Outline
Archaic Genes in Modern Humans
Alan R. Rogers
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History of thought about archaic admixture
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Inferring admixture from derived allele patterns and aDNA.
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Inferring admixture from LD in modern DNA.
November 30, 2015
Hypotheses of modern human origins
Multiregional Modern humans evolved in a worldwide population
united by gene flow (Wolpoff 1989).
Replacement “A single origin, outward migration of separate
stirps, like the sons of Noah, and an empty world to
occupy, with no significant threat of adulteration by
other gene pools or even evaporating gene puddles”
(Howells 1976).
Admixture Expansion from a single origin, involving “encounters
between populations of modern man and of other
forms, with consequent gene flow” (Howells 1976;
also: Brauer 1984, Smith et al 1989, Trunkhaus
2005).
Fossils From Vindija Cave, Croatia
Geneticists on admixture
Consensus among geneticists during 1990s: little or no admixture
between moderns and archaics.
Eswaran et al 2002, 2005: argued for admixture
Hawks et al 2006: Small amounts of admixture can have a big
effect, because advantageous alleles are most likely to introgress.
Green et al 2010: sequenced Neanderthal genome; showed that
1.3–2.7% of European genes came from Neanderthals. [current
estimate 1.5–2.1%]
Hominin tooth from Denisova Cave, Altai Mtns, southern
Siberia
Outline
Nucleotide site patterns
Ancestral allele (0) is shared with
chimp.
◦ History of thought about archaic admixture
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Inferring admixture from derived allele patterns and aDNA.
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Inferring admixture from LD in modern DNA.
Eur
Afr
Nea
Chi
#
Nucleotide
Site Pattern
ae
en
an
1
1
0
1
0
1
0
1
1
0
0
0
303,340 103,612 95,347
Mutant allele (1) shared by two
human populations.
Pattern ae: most common;
reflects history of population
splits.
Patterns en & an: how do they
arise?
Why does en exceed an?
Population tree
....
....
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.
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.
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.. . .. ... .... .... .... .... ....
.
.
A
E
N
C
A, Africa; E , Europe; N, Neanderthal; C , chimpanzee
Incomplete lineage sorting
Pattern an
Pattern en
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. . .
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A
E
N
C
A
E
N
C
1
0
1
0
0
1
1
0
These two should be equally common
Embedded gene genealogy with mutation
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.. .. .......... ... .... ..... ....
.. ... ... ... ... .... ...
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.
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A
E
N
C
1
1
0
0
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Genealogy of 4 genes shown
in color.
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Bullet (•) marks mutation
from allele 0 to allele 1.
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Descendants of mutant have
allele 1; others have 0.
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Gene genealogy matches
phylogeny
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Mutant allele shared by
closest relatives, A and E .
Nucleotide site patterns again
European
African
Neanderthal
Chimpanzee
# sites
Nucleotide Site Pattern
ae
en
an
1
1
0
1
0
1
0
1
1
0
0
0
303,340 103,612 95,347
Common pattern (ae) reflects history of population splits.
Absent admixture, the other two should be equally common
Why does en exceed an?
Neanderthal admixture inflates en site pattern
Admixed locus
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.
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.
.
.
.
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.
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.. ..... ... ..... .........................m
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.
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A
E
N
C
0
1
1
0
Not admixed
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.
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A
E
N
C
0
1
1
0
A statistic for estimating admixture
Jne − Jan
Jea − Jan
103, 612 − 95, 347
=
≈ 0.0397
303, 340 − 95, 347
λ−δ
∼ m
λ−ζ
≈ 1.2m
Q =
where m is rate of admixture; λ is archaic separation time; δ is
time of admixture; ζ is separation time of Africa and Eurasia.
Key: A, Africa; E , Europe; N, Neanderthal; C , chimpanzee.
Estimate from Neandertal DNA
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Denisovan DNA most common in Australia, NG, and
Oceania
DNA of modern Eurasians is 1.5–2.1% Neandertal
(Prüfer et al 2014).
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Same is true for modern people of east Asia and Papua New
Guinea, but not Africa.
Green et al (2010)
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Admixture must have occurred after moderns left Africa but
before they expanded throughout the world.
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Eurasian introgressed segments most similar to Neanderthal
from Caucasus.
(Prüfer et al 2014)
Outline
Using LD to discover admixed chromosome segments
◦ History of thought about archaic admixture
1. Recent introgression → modern genomes should contain long
segments archaic chromosome.
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2. These segments should differ a lot, because of the long
separation time.
◦ Inferring admixture from derived allele patterns and aDNA.
Inferring admixture from LD in modern DNA.
OAS1 innate immunity locus
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two forms of gene in Melanesia:
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one shared with rest of world
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one only in Melanesia
Melanesian OAS1 allele w/i Melanesia
Worldwide frequency of Melanesian OAS1 allele
Melanesian OAS1 allele is old yet young
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The 2 alleles differ at many nucleotide sites ⇒ separation
time ∼3.4 my.
Long (90 kb) LD block ⇒ they’ve been together only ∼25 ky
Melanesian allele matches that in Denisovan hominin skeleton.
⇒ archaic admixture into Melanesia
Method of Vernot and Akey (2014)
1. S ∗ statistic (Plagnol & Wall 2006) uses modern LD to find
candidate introgressed segments.
2. Accept candidate if matches Neanderthal sequence better
than chance.
3. Studied 379 Europeans and 286 East Asians.
4. Found 15 Gb introgressed sequence spanning 20% of
Neanderthal genome.
Neandertal segments in modern genomes
red Asians
blue Europeans
Variation among individuals
implies multiple matings between
Neanderthals and moderns.
(Vernot and Akey 2014)
Barrier to gene flow between Neanderthals and moderns
Introgressed segments rare in
genomic regions where moderns
differ greatly from Neanderthals.
Neanderthal inserts
rare where selection
is strong
Suggests partial reproductive
isolation.
Sankararaman et al
(2014)
Decreasing selection →
History of population size from single diploid genomes: the
pairwise sequentially Markovian coalescent (PSMC)
PSMC with Neanderthal as well as Denisova
(Meyer et al 2012)
(Prüfer et al 2014)
Estimated times to most recent common ancestor
(TMRCA)
Long stretches of low TMRCA ⇒ recent close inbreeding.
(Prüfer et al 2014)
Altai Neanderthal was very closely inbred
All of these pedigrees are plausible.
(Prüfer et al 2014)
Long history of small population size
Coding sequence variation in archaics
Castellano et al (2014) study 17,367 protein-coding genes in
several Neanderthals, the Denisovan, and several moderns.
Even after removing the effects of inbreeding during the last few
generations, the Altai Neandertal is still highly inbred.
Neanderthals had low heterozygosity
Species
Neanderthal
Population
El Sidrón
Vindija
Altai
Modern
African
European
Asian
Tree based on mutations (left) and drift (right)
Heterozygosity
×1000
0.143
0.127
0.113
Neighbor-joining tree
FST tree
0.507
0.387
0.358
Low heterozygosity ⇒ small population.
Long runs of homozygosity ⇒ recent close inbreeding.
Castellano et al (2014)
Long archaic branches on FST tree ⇒ small population size.
Castellano et al (2014)
Selection less effective in Neanderthals
Selection less effective in
Neanderthals
Many Neanderthal alleles have
large effect on protein structure
and are probably deleterious.
(Castellano et al 2014)
Summary
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Different methods yield consistent estimates of archaic
admixture.
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Populations vary greatly in level of archaic admixture.
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Neanderthal: all non-African populations have about same
level (1.3–2.7%) of admixture. Suggests that admixture
happened in one region.
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Denisovan: highest levels found in populations far from Africa.
Suggests that admixture accumulated gradually.
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Multiple episodes of admixture into Europeans.
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Partial barrier to gene flow.
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Small archaic populations → many deleterious alleles.