Genes and human historyGil McVean, Department of Statistics, Oxford

Contact: mcvean@stats.ox.ac.uk

2

3

• Where does the variation come from?

• How old are the genetic differences between us?

• Are these differences important?

How different are our genomes?

5

Serological techniques for detecting variation

Human

Rabbit

A

A O

Anti-A antibodies

B AB

6

Blood group systems in humans• 28 known systems

– 39 genes, 643 alleles

System Genes Alleles

ABO 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

43

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

7

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)

8

GATAAGACGGTGATACTCACGCGACGGGCTTGGGCGCCGACTCGTTCAGACGGTGACCCAACTTATCCGATCGACCCCGGGTCCCGATTTAGACTCGGTATCATTTCTGGTGATTATCGCCTGCAGGTTCAAGAACACGTTTGCAGCAAGAAGTGAGGGATTTTGTCAGTGATCCCAGTCTACGGAGCCAGTCACCTCTGGTAGTGAAATTTTATTCGTTCATCTTCATATAAGTCGCAGACCGCACGATGGGGGACAGAATACTCGCACAGGAAGAACCGCGATGAACCGAGGTAACCTAACATCCTAAGCCATTCCAACGAGGCTTTCGTAACCAAATCAGTTCTTCCCAGTCCAGATGAGGCGAACGTAGGTGCTGTTGGAACCATGAGTGGCCAACAGAATACTGTGGATGCTAAGCTAATGGAATGTGTTAATCAGACGTTTGCTGATGTGACACATTGGTCGCTGCTCTTTGATGCGGAAATCTATGAGCGGTCAAACCGATACAAACCCGGCTATGTCGTTCGCACAACAGTCGGGTCCCACCCCATTGTTCTTATGAAGGTATTACTGGTCATACGATGCTTTTGCGACGCATCCCTCCCTATGACGAGAGTGCAGTCAGACCCCTCGACCATTTCCCTTAGAAAGACCACCCATCTCTTCAAAGTTATTCTCCGTGACATGCGAACGCTGAAGGATAAGGAGCGGCATGCAGACTTTTATGTGTGCTCTCTGCTGGTCCAGCGGCATCTAAACGTCTCATCACTAGGGCCACGCAGTCGTTTTTAAGAGGCTCTATTTTTACTAATTATTCTTGTCCACCACGACCTCTCAGCGCGGCAGATAGGTTCACAGGCTAGCGTCGGGTAATGCATTGCAGTTTCGTTACTCGTTCAGACAAGACTCGATGCTTTACACTCACGACCCGCAAAGCCTTGGCCTTACAAGGGTATTAGGCCGAACACTTACTTATCGCCGAAGGTACGTCGGCTATTGTAGCCCAAACCCTAGACTGAGCCCTAACCTCTACGCGTATCTTATAGGTTCAGAACGCCGAAGGACTATTCTCACGGCATTCATGGTTAAAAGAGAGTCGAGGCGCCTGCTATATGTGCCGAGTCCCATTAGTCAGTACACTTGCCATCACATTTGTCCTGTTAGGCGGACACTTAGAGTAAGCGTACAACGCCTTACAACGAGACGCAGATCGCTTTTCTAATTGCGCCGCGTCTCTACCATCGTGGCCAGTTCATACTCACACGGAGGTGTGCAACCCGTAACACGAGTGAGTGCTCACTTTATAATAAGTCAGCGTTCAGGACTGAGTGCAACCAATCTACGCCAGGAATCGCAAACAGCGCTCATAAACTTCTTACCTTTCCATAGCGCGCCTTTCGAGTATTATTGACCGTTAGGACTACGATAGGCTTCGACAATAGACCCTATCTGCGCATCATTACCTCTCACCGGGGGAAAGAAATTCCAATCAATCTGTCCAGGGCGCCCGTTTTTTTAAGACCTTAGTGCCCATGAATGAACTGGCTCAAGCAATAGCGGCTGCTCGTGCCATGCGTGAGCTGGCGGCCAAATCGGACTCACGGACAAGTCTGCCCCCTTGTGAGTTAGTGTTGGCTTGACAACTCTAAAGTCCGAACCCATCGTGCGGCCATCCTACGTGGTGTAGCTTTGGCCCATAACTAACCTGGTTACTCACTATCCTGCGACTCGTCTGGTCTCACTAGGCGATTCCCCCCGGCTTCGTATTGCAACATTCTAACGAATGCGAAGTCAAACAGTCCAGCTTAACAAAGGGGTCTTGACGAGACTCTGTAATCGTCTGCTAGCCCCGGACTCTGTTGTCGAAGGCAATTTGACGACCCACACGAGGTGCAGACGTAGTCAGGCCTGATAGCTATGTATGCAGGCATATCCCTATAAAGTAGCGTTTGGTTATCCTACCATTAGCCGTTTCCGCATCTACCAGTGTCGACCGG

The rise of DNA sequencing

9

SNPs

TGCATTGCGTAGGCTGCATTCCGTAGGC

Single Nucleotide PolymorphismsGATAAGACGGTGATACTCACGCGACGGGCTTGGGCGCCGACTCGTTCAGACGGTGACCCAACTTATCCGATCGACCCCGGGTCCCGATTTAGACTCGGTATCATTTCTGGTGATTATCGCCTGCAGGTTCAAGAACACGTTTGCAGCAAGAAGTGAGGGATTTTGTCAGTGATCCCAGTCTACGGAGCCAGTCACCTCTGGTAGTGAAATTTTATTCGTTCATCTTCATATAAGTCGCAGACCGCACGATGGGGGACAGAATACTCGCACAGGAAGAACCGCGATGAACCGAGGTAACCTAACATCCTAAGCCATTCCAACGAGGCTTTCGTAACCAAATCAGTTCTTCCCAGTCCAGATGAGGCGAACGTAGGTGCTGTTGGAACCATGAGTGGCCAACAGAATACTGTGGATGCTAAGCTAATGGAATGTGTTAATCAGACGTTTGCTGATGTGACACATTGGTCGCTGCTCTTTGATGCGGAAATCTATGAGCGGTCAAACCGATACAAACCCGGCTATGTCGTTCGCACAACAGTCGGGTCCCACCCCATTGTTCTTATGAAGGTATTACTGGTCATACGATGCTTTTGCGACGCATCCCTCCCTATGACGAGAGTGCAGTCAGACCCCTCGACCATTTCCCTTAGAAAGACCACCCATCTCTTCAAAGTTATTCTCCGTGACATGCGAACGCTGAAGGATAAGGAGCGGCATGCAGACTTTTATGTGTGCTCTCTGCTGGTCCAGCGGCATCTAAACGTCTCATCACTAGGGCCACGCAGTCGTTTTTAAGAGGCTCTATTTTTACTAATTATTCTTGTCCACCACGACCTCTCAGCGCGGCAGATAGGTTCACAGGCTAGCGTCGGGTAATGCATTGCAGTTTCGTTACTCGTTCAGACAAGACTCGATGCTTTACACTCACGACCCGCAAAGCCTTGGCCTTACAAGGGTATTAGGCCGAACACTTACTTATCGCCGAAGGTACGTCGGCTATTGTAGCCCAAACCCTAGACTGAGCCCTAACCTCTACGCGTATCTTATAGGTTCAGAACGCCGAAGGACTATTCTCACGGCATTCATGGTTAAAAGAGAGTCGAGGCGCCTGCTATATGTGCCGAGTCCCATTAGTCAGTACACTTGCCATCACATTTGTCCTGTTAGGCGGACACTTAGAGTAAGCGTACAACGCCTTACAACGAGACGCAGATCGCTTTTCTAATTGCGCCGCGTCTCTACCATCGTGGCCAGTTCATACTCACACGGAGGTGTGCAACCCGTAACACGAGTGAGTGCTCACTTTATAATAAGTCAGCGTTCAGGACTGAGTGCAACCAATCTACGCCAGGAATCGCAAACAGCGCTCATAAACTTCTTACCTTTCCATAGCGCGCCTTTCGAGTATTATTGACCGTTAGGACTACGATAGGCTTCGACAATAGACCCTATCTGCGCATCATTACCTCTCACCGGGGGAAAGAAATTCCAATCAATCTGTCCAGGGCGCCCGTTTTTTTAAGACCTTAGTGCCCATGAATGAACTGGCTCAAGCAATAGCGGCTGCTCGTGCCATGCGTGAGCTGGCGGCCAAATCGGACTCACGGACAAGTCTGCCCCCTTGTGAGTTAGTGTTGGCTTGACAACTCTAAAGTCCGAACCCATCGTGCGGCCATCCTACGTGGTGTAGCTTTGGCCCATAACTAACCTGGTTACTCACTATCCTGCGACTCGTCTGGTCTCACTAGGCGATTCCCCCCGGCTTCGTATTGCAACATTCTAACGAATGCGAAGTCAAACAGTCCAGCTTAACAAAGGGGTCTTGACGAGACTCTGTAATCGTCTGCTAGCCCCGGACTCTGTTGTCGAAGGCAATTTGACGACCCACACGAGGTGCAGACGTAGTCAGGCCTGATAGCTATGTATGCAGGCATATCCCTATAAAGTAGCGTTTGGTTATCCTACCATTAGCCGTTTCCGCATCTACCAGTGTCGACCGG1 in 1000 between any two genomes

10

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

11

c. 3,000,000 SNPs in 270 people

12

c. 25,000,000 SNPs in 1000 people

13

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

14

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

15

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

16

Me You

17

Our genomesInherited mutations

Our genealogical tree

Mutations in our ancestors

18

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

20

How old?

21

Human – chimp split

Autosomal MRCA

Origin of H. sapiens

Homo erectus

Australopithecus afarensis

24

Did early humans breed with Neanderthals?

Ovchinnikov et al (2000)

Neanderthals

mtDNA sequences say no…

25

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

39:31-40