Bio380: Waking the DeadNeanderthal genes and genomes

Professor Mark Pallen

Bio380 Genes and Genomes lectures Lecture 1 Waking the Dead Lecture 2 Scatterlings of Africa Lecture 3 Major Population Movements: Peopling of

the World Lecture 4 The Wandering Gene Lecture 5 The Phylogenomics of Cancer Open Education

all lectures on YouTube and Slideshare Facebook Bio380 site Twitter feed #Bio380

Learning outcomes At the end of this lecture you should be able

to answer these questions: who were the Neanderthals? what is their relationship to us?

On this issue, you will be able to evaluate evidence from genes evidence from genomes

You will be able to describe the contribution of other archaic hominins to the modern human gene pool

Neandert(h)al

Valley near Düsseldorf Named after 17th

century pastor, Joachim Neumann

Thal became Tal in 1901 But old form still

used in taxonomy And annoyingly

both forms common in papers!

Discovery Numerous caves and rock shelters along valley,

including Kleine Feldhof Grotte In 1850s, limestone quarrying began by firm of

Beckershoff and Pieper; caves and valley walls removed

August 1856, skull cap and 15 postcranial bones recovered from Kleine Feldhof Grotte• first thought to be cave bear• shown to local teacher and natural historian

Fuhlrott, who identified them as human• first reported scientifically by Fuhlrott and

Schaaffhausen in 1857 Neanderthal 1 became type specimen for Homo

neanderthalensis “prequals”; Gibraltar 1848, Engis, Belgium,

1829

Discovery

Neanderthal 1 became type specimen for Homo neanderthalensis

“prequals” Gibraltar 1848 Engis, Belgium, 1829

Darwin Sept 1864 letter to his close friend, botanist Joseph Hooker: “F[alconer] brought me the wonderful Gibraltar skull.”

Re-discovery...

>400 specimens found

Timeline First proto-Neanderthal features ~350Kya Full-blown Neanderthals:

130Kya-30Kya died out by 50Kya in Asia ?survived to 24Kya in Europe

Overlapped in time and range with AMH but no overlap at any one site

Culture Mousterian culture

tool use, fire, burials, skinning cared for their injuried

? Language: hyoid bone found in 1983 Carnivores (evidence from isotopic studies)

cannibals? ritual defleshing

Anatomically distinct from AMH

differences > than in 2 chimp species more robust than AMH pronounced brow ridge projecting mid-face low flat elongated skull; occipital bun chinless with larger brains!?

Fate of the Neanderthals Coexistence for 15-20 ky Possible fates

Rapid extinction (genocide) Gradual extinction

unable to adapt to end of glaciation

cannot compete with humans, e.g. in hunting, running

Assimilation

Was their genetic exchange between AMH and Neanderthals?

OR

Africa Eurasia Africa Eurasia

Neanderthals

Neanderthals

What can sequences tell us Population genetics of modern populations

Are there sequences in Europeans not found elsewhere old enough to be Neanderthal in origin?

Torroni et al 1994 and Richards et al 1996 say no Ancient DNA

What do Neanderthal sequences look like? Relies on amplification or retrieval of sequences

from fossils Problem of contamination with human DNA

Mitochondrial DNA favoured because

100-10,000 copies per cell D-loop non-coding Maternal transmission

Neanderthal sequence outside modern human

range

Summary of Evidence from mtDNA Neanderthal mtDNA is quite different from

• all present human mtDNA sequences• ancient mtDNA sequences from AMHs

Common interpretations• two separate species• little or no admixture• consistent with out-of-Africa hypothesis

November 2006…

The verdict...

“By contrast, the complete Neandertal mtDNA now offers 133 such positions. This enables a reliable estimation of mtDNA

contamination by analyzing sequence reads from 454 libraries, rather than by PCR-based assays of the DNA

extracts. For example, when we do this in a small preliminary data set initially published from this fossil (Green et al., 2006), 10 of 10 sequences are classified as Neandertal.

However, in further unpublished sequencing runs from that library, 8 out of 75 diagnostic sequences derive from extant

human mtDNA, suggesting a contamination rate of 11% (CI = 4.7%–20%). This is in agreement with the suggestion (Wall

and Kim, 2007) that contamination occurred in that experiment.”

Darwin’s 200th BirthdayFebruary 12th 2009

1X draft sequence of Neanderthal genome announced ~60% of genome Sequenced 68.9 billion bases, 96% of which were

microbial in origin, to cull 3 billion bases of 1X Neanderthal genome

Three bone fragments from two Neanderthal women: no Y chromosome sequences

1000-2000 amino acid differences from AMH (cf 50,000 in chimp) No evidence of admixture No evidence of recently emerging non-African

Microcephalin or MAPT variants Divergence date ~800Ka Formal publication awaited!

Neanderthal genome Comparisons with chimp and AMH genomes

found 78 base substitutions that change protein sequences in AMH lineage; 5 proteins with >1 amino-acid change SPAG17 (axoneme protein); PCD16 (fibroblast

cadherin); TTF1 (transcription termination factor); CAN15 (unknown); RPTN (reptin, skin ECM protein)

Copy number changes, e.g. PRR20 68 copies in Neanderthal; 18 in AMH

Selective sweeps

Selective sweeps Neanderthals fall within variation in modern

humans in many parts of genome Allows search for regions subject to selective

sweeps in AMH Gene affected include:

THADA (associated with type II diabetes) genes implicated in cognitive ability

AUTS2, DYRK1A, NRG3, CADPS2

RUNX2, associated with cleidocranial dysplasia might explain skeletal differences in skull and upper

body between AMH and Neanderthals

But are Neanderthals more closely related to some AMHs than to others? Compare sites with derived SNPs in

Neanderthals/AMH Initial comparison to 2 European Americans, 2

East Asians and 4 West Africans shows Neanderthals significantly closer to non-Africans

Confirmed by comparisons with San, Yoruba, Han, French, Papuan, which also showed direction of flow is from Neanderthal to non-African humans

Chromosomal segments identified in which Craig Venter is more Neanderthal than African!

~1-4% of non-African genome is Neanderthal

Neanderthals

AMH

European

Chinese

Papuan

West African

San

Can molecules tell us anything about what Neanderthals were really like?

Specific studies on candidate genes and molecules

Neanderthals

AMH

European

Chinese

Papuan

West African

San

Denisovans

Overlap of archaic & AMH in Africa?

Conclusions Now have multiple Neanderthal mtDNA

sequences• All outside the range of human variation

Neanderthal genome sequence supports the idea of small-scale mixing

Now have evidence that (some) Neanderthals had pale skin, human-like FOXP2, bitter taste heterozygosity, blood group O

Other archaic admixture from Denisovans and unknown African population

More gene and genome sequences promised!

The last word?Are we really that surprised....?!

Recommended viewing

Search YouTube: For a bad (and I mean bad!) 1970s Neanderthal pop

song use search terms “Neanderthal” and “Hotlegs” For the amusing comparison of Neanderthals and

AMHs, use search terms “Eddie Izzard” and “Neanderthal”

Links to Chris Stringer’s talk and papers and other material available via WebCT

Image sources and rights http://www.flickr.com/photos/erix/142070879/sizes/z/in/photostream/ Some rights reserved by erix!

http://www.flickr.com/photos/54144832@N06/5530175310/lightbox/ Some rights reserved By Jorge Lucero

http://commons.wikimedia.org/wiki/File:Neanderthal_child_(1).jpg CC BY-SA 2.0 Ryan Somma

Stanislav Kozlovskiy http://commons.wikimedia.org/wiki/File:Skull_of_Teshik-Tash_Boy.jpg GNU Free Documentation License, V 1.2

http://en.wikipedia.org/wiki/File:Homo_sapiens_neanderthalensis.jpg Luna04 GNU Free Documentation License, Version 1.

http://en.wikipedia.org/wiki/File:Spy_Skull.jpg GNU Free Documentation License, Version 1.2 We El

http://commons.wikimedia.org/wiki/File:Neandertal_1856.jpg

http://www.flickr.com/photos/gianfrancogoria/3766258280/in/photostream/

http://en.wikipedia.org/wiki/File:Neanderthaler_Fund.png

http://www.flickr.com/photos/lwr/4019436274/sizes/m/in/photostream/

http://commons.wikimedia.org/wiki/File:Neanderthal_child.jpg

Jason Potter http://commons.wikimedia.org/wiki/File:Neanderthal_cranial_anatomy.jpg CC-BY-SA-2.5

http://www.flickr.com/photos/momentsnotice/5361847966/sizes/l/in/photostream/ CC BY-NC-SA 2.0 Massmatt

http://commons.wikimedia.org/wiki/File:MitoChondria_147.jpg

http://commons.wikimedia.org/wiki/File:Mitochondrial_DNA_en.svg

http://commons.wikimedia.org/wiki/File:Plos_paabo.jpghttp://en.wikipedia.org/wiki/File:Neandertaler-im-Museum.jpg

Chris Stringer kindly provided last two slides

.