法测定急性淋巴细胞白血病患儿血清中课件

Population Genomics Gil McVean, Department of Statistics, Oxford 1 Questions about genetic variation How different are our genomes? How is the variation distributed within and between genomes? What does variation tell us about human evolution? 2 How different are our genomes? 3 Serological techniques for detecting variation Human Rabbit A ABABO 4 Blood group systems in humans 28 known systems 39 genes, 643 alleles SystemGenesAlleles ABOABO102 ColtonC4A, C4B7+ Chido-rodgersAQP17 ColtonDAF10 DiegoSLC4A178 DombrockDO9 DuffyFY9 GerbichGYPC9 GILAQP32 H/hFUT1, FUT227/22 IGCNT27 IndianCD442 KellKEL, XK33/30 KiddSLC14A18 KnopsCR124+ Landsteiner- Wiener ICAM43 LewisFUT3, FUT614/20 LutheranLU16 MNSGYPA,GYPB,G YPE 43 OKBSG2 P-relatedA4GALT, B3GALT3 14/5 RAPH-MER2CD1513 RhRHCE, RHD, RHAG 129 SciannaERMAP4 XgXG, CD99- YTACHE4 /bgmut/summary.htm 5 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) 6 The rise of DNA sequence analysis RFLPs Cann et al 1987 Sequencing of small regions Vigilant et al 1991 Whole genome sequencing Ingman et al 2000 7 The human genomes The draft human genome sequence was published in 2001 This is a mosaic from several individuals Since then, several more genomes have been sequenced, at least partially Shotgun sequencing variation discovery Other methods have been developed to look for gross chromosomal differences Nimblegen array CGH 8 The International HapMap Project Launched in 2002 with the goal of characterising single nucleotide variation between 540 human genomes from individuals of European, Nigerian, Chinese and Japanese ancestry Not a sequencing project, rather it types known polymorphisms Has currently assembled information on over 6 million SNPs (single nucleotide polymorphisms) 9 The 1000 Genomes Project 10 How do we differ? Let me count the ways Single nucleotide polymorphisms 1 every few hundred bp Short indels (=insertion/deletion) 1 every few kb Microsatellite (STR) repeat number 1 every few kb Minisatellites 1 every few kb Repeated genes rRNA, histones Large inversions, deletions Y chromosome, Copy Number Variants (CNVs) TGCATTGCGTAGGC TGCATTCCGTAGGC TGCATT-TAGGC TGCATTCCGTAGGC TGCTCATCATCATCAGC TGCTCATCA-GC 100bp 1-5kb 11 Y chromosome variation Non-pathological rearrangements of the AZFc region on the Y chromosome Tyler-Smith and McVean (2003) 12 Mutation is the ultimate source of variation New mutations occur in the germ-line Point mutations at about 2x10-8 per nucleotide per generation You pass on about 60 new mutations to your children, of which perhaps 1 changes the protein sequence encoded by a gene Microsatellite mutations can occur much faster Up to 10-4 per generation Some, e.g. in Huntingtons disease, have important consequences Minisatellites can mutate at rates of up to 10-1 per generation The uniqueness of these patterns gives rise to DNA fingerprinting Most of the differences between genomes are the result of inheriting mutations from our ancestors 13 Our genomes Inherited mutations Our genealogical tree Mutations in our ancestors 14 Different, but not that different Humans are one of the least diverse organisms (excepting cheetahs) SpeciesDiversity (percent) Humans0.08 - 0.1 Chimpanzees0.12 - 0.17 Drosophila simulans 2 E. coli5 HIV130 Photos from UN photo gallery /av/photo 15 An aside on the genetics of race It is sometimes claimed that there is a genetic basis to race What is true is that groups of individuals from different parts of the world tend to have similar genomes because they share recent ancestry But there are very few fixed genetic differences between populations (I can think of one example the FY gene) The differences between populations are in terms of the combinations of variants, Rosenberg et al (2002) 16 How is genetic variation distributed within and between genomes? 17 Diversity is not evenly distributed across the genome I GenomeAverage pairwise differences / kb Relative copy number (a) Autosomes0.5 0.851 X chromosome0.473/4 Y chromosome0.151/4 mtDNA2.81/4 TISMWG (2001) , Jobling et al (2004) Autosomes, sex chromosomes and mtDNA have systematically different levels of diversity This reflects differences in the number of chromosomes and the mutation rate 18 Diversity is not evenly distributed across the genome II TISMWG (2001) Chromosome 6 HLA There are fluctuations in the level of variation across the genome 19 Diversity is not evenly distributed across genes I Purifying selection eliminates deleterious mutations and reduces diversity in regions of strong functional constraint Zhao et al (2003) 20 Diversity is not evenly distributed across genes II Adaptive evolution wipes out diversity nearby due to the hitch-hiking effects of a selective sweep e.g. Duffy-null locus in sub-Saharn africa, protects against P. vivax Pop1 Pop2 European African FY*O mutation Ancestral allele Derived allele Missing dataHamblin and Di Rienzo (2000) 21 Diversity is not evenly distributed across genes III Some genes are under balancing or diversifying selection, where diversity is actively selected for MHC complex: heterozygote advantage and frequency-dependent selection driven by recognition of pathogens Horton et al (1998) 22 Diversity is not evenly distributed across populations I African populations are more diverse than non-African populations More polymorphisms Polymorphisms at less skewed frequencies Differences reflect bottlenecks associated with the colonisation from Africa c.65 KYA Popul ation Segregati ng sites per kb (n = 30) Diversit y per kb Tajima D statistic Haus a (Afric an) 4.80.11-0.33 Italian8 Chine se 3.00.071.19 Frisse et al (2001) 23 mtDNA phylogeography Ingman et al (2000) African Non-African 24 The colonisation process as inferred from mtDNA variation 25 What does genetic variation tell us about human evolution? Modern humans appear in the fossil record about 200K years ago The mitochondrial Eve dates back to about 150K years ago The Y-chromosome Adam dates back to about 70K years ago For most of our genome, however, the common ancestor is about 500K 1M years ago This predates the origin of Homo sapiens considerably 26 Human chimp split Autosomal MRCA Origin of H. sapiens 27 Did early humans interbreed with Neanderthals? Ovchinnikov et al (2000) Neanderthals mtDNA sequences say no 28 But There is some evidence for this in the presence of unusual haplotypes found in Europe composed of SNPs not found in non-European populations Plagnol and Wall (2006) 29 Deeper trees in the human genome There is growing evidence that some regions of our genome have truly ancient common ancestors Dystrophin has an ancient haplotype found primarily outside Africa suggesting a colonisation of 160KYA There is an inversion found primarily in Europeans that is roughly 3MY old Stefansson et al (2005) Haplotype 1 Haplotype 2 30 What are the genetic differences that make us human? 31 Chromosomal changes Human chromosome 2 is a fusion of two chromosomes in great apes There are several inversion differences between the chromosomes Feuk et al (2005) 32 Gene loss Loss of enzymes that make sialic acid Sugar on cell surface that mediates a variety of recognition events involving pathogenic microbes and toxins Myosin heavy chain Associated with gracilization Wang et al (2006) 33 Gene evolution FOXP2 is a highly conserved gene (across the mammalia), expressed in the brain. Mutations in the gene in humans are associated with specific language impairment Across the entire mammalian phylogeny, there have only been a very few amino acid changing substitutions However, two amino acid changes have become fixed in the lineage leading to modern humans since the split with the chimpanzee lineage Enard et al. (2002) 34 What are the genetic differences that make people and peoples different? 35 Detecting recent adaptive evolution Lets look closely at the dynamics of the fixation process for adaptive mutations The fixation of a beneficial mutation is associated with a change in the patterns of linked neutral genetic variation This is known as the hitch-hiking effect (Maynard Smith and Haigh 1974) Looking for the signature of hitch-hiking can be a good way of detecting very recent fixation events 36 Long haplotypes A selective sweep at the Lactase gene in Europeans 37 Strong population differentiation Lamason et al (Science 2005) SLC24A5 38 39 Classes of selected genes Voight et al. (2005) 40 Reading Human genetic variation Rosenberg et al. Genetic structure of human populations. Science 2002, 29