HC70A & SAS70A Winter 2009 Genetic Engineering in Medicine, Agriculture, and Law Professors Bob Goldberg & John Harada Lecture 6 Identifying Human Origins: Past and Present Course AdministratorpTHEMES 1. DNA Sequence Variation - A Review 2. What is a Haplotype? 3. How Will the HapMap Project Provide Insight Into Human Genetic Variability and Disease? 4. How Can Haplotypes Be Used To Trace Human Ancestry? 5. What is the Conceptual Basis of Using Markers To Trace Human Origins and Ancestry? 6. How Can Mt-DNA, Y-Chromosomes, & Whole Genome Comparisons Be used to Trace Human Origins? 7. Where Have We Come From and How Are Human Groups Related to Each Other? 8. Are There Races?Human Gene Variation is What Makes Us Individuals It Can Be Used to Trace Our Origins & Ancestry in Addition to Profiling the Presence of Alleles That Make Us Susceptible to Disease That is - Who We Are & Where We Come From!!Scientific American Library 1982 ISBN 07167-14698International HapMap Project 1. Discover Genetic Variants Associated with Disease & Individual Responses to Therapeutic Agents (Pharmacogenetics) 2. New Medical Treatments 3. Structure of Human Populations or Ancestry! The 0.1% Thatʼs Different Between Individuals!International HapMap Groups “Group” Genetic Diversity to Disease + Other Aspects of Biology 1. Northern European 2. Western European 3. Yoruba/ Nigerian/ Africa 4. Japanese & Han Chinese/ AsianThe 1,000 Genomes Project Will Provide Complement and Extend The HapMap Project Sequence Two Human Genomes Every 24 hrs !Haplotypes or SNPs on a Chromosome Inherited as a Unit 1. There Are Millions Of SNPs That Differ Among Individuals… 2. But a Small Few Reflect Our Ancestry & “Travel” in Groups on Chromosomes - Are Linked & May Show Specific Group (and Gene) Linkages! 3. These Are Called Haplotypes! Four Haplotypes! Detected By DNA Chips And/or Whole Genome DNA SequencingClosely-Linked SNPs Are Inherited as a Unit and Are Called Haplotypes No Crossing Over <5Kb ∴ Haplotype or Complex Polymorphic Locus Inherited as a Unit Haplotype AB vs. abHaplotypes Are Markers That Can Be Associated With Diseases &/or Groups of Individuals The 0.1% Thatʼs Different Between Individuals! The HapMap Catalogs Common Genetic Variants In Human Beings To Make Haplotype Identification Simpler! Tag SNA Diagnostic SNPs for Each Haplotype SNPs That Vary Across 6,000 bpSNPs Are Markers Specific Chromosomal RegionAssociate Diseases With Specific Groups and Understand How We Are Related To Each Other and Where We Come FromAssociation Studies Correlate Diseases With Specific Haplotypes (SNPs) 1. Provide Disease Genetic Markers 2. If Close Linkage- Lead to Gene Identity Population StudiesDNA Chips Can Detect SNP Genotypes (Or Haplotypes) Across An Individuals Genome This Can Then Be Correlated With Diseases &/or Geographical AssociationsWhole Genome SNP Chips & Personal DNA Sequencing Can Trace Our Ancestry Most Haplotypes Found In All Human Populations- Some May Be Unique To A Population &/or be Represented At Higher Frequency In A PopulationTracing Human Populations Using DNA PolymorphismsVariation in Both the Mitochondrial and Nuclear Genomes Can be Used to Trace Ancestry • MtDNA For Maternal Lineages • Y-Chromosomes For Paternal LineagesOldest Populations Contain the Most Diversity Oldest Population Newest Population Time Lots of “Old” Variants Subset of “Old” Variants + New Variants Detected By Using Specific Markers or SNPSMost Genetic Diversity Originated in the Founder Populations to Modern Humans!THE DISPERSAL OF MODERN HUMAN POPULATIONS Adapted from S. B. Hedges, Nature 408 (2000): 652-653.Tracing Human Populations Using Y-Chromosome SNPs “Adam”Origins of Human Populations From DNA Sequence Comparisons Adam & EveHuman Population Relationships Using Whole-Genome Comparisons Most Genetic Diversity In African PopulationsPhylogenetic Tree of Human Populations Using Mt-DNA Adapted from M. Ingman,et al.,Nature 408 (2000):708-713. “Eve” Most Diversity In African PopulationsJ. Novembre et al. Nature November 6, 2008 SNPs Can Be Used To Distinguish Between “Local” Populations!!!!!Summary Mt-DNA, Y-Chromosome, and Whole-Genome Comparisons All Trace Human Origins Back to Africa 100,000-200,000 Years AgoAre There Human Races? a. Yes b. NoHuman Races Have a Genetic Basis: a. Yes b. NoAre There Human “Races?” What is the Biology & the History?Only a Few Genes Affect Skin Color!How About Using Other “Simple” Traits to Classify Humans Into “Races?”Race is Primarily a Sociological Concept That Has Caused Much Human Suffering Based on a Very Few Genes That Vary Between Groups Far More Than Majority-Vast, Vast Majority of Other Genes Donʼt Vary Between Groups 1. Most Variation shared 2. Differences due to Migration & Geographic Isolation 3. Most Variation Shared by groups!Scientific American Library 1982 ISBN 07167-14698Similarity and Differences in Blood Group Allele Frequencies by “Race” or Population How Does Genetic Variation (different alleles) Differ Between & Within Populations? 1. Most alleles in All “races”/ populations 2. No Homozygousity at any locus 3. Some allelic frequencies differ between “races” + some are the same! e.g., Duffy differs + Xg is the same. Why? Adaptive Value. 4. Auberger, Xg, + Secretor Loci show how alleles vary within populations similarly + show NO between population differences. 5. Wide range of different alleles within/between “races”There is a Large Variation in D1580 VNTR Alleles Within Populations but Little Between Just as Predicted From Class Genotypes VNTR Used for HC70A DNA Fingerprint No Adaptive Value !! Good Locus For Forensics- Group Neutral!HC70A/SAS70A Winter 2009 Class DNA Fingerprints What Do You Notice About Most Individualʼs DIS80 Genotypes? Thanks to Min Chen & Chen ChengReasons for Allelic Variation Between Populations 1. Founder Effect/Geographical Isolation Selective Mating due to Geography/ Culture or Both. 2. Adaptive Value Have Positive Effect in Specific Environments e.g., Hbs Sickle Cell Globin Allele (India, Africa, Mediterranean) Duffy Alleles Skin Color Genes Geographical &/or Adaptive Value But Do Not Vary Across Whole Genomes As Most Loci Are “Neutral”Adaptive Value of the Hbs Allele Protection Against MalariaThere is More Genetic Diversity Within Populations than Between