Post on 19-Dec-2015
3
• Where does the variation come from?
• How old are the genetic differences between us?
• Are these differences important?
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
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
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
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
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