Genetic Engineering in Medicine, Agriculture, and Law 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 Administratorp

THEMES DNA Sequence Variation - A Review What is a Haplotype? How Will the HapMap Project Provide Insight Into Human Genetic Variability and Disease? How Can Haplotypes Be Used To Trace Human Ancestry? What is the Conceptual Basis of Using Markers To Trace Human Origins and Ancestry? How Can Mt-DNA, Y-Chromosomes, & Whole Genome Comparisons Be used to Trace Human Origins? Where Have We Come From and How Are Human Groups Related to Each Other? 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 07167-14698

International HapMap Project The 0.1% That’s Different Between Individuals! Discover Genetic Variants Associated with Disease & Individual Responses to Therapeutic Agents (Pharmacogenetics) New Medical Treatments Structure of Human Populations or Ancestry!

International HapMap Groups 1. Northern European 2. Western European 3. Yoruba/ Nigerian/ Africa 4. Japanese & Han Chinese/ Asian “Group” Genetic Diversity to Disease + Other Aspects of Biology

Sequence Two Human Genomes Every 24 hrs ! The 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 There Are Millions Of SNPs That Differ Among Individuals… But a Small Few Reflect Our Ancestry & “Travel” in Groups on Chromosomes - Are Linked & May Show Specific Group (and Gene) Linkages! These Are Called Haplotypes! Detected By DNA Chips And/or Whole Genome DNA Sequencing Four Haplotypes!

Closely-Linked SNPs Are Inherited as a Unit and Are Called Haplotypes  Haplotype or Complex Polymorphic Locus Inherited as a Unit No Crossing Over <5Kb Haplotype AB vs. ab

Haplotypes Are Markers That Can Be Associated With Diseases &/or Groups of Individuals SNPs That Vary Across 6,000 bp Diagnostic SNPs for Each Haplotype To Make Haplotype Identification Simpler! Tag SNA The 0.1% That’s Different Between Individuals! The HapMap Catalogs Common Genetic Variants In Human Beings

Specific Chromosomal Region SNPs Are Markers

Associate Diseases With Specific Groups and Understand How We Are Related To Each Other and Where We Come From

Association Studies Correlate Diseases With Specific Haplotypes (SNPs) Provide Disease Genetic Markers If Close Linkage- Lead to Gene Identity Population Studies

DNA Chips Can Detect SNP Genotypes (Or Haplotypes) Across An Individuals Genome This Can Then Be Correlated With Diseases &/or Geographical Associations

Whole 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 Population

Tracing Human Populations Using DNA Polymorphisms

MtDNA For Maternal Lineages Y-Chromosomes For Paternal Lineages Variation in Both the Mitochondrial and Nuclear Genomes Can be Used to Trace Ancestry MtDNA For Maternal Lineages Y-Chromosomes For Paternal Lineages

Oldest Populations Contain the Most Diversity Time Detected By Using Specific Markers or SNPS Subset of “Old” Variants + New Variants Newest Population Lots of “Old” Variants Oldest Population

Most 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 & Eve

Most Genetic Diversity In African Populations Human Population Relationships Using Whole-Genome Comparisons Most Genetic Diversity In African Populations

Phylogenetic Tree of Human Populations Using In African Populations Mt-DNA “Eve” Most Diversity In African Populations Adapted from M. Ingman,et al.,Nature 408 (2000):708-713.

J. Novembre et al. Nature November 6, 2008 SNPs Can Be Used To Distinguish Between “Local” Populations!!!!! J. Novembre et al. Nature November 6, 2008

Summary Mt-DNA, Y-Chromosome, and Whole-Genome Comparisons All Trace Human Origins Back to Africa 100,000-200,000 Years Ago

Are There Human Races? Yes No

Human Races Have a Genetic Basis: Yes No

Are 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 Most Variation shared Differences due to Migration & Geographic Isolation Most Variation Shared by groups! Based on a Very Few Genes That Vary Between Groups Far More Than Majority-Vast, Vast Majority of Other Genes Don’t Vary Between Groups

Scientific American Library 1982 ISBN 07167-14698

Similarity and Differences in Blood Group Allele Frequencies by “Race” or Population How Does Genetic Variation (different alleles) Differ Between & Within Populations? 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!

Class DNA Fingerprints HC70A/SAS70A Winter 2009 Class DNA Fingerprints What Do You Notice About Most Individual’s DIS80 Genotypes? Thanks to Min Chen & Chen Cheng

Reasons 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 Malaria

More Genetic Diversity Within Any Population Than Between Polulations There is More Genetic Diversity Within Populations than Between Populations!! So Much for the Concept of racial “purity”!!!! More Genetic Diversity Within Any Population Than Between Polulations 1. 85% of Human Genetic Variations Occurs within Populations & Between Individuals in that Populations! 2. Remaining 15% of Human Genetic Variation Split Between Different Populations of Same “race” (8%) & Between Different “races” (6%) 3. Only 6% of Human Genetic Variation are to Differences between races!!! Mostly Geographic

Within Population Differences Account For 95% of Human Genetic Variation But - There Are Differences!

Variation That Occurs in Ancestral Population Conclusions If 85% of Human Genetic Variation Occurs Between Different People Within Any Gven Population (localized) If only 7% of Human Genetic Variation Occurs Between “Races” (novel alleles specific to “races”) e.g. FyB ES Then Losing all “Races” Except One Retains 94% of all Human Genetic Variation! [85% + (15%-7%) ]= 94% Variation That Occurs in Ancestral Population 85% Within Population genetic variability 8% between populations of same “race” 7% between “race” genetic variability  Human Highly Heterozygous or Hybrids- & If Above Not True- Most of Us Would Not Be Here- Need Genetic Variation to Survive!

So What is a “race”? Primarily a sociological concept- but could be a localized or inbred population that has a higher frequency of alleles at a very small number of loci. Affects few physical features. High frequency alleles in one “race” are present at lower frequencies in other “races”. All humans have same genes- differ in form mostly within populations! Heterozygosity (variation) high in human populations- all populations. None homozygous at all loci! No such thing as a “pure” race - would have little variation Genes affecting physical features not representation of genes across genome- Geographical Ancestry is relevant-many “racial” groups now have multiple ancestries because of admixture and migration

How Did We Get to Where We Are? Inventor of Modern “Racial” Classification Gave Caucasian Name Johan Freidrich Blumenbach

John Freidrich Blumenbach Changed Linnean Neutral- geography-based Human classification to a value-based classification Said all “races” originated from one place/origin - in Europe around Mt.Caucasus- because they are the most “beautiful” race- even though the all races were equal in all respects + argued with people that didn’t! Classified five “races” - Caucasian Mongolian Ethiopian American Malay Value-based Classification + putting Caucasians on top- most beautiful- had disastrous consequences!

Conclude………….. Races are arbitrary entities- social construct that are culturally generated Yes- there is genetic differences between “races” or relatively inbred geographical populations that can lead to physical + other differences - due to very small # genes + not reflective of whole genome Within population genetic variation much greater than between population genetic variation- many loci have same allele frequencies- some differ Only minor differences between genomes of different people or groups of people- unity >>>Differences! We are all the same- but different. You now know why! But…..There Can Be Differences Between “Races” or Geographical Groups That Make Them More Susceptible to Specific Diseases Able To Use or Not Use Certain Therapeutic Agents (Drugs). We Will Learn These facts From Studying the Genomes of Groups of People, but The Information Must be Considered Carefully and Critically! Race Classifications Arbitrary, Unscientific, & Divisive