The Human Genome and Human Advancement.

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The Human Genome and Human Advancement Chris Tyler-Smith The Wellcome Trust Sanger Organization Plot Data from fossils and antiquarianism Unbiased (or thought to-be-nonpartisan) hereditary markers Established markers Y chromosome Demographic changes Qualities under determination Adjusting choice
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The Human Genome and Human Evolution Chris Tyler-Smith The Wellcome Trust Sanger Institute

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Outline Information from fossils and paleontology Neutral (or thought to-be-unbiased) hereditary markers Classical markers Y chromosome Demographic changes Genes under choice Balancing determination Positive choice

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Who are our nearest living relatives? Chen FC & Li WH (2001) Am. J. Murmur. Genet. 68 444-456

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Phenotypic contrasts in the middle of people and different gorillas Carroll (2003) Nature 422 , 849-857

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Chimpanzee-human disparity 6-8 million years Hominids or hominins Chimpanzees Humans

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Origins of primates Sahelanthropus tchadensis Chad (Central Africa) Dated to 6 – 7 million years prior Posture questionable, yet marginally later primates were bipedal ‘Toumai’, Chad, 6-7 MYA Brunet et al. (2002) Nature 418 , 145-151

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Hominid fossil outline Found just in Africa Found both in Africa and outside, or just outside Africa

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Origins of the family Homo erectus/ergaster ~1.9 million years prior in Africa Use of stone apparatuses H. erectus in Java ~1.8 million years prior Nariokatome kid, Kenya, ~1.6 MYA

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Additional movements out of Africa First known Europeans date to ~800 KYA Ascribed to H. heidelbergensis Atapueca 5, Spain, ~300 KYA

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Origins of current people (1) Anatomically present day people in Africa ~130 KYA In Israel by ~90 KYA Not colossally fruitful Omo I, Ethiopia, ~130 KYA

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Origins of cutting edge people (2) Modern human conduct begins to create in Africa after ~80 KYA By ~50 KYA, elements, for example, complex apparatuses and long-separation exchanging are set up in Africa The first craftsmanship? Engraved ochre, South Africa, ~77 KYA

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Expansions of completely cutting edge people Two extensions: Middle Stone Age innovation in Australia ~50 KYA Upper Paleolithic innovation in Israel ~47 KYA Lake Mungo 3, Australia, ~40 KYA

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Routes of relocation? archeological proof Upper Paleolithic ~130 KYA Middle Stone Age

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Strengths and shortcomings of the fossil/archeological records Major wellspring of data for more often than not period Only hotspot for wiped out species Dates can be dependable and exact need suitable material, C adjustment needed Did they leave relatives? 14

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Mixing or substitution?

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Human hereditary differences is low

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Human hereditary assorted qualities is equally appropriated Most variety between populaces Most variety inside of populaces Templeton (1999) Am. J. Anthropol. 100 , 632-650

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Phylogenetic trees usually show a late starting point in Africa Y chromosome

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Modern human mtDNA is unmistakable from Neanderthal mtDNA Krings et al . (1997) Cell 90 , 19-30

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Classical marker studies Based on 120 protein-coding qualities in 1,915 populaces Cavalli-Sforza & Feldman (2003) Nature Genet. 33 , 266-275

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Phylogeographic studies Analysis of the land disseminations of genealogies inside of a phylogeny Nodes or transformations inside of the phylogeny may be dated Extensive investigations of mtDNA and the Y chromosome

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Y haplogroup circulation Jobling & Tyler-Smith (2003) Nature Rev. Genet. 4 , 598-612

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An African inception

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SE Y haplogroups

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NW Y haplogroups

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Did both movements leave relatives? General SE/NW hereditary qualification fits two-movement model Basic hereditary example built up by starting colonization All people outside Africa offer same subset of African differences (e.g. Y: M168, mtDNA: L3) Large-scale substitution, or relocations were not free How much consequent change?

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Fluctuations in atmosphere Ice ages Antarctic ice center information Greenland ice center information

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Possible purposes behind hereditary change Adaptation to new situations Food creation – new eating methodologies Population increment – new infections

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Debate about the Paleolithic-Neolithic move Major changes in nourishment generation, way of life, innovation, populace thickness Were these for the most part because of development of individuals or development of thoughts? Solid spotlight on Europe

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Estimates of the Neolithic Y commitment in Europe ~22% (=Eu4, 9, 10, 11); Semino et al . (2000) Science 290 , 1155-1159 >70% (expecting Basques = Paleolithic and Turks/Lebanese/Syrians = Neolithic populaces); Chikhi et al. (2002) Proc. Natl. Acad. Sci. USA 99 , 11008-11013

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More late reshaping of assorted qualities ‘Star cluster’ Y haplotype began in/close Mongolia ~1,000 (700-1,300) years prior Now conveyed by ~8% of men in Central/East Asia, ~0.5% of men overall Suggested relationship with Genghis Khan Zerjal et al. (2003) Am. J. Murmur. Genet . 72 , 717-721

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Is the Y an unbiased marker? Intermittent fractional erasures of a locale needed for spermatogenesis Possible negative determination on various (14/43) genealogies Repping et al . (2003) Nature Genet . 35 , 247-251

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Demographic changes Population has extended in extent and numbers Genetic effect, e.g. overwhelmingly negative estimations of Tajima’s D Most information not predictable with straightforward models e.g. consistent size took after by exponential development

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Selection in the human genome time Negative (Purifying, Background) Positive (Directional) Neutral Balancing Bamshad & Wooding (2003) Nature Rev. Genet. 4 , 99-111

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The Prion protein quality and human malady Prion protein quality PRNP connected to ‘protein-only’ infections e.g. CJD, kuru A typical polymorphism, M129V, impacts the course of these maladies: the MV heterozygous genotype is defensive Kuru procured from custom human flesh consumption was accounted for (1950s) in the Fore individuals of Papua New Guinea, where it brought on up to 1% yearly mortality Departure from Hardy-Weinberg harmony for the M129V polymorphism is found in Fore ladies more than 50 (23/30 heterozygotes, P = 0.01)

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Non-nonpartisan advancement at PRNP McDonald-Kreitman test Resequence coding district in ? people and primates N S Diversity 5 1 Divergence (Gibbon) 2 13 P - esteem = 0.0055 Mead et al. (2003) Science 300 , 640-643 ‘coding’ ‘non-coding’

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Observed Expected Balancing choice at PRNP Excess of middle of the road recurrence SNPs: e.g. Tajima’s D = +2.98 (Fore), +3.80 (CEPH families) Deep division between the M and V ancestries, assessed at 500,000 years (utilizing 5 MY chimp-human split) 24 SNPs in 4.7 kb district, 95 haplotypes

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Effect of positive determination Neutral Selection Derived allele of SNP

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What changes do we anticipate? New qualities Changes in amino-corrosive grouping Changes in quality expression (e.g. level, timing or area) Changes in duplicate number

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How would we discover such changes? Chance φ hHaA sort I hair keratin quality inactivation in people Identify phenotypic changes, examine hereditary premise Identify hereditary changes, research utilitarian outcomes

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Inheritance of a dialect/discourse deformity in the KE family Autosomal predominant legacy design Lai et al . (2000) Am. J. Murmur. Genet . 67 , 357-367

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Mutation and development of the FOXP2 quality Chr 7 7q31 Nucleotide substitutions FOXP2 quality noiseless substitution Enard et al . (2002) Nature 418 , 869-872

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Positive determination at the FOXP2 quality Resequence ~14 kb of DNA contiguous the amino-corrosive changes in 20 various people, two chimpanzees and one orang-utan No lessening in differences Excess of low-recurrence alleles (Tajima’s D = - 2.20) Excess of high-recurrence inferred alleles (Fay & Wu’s H =-12.24) Simulations recommend a specific compass at (0 – 200,000) years Constant rate of amino-corrosive substitutions? Positive choice in people? substitution (non-synonymous) d N quiet (synonymous) d S Orang Gorilla Chimp Human-particular increment in d N/d S proportion (P<0.001) Enard et al . (2002) Nature 418 , 869-872

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A quality influencing mind measure Microcephaly (MCPH) Small (~430 cc v ~1,400 cc) however generally ~normal cerebrum, just gentle mental hindrance MCPH5 demonstrates Mendelian autosomal latent legacy Due to loss of action of the ASMP quality ASPM-/ASPM-control Bond et al. (2002) Nature Genet . 32 , 316-320

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Evolution of the ASPM quality (1) Summary d N/d S qualities Sliding-window d N/d S examination 0.62 0.52 0.53 1.44 0.56 Orang Gorilla Chimp Human-particular increment in d N/d S proportion (P<0.03) Evans et al. (2004) Hum. Mol. Genet. 13 , 489-494

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Evolution of the ASPM quality (2) McDonald-Kreitman test Sequence ASPM coding locale from 40 differing people and one chimpanzee N S Diversity 6 10 Divergence 19 7 P - esteem = 0.025 Evans et al. (2004) Hum. Mol. Genet. 13 , 489-494

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asp Microtubules DNA do Carmo Avides and Glover (1999) Science 283 , 1773-1735 What changes? FOXP2 is an individual from an extensive group of interpretation elements and could in this manner impact the declaration of a wide mixed bag of qualities The Drosophila homolog of ASPM codes for a microtubule-tying protein that impacts axle introduction and the quantity of neurons Subtle changes to the capacity of very much monitored qualities

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broad quest for protein arrangement advancement 7645 human-chimp-mouse quality trios analyzed Most noteworthy classifications indicating positive determination include: Olfaction: feeling of smell Amino-corrosive digestion system: diet Development: e.g. skeletal Hearing: for discourse observation Clark et al. (2003) Science 302 , 1960-1963

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Increased expression Decreased expression Gene expression contrasts in human and chimpanzee cerebral cortex Affymetrix oligonuclotide cluster (~10,000) qualities 91 show human-particular

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