAGCGGCTGCTCGTGCCATGCGTGAGCTGGCGGCCAAATCGGACTCACGGACAAGTCTGCCCCCTTGTGAGTTAGTGTTGGCTTGACAACTCTAAAGTCCGAACCCATCGTGCGGCCATCCTACGTGGTGTAGCTTTGGCCCATAACTAACCTGGTTACTCACTATCCTGCGACTCGTCTGGTCTCACTAGGCGATTCCCCCCGGCTTCGTATTGCAACATTCTAACGAATGCGAAGTCAAACAGTCCAGCTTAACAAAGGGGTCTTGACGAGACTCTGTAATCGTCTGCTAGCCCCGGACTCTGTTGTCGAAGGCAATTTGACGACCCACACGAGGTGCAGACGTAGTCAGGCCTGATAGCTATGTATGCAGGCATATCCCTATAAAGTAGCGTTTGGTTATCCTACCATTAGCCGTTTCCGCATCTACCAGTGTCGACCGG

The rise of DNA sequencing

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SNPs

TGCATTGCGTAGGCTGCATTCCGTAGGC

Single Nucleotide PolymorphismsGATAAGACGGTGATACTCACGCGACGGGCTTGGGCGCCGACTCGTTCAGACGGTGACCCAACTTATCCGATCGACCCCGGGTCCCGATTTAGACTCGGTATCATTTCTGGTGATTATCGCCTGCAGGTTCAAGAACACGTTTGCAGCAAGAAGTGAGGGATTTTGTCAGTGATCCCAGTCTACGGAGCCAGTCACCTCTGGTAGTGAAATTTTATTCGTTCATCTTCATATAAGTCGCAGACCGCACGATGGGGGACAGAATACTCGCACAGGAAGAACCGCGATGAACCGAGGTAACCTAACATCCTAAGCCATTCCAACGAGGCTTTCGTAACCAAATCAGTTCTTCCCAGTCCAGATGAGGCGAACGTAGGTGCTGTTGGAACCATGAGTGGCCAACAGAATACTGTGGATGCTAAGCTAATGGAATGTGTTAATCAGACGTTTGCTGATGTGACACATTGGTCGCTGCTCTTTGATGCGGAAATCTATGAGCGGTCAAACCGATACAAACCCGGCTATGTCGTTCGCACAACAGTCGGGTCCCACCCCATTGTTCTTATGAAGGTATTACTGGTCATACGATGCTTTTGCGACGCATCCCTCCCTATGACGAGAGTGCAGTCAGACCCCTCGACCATTTCCCTTAGAAAGACCACCCATCTCTTCAAAGTTATTCTCCGTGACATGCGAACGCTGAAGGATAAGGAGCGGCATGCAGACTTTTATGTGTGCTCTCTGCTGGTCCAGCGGCATCTAAACGTCTCATCACTAGGGCCACGCAGTCGTTTTTAAGAGGCTCTATTTTTACTAATTATTCTTGTCCACCACGACCTCTCAGCGCGGCAGATAGGTTCACAGGCTAGCGTCGGGTAATGCATTGCAGTTTCGTTACTCGTTCAGACAAGACTCGATGCTTTACACTCACGACCCGCAAAGCCTTGGCCTTACAAGGGTATTAGGCCGAACACTTACTTATCGCCGAAGGTACGTCGGCTATTGTAGCCCAAACCCTAGACTGAGCCCTAACCTCTACGCGTATCTTATAGGTTCAGAACGCCGAAGGACTATTCTCACGGCATTCATGGTTAAAAGAGAGTCGAGGCGCCTGCTATATGTGCCGAGTCCCATTAGTCAGTACACTTGCCATCACATTTGTCCTGTTAGGCGGACACTTAGAGTAAGCGTACAACGCCTTACAACGAGACGCAGATCGCTTTTCTAATTGCGCCGCGTCTCTACCATCGTGGCCAGTTCATACTCACACGGAGGTGTGCAACCCGTAACACGAGTGAGTGCTCACTTTATAATAAGTCAGCGTTCAGGACTGAGTGCAACCAATCTACGCCAGGAATCGCAAACAGCGCTCATAAACTTCTTACCTTTCCATAGCGCGCCTTTCGAGTATTATTGACCGTTAGGACTACGATAGGCTTCGACAATAGACCCTATCTGCGCATCATTACCTCTCACCGGGGGAAAGAAATTCCAATCAATCTGTCCAGGGCGCCCGTTTTTTTAAGACCTTAGTGCCCATGAATGAACTGGCTCAAGCAATAGCGGCTGCTCGTGCCATGCGTGAGCTGGCGGCCAAATCGGACTCACGGACAAGTCTGCCCCCTTGTGAGTTAGTGTTGGCTTGACAACTCTAAAGTCCGAACCCATCGTGCGGCCATCCTACGTGGTGTAGCTTTGGCCCATAACTAACCTGGTTACTCACTATCCTGCGACTCGTCTGGTCTCACTAGGCGATTCCCCCCGGCTTCGTATTGCAACATTCTAACGAATGCGAAGTCAAACAGTCCAGCTTAACAAAGGGGTCTTGACGAGACTCTGTAATCGTCTGCTAGCCCCGGACTCTGTTGTCGAAGGCAATTTGACGACCCACACGAGGTGCAGACGTAGTCAGGCCTGATAGCTATGTATGCAGGCATATCCCTATAAAGTAGCGTTTGGTTATCCTACCATTAGCCGTTTCCGCATCTACCAGTGTCGACCGG1 in 1000 between any two genomes

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Different, but not that different• Humans are one of the least diverse organisms

Species Diversity (percent)

Humans 0.08 - 0.1

Chimpanzees 0.12 - 0.17

Drosophila simulans 2

E. coli 5

HIV1 30

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c. 3,000,000 SNPs in 270 people

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c. 25,000,000 SNPs in 1000 people

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How do we differ? – Let me count the ways• Single nucleotide polymorphisms

• Short indels (=insertion/deletion)

• Microsatellite (STR) repeat number

• Minisatellites

• Repeated genes– rRNA, histones

• Large inversions, deletions– Y chromosome, Copy Number Variants (CNVs)

TGCATTGCGTAGGCTGCATTCCGTAGGC

TGCATT---TAGGCTGCATTCCGTAGGC

TGCTCATCATCATCAGCTGCTCATCA------GC

≤100bp

1-5kb

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Y chromosome variation• Non-pathological rearrangements of the AZFc region on the Y chromosome

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Where do mutations come from?

• You will pass on about 60 new mutations to each of your children

• Most of these are destined to die out within a few generations

• Most variation is inherited from our ancestors

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Me You

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Our genomesInherited mutations

Our genealogical tree

Mutations in our ancestors

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mtDNA Eve

19Recombination means that different parts of the genome have different tree

• Looking back in time, recombination means that different parts of your chromosomes follow different evolutionary paths

• This means that the genealogical tree will change along the genome

TCAGGCATGGATCAGGGAGCT TCACGCATGGAACAGGGAGCT

Grandpaternal sequence Grandmaternal sequence

TCAGGCATGG AACAGGGAGCT

x

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How old?

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Human – chimp split

Autosomal MRCA

Origin of H. sapiens

Homo erectus

Australopithecus afarensis

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Did early humans breed with Neanderthals?

Ovchinnikov et al (2000)

Neanderthals

mtDNA sequences say no…

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Reading

• Human genetic variation– Rosenberg et al. Genetic structure of human populations. Science 2002, 298:2381-2385.– Conrad et al. A worldwide survey of haplotype variation and linkage disequilibrium in the human genome.

Nature Genet. 2006, 1251-1260.– McVean et al. Perspectives on human genetic variation from the International HapMap Project. PLoS

Genetics 2005, 1:e54.

• The origin of modern humans– Reed & Tishkoff. African human diversity, origins and migrations. Curr Opin Genet Dev. 2006 16:597-605.– Jobling et al. Human evolutionary genetics: origins, peoples, and disease. Garland Science, 2004.– Harding & McVean. A structured ancestral population for the evolution of modern humans. Curr. Op.

Genet. Dev. 2004, 14: 667-674.

• Natural selection– Lamason et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans.

Science 2005, 310:1782-1786.– Sabeti et al. Positive natural selection in the human lineage. Science 2006, 312:1614-1620. – Tishkoff et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet. 2007

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