GREEN, Ed, NEADERTHAL DNA, UC Santa Cruz, June 11 2013

he credits Svante Paabo  (his former boss at UC Berk)

he is an asst prof at UC Santa Cruz...

this is a Cafe Sci Lecture at SRI Menlo Park at 6 PM  today.

Consider chimps:   no complex language, smaller brain, knuckle-walking,
 more hair, smaller social groups, public sex,  small exposed sclera,
no immunocompromise following HIV  etc.

All of these are due to differences encoded in their genome versus us.

eg consider bipedal individuals... walking on two feet...
it is 100% heritable...
every chimp does knuckle-walking and all us
walk on two feet...

we were all a fertilized egg at one point
one set of dna from mom and one set from dad... that is what DIPLOID means.

where in that genome are these uniquely human characteristictics encoded...

what makes humans unique genetically?.

35M  SNP changes  (single nucleotide polymorphisms.)
5M  insertion/deletions
9 pericentric inversions and
1 chromosome fusion

out of  3B  BPs...
99 places are the same and 1 is difft  btwn humans and chimps...

our chromo #2  was actually TWO separate  chromosome in other great apes...
at some time in the past... we all have just one chromosome #2...

we want a complete map  that shows the differences and the changes that really matter
(btwn us and chimps... most changes do not matter... but some are v impt)
where are the ones that give us our big brain,  bipedality, language, etc...

how abt something closer to us than chimps...

there are more physical antropologists than there are bones to look at!! (big laugh)

Neadertal  La Ferrassie 1  (a cave in Europe) had a big brow, big occiput...

look at  Cro magnon 1  (modern human)  all of us come from them
(he pronounces it as in the French.. crow  man NeeYON.)

our closest living relative is the chimpanzee...
chimps  super-sized  mandible and big attachment, tiny brow ridge , tiny brain...

Neadertals...  had a bigger  mandible than we do...

Neadertals  show up 200K years ago...
they were extinct at 30K years ago...

our phenotype shows up  at 130K years ago

so,  we and Neader shared the planet thru much of that time...

also v  short prevalence of Homo floriensis...( the "Hobbits")

Neadertal geographic range... in Europe

in France, Spain, Italy,  Germany,  
prob in middle east... etc.

his alma mater: is Cal Berkelely...

ancient dna was one of the first applicaitons of PCR...
did the sp?  Quaga...  related to a horse...

hi thruput sequecing has revolutionized this field...
faster than Moore's Law...

revolutonizing  study of ancient DNA..

today:  can generate a human dna  seq  in one day  for a few thousand bucks!

it will certainly be a part of future medical care... hard part is understanding it and using the info...

Vindija  cave was the source of these 3 bones...  from Croatia  that  had dna and least amt of contamination..
he shows the three bones...  they were labeled  CAVE BEAR...
(they look like femurs  (long bones)

generated 1 Gbase of seq data...

had abt  1.3 X one fold coverage...

Vindija  33.16  got 1.2 Gb
etc.  (for  6 bones)

see Green et al in Nature  444  (7117)  330  in 2006
cover story of Nature...

most of this dna was stuff that was contam fromteh ground  eg
5% was  actinomycetales
primate was only  3.5% of it
unclassified enviro was 4.1% of it
Burkholderales  was 0.8%...

first concentrated on mitochondrial genome

only from mom;  it is 16.5 kbase  abt  1000 copies per cell
in great  excess of the nuclear genome...
only from  mom and get abt 1000 copies in each cell
in contrast in each cell only one copy of mom's dna and one copy of dad's

also see  green in CELL  134  in  2008

if u have high enuf coverage, u can  infer the correct bases (despite errors etc)

Cytosine deamination is the real process that screw us up;
it sponatenous  deaminates into uracil  and we read it as a thymidine in our machines...
this is our main source of screw ups...

how often do u see a C => T substitution...

rate is  40%  if it happens to be  right at the start of the READ.

mirror image at  3 prime end of molecule...

but it falls off rapidly as u move into the interior of the dna...

by the time u get to positon 5... it's perhaps only 5% and tails off from there...

it really tells us the distrib of the single strand overhangs at the very end...

so,  it should be  C pairing with a G  but instead...
(in error)  the C has deaminated to a T  (at the start of the read).. and it would bind with an A...

see Green in Science  328   in  2010...

he comments after u leave lecture, u will leave hair, skin here on seats...

Neadertal  mitochondra  has  perhaps 100 difft substitutions on .... the mitochon DNA...

infer that contamin was only abt  0.27%

eg any Y chronosome seq  is by defn contamination...  =>  < 1% contamination from males...

he shows a table where each row is a bone sample
each  Neadertal has 28K  bps...

align  chimp,  Neader, and human  genes...  to see the diffs...

transitions occur far more often than transversions...

Neadertal...  is heavily enriched with sequencing errors  (that's why there is all that variety)
most of wha tis on human branch is real... it is actual evolution (as opposed to seq error)

when  did common ancestor of humans  and chimps live =  6.5 M years ago

human and neadertal common ancestor was 800K years ago...

*********************
briefly overview of genetics  (genetics 101 of diploids)

he show grandparents  diploids...

we are diploids... every chromo.. we have 2 copies  one from mom and one from dad...

BUT  copy  of dads  dna  does not exist in dad  and similar for mom

father did recombination  at  little x  there was stitching/ recombo in dad to make
the partic  dna in the sperm that made you...

and same for mom  for egg...

my geneology is difft depending on where you are looking at you dna...
so, your common ancestor  with anyone else  really is DIFFT depending on where you look
for any particular base pair... may eg be  200 generations ago or 500 gens ago , etc.

Avergae hmann Neadertal coalescent was 850 K years aog

for average  huma to human coalenscense was about  450K years ago...
and this is FURTHER BACK  then  
human/ Neadertal population split  was abt  300K  years ago...

we may be more closely related to Neadertals  than to other humans...

has there been genetic exchange btwn human and neandertals...

our ancestors were all still in Africa...****

we seq genes of 5 individuals

from  French guy.. from Yoruba from San  from Chinese  etc. from Papuan New Guinea...

how diff is Neader from each of these....

compare:  eg  Neadertal to Yoruba and the French guy...

look at  all diffs in bps btwn eg  YOruba and French  vs the Neadertal at that position...
whoudl be 50:50 but

in fact,  Neadertals more closely matched  the non-Africans than the Africans... eg
more closely matched the French, the Han and the PNG  rather than the Yoruba and San  dnas

so,  when human ancestors came ou tof Africa  70 to 80K years ago...
got admixture of humans and neaders and they spread to  PNG and to australis and to china...
(their hypothesis)

that's how things stood for 2 months! (big laugh!)  until

Denisova... research...
another individual...

got really good specimen with lower errors... got 40 fold coverage of this genome...

Denisova  den EES us vuh... is more simialr to the other Neadertals..
s
but was it a separ race or tribe or ...

PNG  has abt  5 to 8 % of their dna that looks like it comes from  Denisova
this is weird and perplexing cuz  Denisova bone came from  ? Russia...

see Reich et al  in AMHJ in 2011...

(this was from the Denisova cave)...

hypothesis:  firs tmigrants out of Africa... stayed on the beach on teh coast and
went first to PNG/ Australia...
so, perhaps  early  fast moving migrants admixed witht ehthe Denisovans  (maybe

last ref is to Meyer et al in Science  338 in 2012...
can capture  single stranded dna...
can get a lot more data..

so from Denisova  can get 40 fold coverage...

present day humans diverge by 12.5%  .. common ancestor about  800K years ago...

our common ancestor with chimps was  6.5 M yrears ago...

how much  evolutionnis the Denisova missing =  abt 80K years
it is missing abt  1.2% divergence  (cuz it died out)

can also find out  (for each position in your genome)
how far back were the common ancestors of YOUR mother and father...
difft  for each position in your dna...

can figure out where the bottlenecks are...

appears tha there was a bottle in the out of africa phenomenon...

Denisova  was prob  v small and just hanging on in frozen Siberia in Pleistocene...

Brandon Rice is ihis student
and Sam Vohr is another of his students...

we did symbolic abstract art
we got into boats..
we colonized new areas...

we have an intere immunity gene that came from neaders...

ed@soe.ucsc.edu...

in response to  a Q he says... larger populations genl have bigger diversity than smaller

all the great apeas are critically  endangered

there are < 100K of  ALL the great apes and  7G of us...
but they have greater  diversity... they are losing their habitat to us...

we must protect their habitat!  (the gentics is almost a distraction)...

Q  abt accelerate dmutaiton sites in Denisova..

A  study done by Katy Pollard (my colleague)

there are sites that have evolved extremely fast in humans...
subfireld of comarative genomics...

recombination hot spots are what is driving this fast  evolution..
(I prev said it was random.. but not so)
biased gene conversion... if heterozyg...  CG is less thermodynam stable...

whereever these recombo hotspots land... that is where rapid evol occurs...

Q  abt  Floriensis and how they differ form  DEnisova...
A  Svante is working on that... don't know...

he says  prob not a catastrophic event that kiled Neadertals... they were always a small population..

Q.. u didd not use the word species..is that outdated?
A  maybe...
this linean idea...  (is prob outmoded)  this idea always BREAKS...
there is NOT a single concept of species where everyone agrees...

eg  reproduc incomatibile is  acommon  idea
but humans  and neadertals can interbreed

so cna grizzly and polar bears... they interbree all the time andhave viable  kids..

so, it's really a continuum... there may be  single indivudals in speices than cannot make hybrids but
species mix all the tiime... happens in birds all the time... v common

all that stuff, species, subspecies, races... all  obsolete... not a good description...

Q  red hair gene... MT1R gene  mickey hallbrieter group... gene has variancein it today that causes red hair..
red hair is not a single locus trait...  inactivation causes red hair..
we did NOT get that gene from them...

Q  how do u revmove variablity among us...
A  we just used  5 modern individuals  it's always an indivudal  to indiv  comparisos
we did just ONE French guy, eg...

Q  did Neandertals have SPEECH!!!!!
A  that would be the reason to bring back Neadertals... try to teach them speech!!!
he cites Stanford guy.. who thinks that speechwas the key thing...
perhaps  100K years aog...  we hit warp speed cuz of language!

Lanugae...  FoxP2... but looks the same btwn  humans and Neadrtals...
we only have one speech gene so far...

Q  interbreeding btn Neadertla and hauans...
A lookat  sex-linked loci..

males contribute only half as much of the X chromos are females...

Q (Ken Lum);  where did  Neadertals originate?  

A  ancesotrs of Neadertals... called the muddle in the middle...

?  homo erectus... but its a  muddle...

all hominins originated in Africa... that is clear  (at somepoint in the past)
prob some level of migration from Africa thru theyears...

so,  where id Neaerals come from... A  came from Africa..

Australopithecines all came from Rift Valley, eg..
but 1.5M yrs ago see Erectus in Indonesia and China...

no Neadertals in Africa... they evolved outside of Africa...

over 100K yrs ... dna decompsed  but  there is a horse speciment that is 700K years ago
(preserved in ice)...

since Holocnee.. bones thawed so dna decomposed...

Q  abt perosnality traits  (questioner says.. looka t diff btwn  timber wolf and  poodle eg)

A  there is an idea  we are  self-domesticated..

we communicate an enormous amt of info when we look at one another...
chimps do not do that.. they do not know when someone is staring...
when oen stares it means he's soon going to be fighting!

Theory of Mind... magical thing abt human brain...  chimps are social but
nothing to our level...
we domesticated ourselves... learn from one another..

can dog tell where I'm looking...  eg puppies can do it...
puppies will look at human gaxe to see where food is hidden under which bowl)

Q  Teh great leap  forward...  was it speech..  don't know
A  Richard Klein... makes convincing argument  that...
all of a sudden making sybolicf art, figuriens, needles, sheels, drawings all of a suddent perhaps abt 30K years ago...
never did that for a long time.. but all of a sudden .. boom there it is...

Q  why is always migratout OUT of Africa..  rather than backward...

A  his answer... go to area that is UNinhabitated for more resources
(like East to West in America)...