Reconstructing the 3D genome organization of Neanderthals reveals that chromatin folding shaped phenotypic and sequence divergence

Abstract

Changes in gene regulation were a major driver of the divergence of archaic hominins (AHs)---Neanderthals and Denisovans---and modern humans (MHs). The three-dimensional (3D) folding of the genome is critical for regulating gene expression; however, its role in recent human evolution has not been explored because the degradation of ancient samples does not permit experimental determination of AH 3D genome folding. To fill this gap, we apply novel deep learning methods for inferring 3D genome organization from DNA sequence to Neanderthal, Denisovan, and diverse MH genomes. Using the resulting 3D contact maps across the genome, we identify 167 distinct regions with diverged 3D genome organization between AHs and MHs. We show that these 3D-diverged loci are enriched for genes related to the function and morphology of the eye, supra-orbital ridges, hair, lungs, immune response, and cognition. Despite these specific diverged loci, the 3D genome of AHs and MHs is more similar than expected based on sequence divergence, suggesting that the pressure to maintain 3D genome organization constrained hominin sequence evolution. We also find that 3D genome organization constrained the landscape of AH ancestry in MHs today: regions more tolerant of 3D variation are enriched for introgression in modern Eurasians. Finally, we identify loci where modern Eurasians have inherited novel 3D genome folding from AH ancestors, which provides a putative molecular mechanism for phenotypes associated with these introgressed haplotypes. In summary, our application of deep learning to predict archaic 3D genome organization illustrates the potential of inferring molecular phenotypes from ancient DNA to reveal previously unobservable biological differences.

Resurrecting the Alternative Splicing Landscape of Archaic Hominins using Machine Learning

“…We adjusted our significance level due to multiple testing by correcting for the false discovery rate (FDR). We used a subset (N = 1 × 10 3 ) of the empirical null observations and selected the highest p-value threshold that resulted in a V / R < Q where V is the mean number of expected false discoveries and R is the observed discoveries (McArthur et al, 2022). We calculated adjusted significance levels for each set for Q at both 0.05 and 0.1.…”

“…Given that the biology linking genotype to organism-level phenotype is complex and that the mapping may not generalize across human populations (Martin et al, 2019), predicting “low-level” molecular phenotypes from genetic information is a promising alternative. Recent work has successfully explored such differences in protein-coding sequence (Castellano et al, 2014) and differences relevant to gene expression, such as divergent gene regulation (Colbran et al, 2019), differential methylation (Gokhman et al, 2019), and divergent 3D genome contacts (McArthur et al, 2022).…”

In silico discovery of repetitive elements as key sequence determinants of 3D genome folding

“…Mean squared error captures large-scale contact map changes, and has been used previously to rank predictions [20]. Pearson/Spearman correlation is also an appropriate choice [27].…”

“…We can probe these models as computational oracles to predict the behavior of DNA sequence at scales intractable experimentally [25]. Models have been applied to predict the impact of structural variants on human genome folding [20,26], confirm the importance of CTCF through computational mutagenesis [20], and resurrect the folding of Neanderthal genomes [27]. These early reports show that many highly disruptive perturbations lack CTCF or annotated regulatory elements, hinting that there may be sequences that encode information needed for genome folding left to uncover.…”

Loquens : A characterization of “Hunter-Gatherers of Words”

“…There was no "great leap forward". Detailed comparative analyses of ancient genomes cataloging changes that set contemporary humans apart from neanderthals and denisovans (Pääbo, 2014;Kuhlwilm and Boeckx, 2019;McArthur et al, 2022), did not, and are highly unlikely to reveal "big bang" mutations of the sort Berwick and Chomsky (2016)…”