Sequencing
Neanderthal DNA
Lauren Edelson
Road Map
• Sequencing ancient
DNA: methods &
outcomes (Review
article)
• DNA sequencing to infer
Neanderthal ancestry in
modern humans
(Sankararaman et al)
• Examining the Altai
Neanderthal population
in depth (Prüfer et al)
Learning About Human Population
History From Ancient And Modern
Genomes (Review, 2011)
Mark Stoneking and Johannes Krause
High-throughput
sequencing of
ancient DNA
Challenges of sequencing ancient DNA
• Repairing damaged DNA
• Avoiding contaminant DNA
Challenges of sequencing ancient DNA
(continued)
• Post-mortem chemical damage
We can use cytosine deamination to test the authenticity of ancient DNA sequences!
Okay, so we sequenced some
Neanderthal DNA.
What now?
How much can you actually tell from ancient DNA?
• Genetic composition of
organisms
• Phylogenetic relationships
• Divergence times
• Population structure
• Population hybridization
• Population bottlenecks
• Phylogeographic patterns
Emerging technologies allow for more
complex population divergence models
Our best models as of 2009 for population divergence
SNP data used to compare possible
dispersal route scenarios
Key Dates
• Neanderthal/Denisovan split with humans:
820,000 ya (350,000 ya?)
• Neanderthal and Denisovan split: 680,000 ya
• Out of Africa: 50,000 ya
• Further human population divergence: 3550ya
The genomic landscape
of Neanderthal ancestry
in present-day humans
(March 2014)
Sriram Sankararaman et al
Subjects
1004 modern humans
– 176 West African
(Yoruba tribe:
Ibadan, Nigeria)
– 758 Europeans
– 572 east-Asians
Three features of genetic information
1. Allelic pattern at
SNPs
1. High sequence
divergence
2. Haplotype length
These features are then used to generate a Conditional Random Field (CRF)!
Conditional Random Fields (CRFs)
• Based on “3 features”
• Used to predict likelihood of Neanderthal
ancestry in a given DNA sequence
• Feature functions
1. Single SNP in Africans vs Europeans vs Test
2. Multiple SNPs used to capture ancestry
(divergence)
Tiling path from inferred
Neanderthal Haplotypes
Chromosome 9 in several Europeans
Average contig length
Maps of Neanderthal Ancestry
European
East Asian
African
Neanderthal Ancestry in 1000 modern
genomes
European
East Asian
High selection against Neanderthal
DNA on X chromosome
Male hybrid sterility
Male donkey
Female horse
Mule (infertile)
• After crossing two species, offspring are often
infertile, keeping the two species distinct
• Evidence for this in humans and
Neanderthals? Yes!
• But it’s not the only factor causing selection
against Neanderthal genome
B statistic
• Background selection (B) value “indicates the
expected fraction of neutral diversity that is
present at a site”
• Ranges from 0-1
Values near 0:
Almost all diversity
removed by selection
Values near 1: little
effect of selection
• Relatively obscure
“Widespread Genomic Signatures of Natural Selection in Hominid Evolution”
(McVicker et al, 2009)
Functionally important regions are
deficient in Neanderthal ancestry
Neanderthal GWAS
Genome-Wide Association Studies (GWAS) can be used to
associate Neanderthal-derived alleles with modern phenotypes
Genome-wide estimates of Neanderthal ancestry
• Neanderthal ancestry: east-Asian > European
• Larger European population: less time for
selection to remove deleterious alleles
The complete genome sequence of a
Neanderthal from the Altai Mountains
(January 2014)
Kay Prüfer et al
Phylogenetic relationships of the Altai Neanderthal
Modern
humans
Neanderthals
Homozygosity
• Inheriting identical
copies of the same
gene from each parent
• Eg Tay-Sachs (from
population bottleneck)
• Long runs of
homozygosity indicate
inbreeding
Indications of
Inbreeding in Altai
Neanderthal
individual
Heterozygosity estimates by group
Inference of population size change over time
Possible model of gene flow
Remember this guy?
Possible model of gene flow
Takeaways
• Although major challenges exist, it is possible to
accurately sequence ancient DNA with modern
technology
• We can use these methods to compare ancient
and modern DNAAll non-African modern day
humans have a small genetic presence of
Neanderthal ancestry
• We can learn much about ancient populations (eg
bottlenecks & inbreeding of Altai Neanderthals)
by looking solely at one bone fragment!
thank you
QUESTIONS?