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Human Polymorphisms and Genetic Anthropology Prof. Connie J. Mulligan Department of Anthropology September 20, 2012 C. Mulligan, Copyright 2011 All rights reserved Molecular genetics • Genetics is the study of heredity and variation of organisms – Classical, Mendelian genetics traces the inheritance of particular traits, or phenotypes • Molecular genetics is the study of heredity and variation using molecules, such as DNA Human karyotype – Traces the inheritance of genes or genetic variants C. Mulligan, Copyright 2011 All rights reserved A little terminology • A gene is a piece of DNA that is responsible for the inheritance of a specific characteristic – eye color – ability to process lactate (drink milk) • Gene protein Human chromosomes, Genetics, HartlC.and Jones, 2000 Mulligan, Copyright 2011 All rights reserved A little terminology • A gene is a piece of DNA that is responsible for the inheritance of a specific characteristic – eye color – ability to process lactate (drink milk) • Gene protein – Coding = genes (~3%) – Non-coding (~97%) Human chromosomes, Genetics, Hartl C. and Jones, 2000 Mulligan, Copyright 2011 All rights reserved DNA = Deoxyribonucleic acid • DNA is represented as a sequence of letters (nucleotide bases) – – – – – Adenosine = A Guanine = G Cytosine = C Thymine = T A-T and G-C pairs TGTG • DNA is a blueprint to direct the synthesis of proteins Genetics, 2001, Hartl and Jones, Jones C. Mulligan, Copyright 2011 and Bartlett Publishers, Inc All rights reserved Genetic variants are changes in DNA sequence between individuals (A C-to-T variant is depicted in the DNA sequence below) C. Mulligan, Copyright 2011 All rights reserved Terminology • • • • • • • Genetic variant Genetic marker Mutation Polymorphism SNP (single nucleotide polymorphism) Biallelic marker All of these terms are used to refer to genetic differences between individuals or populations C. Mulligan, Copyright 2011 All rights reserved A little more terminology • Phenotype – Physical characteristics of an individual • Genotype – An individual’s DNA sequence or set of genetic markers • An individual’s genotype is responsible for an individual’s phenotype C. Mulligan, Copyright 2011 All rights reserved How do you interpret a genetic variant? • What does a C-to-T change mean? • Smarter, prettier, faster, stronger??? – No, just different • Most variants are neutral = no effect – Genes make up only ~3% of genome and genes make our phenotype C. Mulligan, Copyright 2011 All rights reserved Genetic anthropology Types of studies Peopling of the Americas Expansion out of Africa • Population history – Origins – Relationships • Populat’n movements – Migrations/colonization – Fission/fusion • Ancient DNA – Link ancestral and descendant pops Domestication of the donkey Modified from Balaresque et al. 2007 Origin and expansion of Semitic speakers • Disease – Origin of disease – Genetic basis of disease Genetic and cultural C. Mulligan, Copyright 2011 components to ethnicity and health All rights reserved How do we interpret genetic variants to ask anthropological questions? • Look at the patterns of genetic variation • What has created the patterns of genetic variation? – Evolutionary history of humans Shriver and Kittles, 2004 C. Mulligan, Copyright 2011 All rights reserved ~ 200 kya Slides by C. Ryan Mulligan, Copyright 2011 Raaum All rights reserved 100-200 kya C. Mulligan, Copyright 2011 All rights reserved by 80 kya C. Mulligan, Copyright 2011 All rights reserved ~ 60 kya C. Mulligan, Copyright 2011 All rights reserved 45-60 kya C. Mulligan, Copyright 2011 All rights reserved by 45 kya C. Mulligan, Copyright 2011 All rights reserved 40-50 kya C. Mulligan, Copyright 2011 All rights reserved ~ 35 kya Thanks, Ryan C. Mulligan, Copyright 2011 All rights reserved Human evolution encompasses both demographic history and adaptation • Demographic history • Adaptation – Neutral markers • Not subject to natural selection – Non-coding, ~97% • Origin of anatomically modern humans • Neanderthal genetics – Non-neutral markers • Subject to natural selection – Genes, ~3% genome • Skin color, eye color, facial morphology, race C. Mulligan, Copyright 2011 All rights reserved Genetic evidence for the origin of modern humans • H. sapiens are characterized by very little genetic variation relative to other primates – What does this suggest? Jobling et al. 2003 C. Mulligan, Copyright 2011 All rights reserved Genetic evidence for the origin of modern humans • H. sapiens are characterized by very little genetic variation relative to other primates – What does this suggest? • Relatively recent evolution • Selection • Or, more recent research suggests it might relate to generation time – Longer generation time in humans → fewer opportunities for germ line mutations → slower mutation rate → less variation/shallower time depth – Mutation rate follows generation time • Humans < chimps • hominoids < Old World monkeys • Old World monkeys < marmosets C. Mulligan, Copyright 2011 All rights reserved Genetic evidence for the origin of modern humans • Greatest genetic diversity is in African populations – Consistent w/ out-of-Africa theory of human origin • Most genetic variation in humans is within populations, not between populations – ~85% w/i pops – ~5% b/t pops on same continent – ~10% b/t pops on different continents, i.e. races C. Mulligan, Copyright 2011 All rights reserved Types of DNA • Mitochondrial (mtDNA) – no recombination – high copy number (but haploid) – maternal inheritance – high mutation rate – studied first – large comprehensive database Holland & Huffine 2001 • Nuclear DNA (nDNA = autosomes + sex chromosomes) – – – – – – homologous recombination single genome/diploid cell biparental inheritance variable mutation rate studied more recently multiple studied loci make comparisons more difficult C. Mulligan, Copyright 2011 All rights reserved Mitochondrial Eve - the mother of us all • What is the mitochondrial Eve theory? C. Mulligan, Copyright 2011 All rights reserved Mitochondrial Eve - the mother of us all • What is the mitochondrial Eve theory? – The idea that we all trace back to a single woman • How can this be? C. Mulligan, Copyright 2011 All rights reserved Mitochondrial Eve - the mother of us all • What is the mitochondrial Eve theory? – The idea that we all trace back to a single woman • How can this be? – B/c mitochondrial DNA does not recombine – We have infinite nuclear ancestors b/c nuclear DNA does recombine C. Mulligan, Copyright 2011 All rights reserved If we can all trace our maternal lineage back to a single women, then why don’t we all have the same mtDNA? C. Mulligan, Copyright 2011 All rights reserved If we can all trace our maternal lineage back to a single women, then why don’t we all have the same mtDNA? • MUTATION! C. Mulligan, Copyright 2011 All rights reserved Race C. Mulligan, Copyright 2011 All rights reserved Genetics and Race • What can biology/genetics tell us about race? • What can biology/genetics tell us about ourselves? C. Mulligan, Copyright 2011 All rights reserved What can genetics tell us about race? • There is no genetic or biological definition for what we refer to as ‘race’ in humans • There is no Caucasian gene, no African gene, no Asian gene • Is there one gene that distinguishes one race from another? No. C. Mulligan, Copyright 2011 All rights reserved Human evolution and genetic variation • Anatomically modern humans have been evolving for over 200,000 years and we are still evolving • There are no ‘pure’ human stocks and there never were • No populations are more highly evolved than others • Human populations are too closely related to be considered subspecies • There is a continuum of genetic variation across the globe C. Mulligan, Copyright 2011 All rights reserved What genes do we have? • We have genes for: – – – – ATP/energy production DNA repair Metabolic pathways … • No one has ever identified a gene for: – – – – – – Intelligence Athleticism Musical ability Language ability Work ethic Personality C. Mulligan, Copyright 2011 All rights reserved How do you interpret a genetic variant? • What does a C-to-T change mean? • Smarter, prettier, faster, stronger??? – No, just different • Most variants are neutral = no effect – Genes make up ~2% of genome C. Mulligan, Copyright 2011 All rights reserved But there are different frequencies of alleles in different populations • Alleles differ in frequency between people and populations, genes don’t differ in frequency – Gene – DNA sequence that encodes a protein – Allele – one of several alternative forms of a DNA sequence (can be coding or non-coding) Human chromosomes, Genetics, Hartl and Jones, 2000 Mulligan, Copyright 2011 Types of alleles, Genetics, C. Hartl and Jones, 2000 All rights reserved But differences in allele frequencies doesn’t mean populations fall into racial categories • Most genetic variation among humans occurs within populations, not between them • Variation in gene frequency is distributed continuously, or clinally, in response to selection or genetic drift C. Mulligan, Copyright 2011 All rights reserved Most genetic variation among humans occurs within populations, not between them Total Species (100%) Between Regional Populations (10%) Within Regional Populations (90%) Between Local Populations Within Regional Populations (5%) Between Individuals Within Local Populations (85%) C. Mulligan, Copyright 2011 All rights reserved But differences in allele frequencies doesn’t mean populations fall into racial categories • Most genetic variation among humans occurs within populations, not between them • Variation in gene frequency is distributed continuously, or clinally C. Mulligan, Copyright 2011 All rights reserved Variation in skin color in 22 populations C. Mulligan, Copyright 2011 All rights reserved • Bad sampling (A) can give the illusion of clusters, but good sampling (B) shows a cline in frequencies Serre, D., and S. Paabo. 2004. Genome Research 14:1679-1685. C. Mulligan, Copyright 2011 All rights reserved But we look different! • We can see differences between people – e.g. dark-skinned, light hair, etc • But, only a few genes (out of ~20,000) determine skin color, hair color, etc. so it doesn’t take many variants to make us look different – The differences are literally only ‘skin deep’ – Skin color is controlled by levels of melanin – Three main genes for melanin production C. Mulligan, Copyright 2011 All rights reserved What can genetics tell us about ourselves? • For a fee, lots of companies will tell you something about your ancestors based on a DNA sample – National Genographic, DNA Ancestry Project, DNA Tribes, Ancestral Origins • https://www.gtldna.net/ancestral-origins-dnaancestry.html?src=google&gclid=CMaqk6jzv58CFQmdnAodO Tr0zw C. Mulligan, Copyright 2011 All rights reserved Neanderthal (+ other archaics) genetics C. Mulligan, Copyright 2011 All rights reserved First publication of DNA sequences from a Neanderthal • Sequence data from Neanderthal type specimen, found in Neander Valley, Germany in late 1800s – Krings et al. 1997 – mtDNA HVRI sequence – Krings et al. 1999 – mtDNA HVRII sequence Holland & Huffine 2001 C. Mulligan, Copyright 2011 All rights reserved Neanderthal genetics What is the evidence against interbreeding between Neanderthals and modern humans? Jobling et al. 2003 C. Mulligan, Copyright 2011 All rights reserved Neanderthal genetics Jobling et al. 2003 • Mitochondrial DNA data show that the majority of Neanderthal genetic variation lays outside modern human genetic variation C. Mulligan, Copyright 2011 All rights reserved Jobling et al. 2003 Neanderthal genetics • Mitochondrial DNA data show that the majority of Neanderthal genetic variation lays outside modern human genetic variation • Phylogenies show Neanderthal as an outgroup Noonan 2010 C. Mulligan, Copyright 2011 All rights reserved Jobling et al. 2003 Neanderthal genetics • Mitochondrial DNA data show that the majority of Neanderthal genetic variation lays outside modern human genetic variation • Phylogenies show Neanderthal as an outgroup • MRCA b/t Neanderthal and humans is 4x older than MRCA of humans Noonan 2010 C. Mulligan, Copyright 2011 All rights reserved Jobling et al. 2003 Neanderthal genetics • Means that Neanderthal mtDNA gene pool evolved for a long time, isolated from humans, and there is no support for a Neanderthal contribution to modern human mtDNA Noonan 2010 C. Mulligan, Copyright 2011 All rights reserved What about nuclear DNA? Represents 3 billion bases, not 16 thousand • Green et al. (2010) published draft nuclear genome sequences of 3 Neanderthals – Posits 1-4% Neanderthal admixture in Europeans and Asians – Since it occurred in both Europeans and Asians, likely to have occurred before those groups split, i.e. ~50-80 kya – No Neanderthal DNA in Africans – Expected difference between mitochondrial and nuclear DNA C. Mulligan, Copyright 2011 All rights reserved Denisova • In 2008, a hominin bone fragment was discovered in the Denisova cave in southern Siberia’s Altai mountains – Child’s finger bone scattered among stone tools and bone implements in layer dated to 48-30 kya • It was believed that modern humans and Neanderthals were the only hominins present there at the time C. Mulligan, Copyright 2011 All rights reserved Phylogenetic analysis • Denisova mtDNA lineage branches much earlier than human and Neanderthal lineages – Most recent common ancestor (MRCA) between humans and Denisovans is ~1mya – MRCA is twice as old as MRCA of humans and Neanderthals C. Mulligan, Copyright 2011 All rights reserved Phylogenetic analysis • Denisova mtDNA lineage branches much earlier than human and Neanderthal lineages – Most recent common ancestor (MRCA) between humans and Denisovans is ~1mya – MRCA is twice as old as MRCA of humans and Neanderthals • Denisova can’t be H erectus b/c H erectus wasn’t in mainland Asia ~40 kya and H erectus left Africa ~2 mya – Denisova must have been in Africa ~2 mya to share a common ancestor with modern humans and Neanderthal C. Mulligan, Copyright 2011 – New hominin! ID’ed by DNA!! All rights reserved What about nuclear DNA? • Changes phylogeny – Denisovan closer to Neanderthal than modern humans C. Mulligan, Copyright 2011 All rights reserved What about nuclear DNA? • Changes phylogeny – Denisovan closer to Neanderthal than modern humans • 4-6% admixture in Southeast Asians C. Mulligan, Copyright 2011 All rights reserved Major paradigm shift • We do have Neanderthal DNA in us! • And Denisovan, another archaic hominin • Recent papers propose admixture from possibly two more, unidentified archaic hominins • Allele in a gene in our immune system has recently been identified as coming from Neanderthals and conferring a selective advantage (Mendez et al. AJHG, 2012) C. Mulligan, Copyright 2011 All rights reserved Current status • Some debate about archaic admixture vs ancient population substructure in Africa (> 100-200kya) that could create signal of archaic admixture but is really just separate gene pools in Africa, only one of which left and gave rise to European and Asians C. Mulligan, Copyright 2011 All rights reserved Cro-Magnon, n=2 Conclusion - Modern humans clearly group w/ Cro-Magnon and show no shared ancestry with Neanderthal Cro-Magnon Neanderthal Caramelli et al. 2003 Multidimensional scaling of HVRI sequences of 60 modern Europeans (filled squares), 20 modern nonEuropeans (filled circles), 4 Neanderthals (open diamonds), Lake Mungo specimen (open circle), and Paglicci specimens (open squares) C. Mulligan, Copyright 2011 All rights reserved