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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).
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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)
Mark Stonekingand Johannes Krause Learning About Human Population History From Ancient And Modern Genomes(Review, 2011)
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!
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
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: 35-50ya
SriramSankararaman et al The genomic landscape of Neanderthal ancestry in present-day humans (March 2014)
Subjects 1004 modern humans • 176 West African (Yoruba tribe: Ibadan, Nigeria) • 758 Europeans • 572 east-Asians
Three features of genetic information • Allelic pattern at SNPs • High sequence divergence • 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 • Single SNP in Africans vs Europeans vs Test • 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 • 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 Male donkey Mule (infertile) Female horse
B statistic • Background selection (B) value “indicates the expected fraction of neutral diversity that is present at a site” • Ranges from 0-1 • Relatively obscure Values near 0: Almost all diversity removed by selection Values near 1: little effect of selection “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
Kay Prüfer et al The complete genome sequence of a Neanderthal from the Altai Mountains(January 2014)
Phylogenetic relationships of the Altai Neanderthal Modern humans Neanderthals
Homozygosity • Inheriting identical copies of the same gene from each parent • EgTay-Sachs (from population bottleneck) • Long runs of homozygosity indicate inbreeding
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 DNAAllnon-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?