Lecture 18 Human Population Genetics and Evolution October

Lecture 18: Human Population Genetics and Evolution October 26, 2012

Announcements § Exam Next Wednesday (Oct 31) § Review on Monday § Bring questions § Covers material from genetic drift (Sept 28) through Coalescence (Friday) § I will be gone Monday, Oct 29 (after office hours) through Oct 31 § Bring questions on Monday!

Last Time § Phylogenetics and forensics examples § Limitations of phylogenetic analysis § Coalescence introduction § Influence of demography on coalescence time

Today § Human origins § Human population structure § Signatures of selection in human populations § Neanderthals, Denisovans and Homo sapiens

Origins of Modern Humans u Most fossil evidence points to origins in Africa and subsequent migrations Skulls found in Omo Valley, Ethiopia Dated at ~195 K Omo 1 Modern http: //wwwv 1. amnh. org/exhibitions/p ermanent/humanorigins/hi story/origin. php http: //www. dhushara. com/book/unraveltree/unravel. htm

Human Phylogeography: mt. DNA u. Most ancient and diverse haplotypes in Africa (dots) u. Migration and admixture is evident from presence of African haplotypes in other clades

Human Phylogeography: X-chromosome genes u Pyruvate dehydrogenase E 1 alpha subunit sequence u 25 polymorphic sites, 23 of which were in African sample u Using chimp sequence as outgroup, estimated that time to most recent common ancestor of humans is 1. 9 million years ago u African-European split at about 200, 000 years

Complexities to Human Phylogeography u Some genes show evidence of Asian origin Ø Sequence of X-linked ribonucleotide reductase M 2 pseudogene 4 (RRM 2 P 4) Garrigan 2007 Nature Reviews Genetics 7: 669

Why might some X-linked genes show a human origin in Africa (e. g. , PDHA 1), while others suggest an Asian origin e. g. , (RRM 2 P 4)?

Evidence of Population Structure in Ancient Humans Garrigan and Hammer 2006 Nature Reviews Genetics 7: 669

Time to Coalescence Affected by Population Structure

Evidence for Ancient Population Structure in Nuclear but not Mitochondrial Trees Garrigan and Hammer 2006 Nature Reviews Genetics 7: 669

Why does mitochondrion show shorter coalescence times than nuclear loci? Why does rate vary much more for nuclear loci?

Probability of Coalescence § For any two lineages, function of population size § Also a function of number of lineages where k is number of lineages

Models of Human Origin of modern humans Garrigan and Hammer 2006 Nature Reviews Genetics 7: 669

Human Evolutionary History http: //www. cartage. org. lb/en/themes/sciences/paleontology/paleozoology/fossilhominids/Chart. Human. Evolution. htm

Neanderthals § Occurred in Europe and central Asia from 400, 000 to 30, 000 ybp § Morphological features distinguished them from modern humans: Nature 465: 148, 2010 Ø strongly-built, stocky frame Ø long, low skull with large cranial capacity Ø Double-arched brow ridges Ø occipital ‘bun’ Ø large nose, big front teeth § Disappeared from fossil record shortly after Homo sapiens appeared in Europe http: //www. msnbc. msn. com

What happened to the Neanderthals? § Extinction with no genetic legacy? § Do Neanderthals live on within our own genomes? § Neanderthal genome sequences are now answering those questions! http: //www. isayev. info

Neanderthal Mitochondrial Sequence § DNA extracted from bone fragments from 4 locations § Sequenced using Next-Gen technology: Roche 454 FLX § One individual (from Croatia) sequenced to great depth to give reference genome Briggs et al. 2009 Science 325: 318

Neanderthal Mitochondrial Sequence § Challenge for paleontological samples is isolating target sequence from contamination § Used reference genome sequence to select targets with biotinylated probes and primer extenstion § Sequences captured with streptavidin beads Briggs et al. 2009 Science 325: 318

Neanderthal Mitochondrial Sequence Neanderthals Modern Humans Briggs et al. 2009 Science 325: 318 60 -70 K ybp 38 -40 K ybp § Neanderthals and humans show no evidence of admixture § Most ancient Neanderthals (easternmost) are also most differentiated § Very low population structure and low diversity in most recent Neanderthals § Low effective population size? Bottleneck?

Neanderthal “Complete” Genome Sequence § DNA extracted from bone fragments from Vindijia Cave, Croatia § 95 -99% of DNA was from microbes § Cut DNA with restriction enzymes with high Cp. G recognition sites: eliminate bacterial DNA § Sequenced with 454 and Illumina GAII § 5. 3 Gb of sequence produced Green et al. 2010 Science 328: 710

Neanderthal “Complete” Genome Sequence § Assembled sequence to human and chimpanzee references § Incorporated typical degradation mutations: C-T and biased toward 5’ ends § Estimated modern human contamination by Ø comparing mt. DNA sequences Ø detection of Y-chromosome sequences in fossil females Ø Derived versus ancestral alleles § 0. 5 to 0. 7% contamination Green et al. 2010 Science 328: 710

Distance from Modern Humans Human-Neanderthal Hybridization Distance from Neanderthal u Segments in European human genome with high identity to Neanderthals are very different from other human sequences u Not true for African sequences u Evidence for hybridization with Europeans, not Africans Green et al. 2010 Science 328: 710

Human-Neanderthal Hybridization u Four possible scenarios for hybridization u Scenario 3 most likely: hybridization with ancestor of all modern Asian and European lineages after splitting from Africa Green et al. 2010 Science 328: 710

Why would mitochondrial DNA give a different answer than nuclear DNA? What other questions could be addressed with ancient, introgressed DNA?

A new human ancestor: Denisovans

A new human ancestor: Denisovans u Single finger bone and some teeth discovered in cave in Siberia u Found in conjunction with human-like artifacts: bracelets and necklaces u Sequenced mitochondrion and whole genome (1. 9 X) using Illumina GAII u DNA sequence reveals this is not a human bone! http: //www. time. com/time/health/article/0, 859 9, 1974903, 00. html

Denisovans are closer to Neanderthals, but very different Neanderthals Modern Humans

Denisovans show some introgression with Melanesians but not other modern humans

Eurasians Probably had continued introgression from other hominids after divergence from Africans