Lecture 24: Human Origins and Signatures of Selection April 11, 2014

Announcements  Switched labs 11 and 12  Phylogenetics and Coalescence this week (lab 12 in the manual)  Signatures of selection next week (lab 11 in the manual)

Last Time uGene trees versus species trees uCoalescence uInfluence of demographic factors on coalescence times

Today uHuman origins: Neanderthals and Denisovans uSignatures of selection

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

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

Human Evolutionary History

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

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!

Archaic Genomics - Svante Pääbo March 27, 2014, NIH

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 Science 325:318

Neanderthal and Human Mitochondrial Tree  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? Stay tuned.

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 CpG recognition sites: eliminate bacterial DNA  Sequenced with 454 and Illumina GAII  5.3 Gb of sequence produced Green et al Science 328: 710

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

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

Mithochondrial and Nuclear Stories are Different

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

Expectations for Hybridization

Do Ancient Humans Show Larger Chromosome Segments from Neanderthals than Modern Humans?

45,000 year old human fossil genome

More admixture in 45,000 year old human (and Asians)

A new human ancestor: Denisovans

599, ,00.html uSingle finger bone and some teeth discovered in cave in Siberia uFound in conjunction with human-like artifacts: bracelets and necklaces uSequenced mitochondrion and whole genome (1.9X) using Illumina GAII uDNA sequence reveals this is not a human bone!

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

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

Patterns of Introgression in Modern Humans and Relatives

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Are Neanderthal and Denisovan Genome Remnants Adaptive?

The main power of neutral theory is it provides a theoretical expectation for genetic variation in the absence of selection.

Assume you take a sample of 100 alleles from a large (but finite) population in mutation-drift equilibrium. A. Number of Observations of Allele Number of Alleles B C What is the expected distribution of allele frequencies in your sample under neutrality and the Infinite Alleles Model?