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Unique Fraction of Modern Human Genome Surprisingly Small, Comparison With Archaic Hominins Suggests

NEW YORK – Just a small fraction of the modern human genome is distinct from genomic sequences of Neanderthals and Denisovans, according to research from the University of California, Santa Cruz that was published in Science Advances on Friday.

"We were surprised by the small fraction of the genome that is truly human-specific. We were also surprised by the enrichment of genes involved in some aspect of neural development and neural function," senior author Richard Green, a researcher with the UCSC Genomics Institute and biomolecular engineering department, said in an email.

Rather than using methods based on linkage disequilibrium or direct comparison to search for archaic hominin ancestry in the human genome, the researchers relied on an ancestral recombination graph (ARG) algorithm known as "speedy ancestral recombination graph estimator" (SARGE), which was designed to parsimoniously put together the available genetic data, filling in remaining gaps in the ARG trees with recombination markers.

"Compared to other methods, our ARG has fewer assumptions and can handle input data from archaic genomes that have admixed with modern genomes," Green explained, noting that the method may not pick up recent relationships that are missing informative substitution or recombination markers but is well suited for dealing with deeper, more ancient relationships.

After validating the ARG approach on simulated and real datasets, the researchers applied it to 279 phased modern human genomes from the Simons Genome Diversity Project, along with high-coverage genome sequences from two Neanderthals and one Denisovan individual.

With the graph produced by SARGE, they then put together a human genome map that distinguished between human-specific parts of the genome and those stemming from admixture with the archaic hominins or from incomplete lineage sorting at sequences passed down from a shared common ancestor.

With this strategy, the team estimated that between 1.5 percent and 7 percent of the modern human genome is human-specific. By retracing the timing of those mutations, the investigators flagged two adaptive surges that contributed to distinctly human parts of the genome, including mutational bursts some 600,000 years ago and 200,000 years ago that have impacted genes involved in processes such as neuron growth, synaptic function, brain development, and RNA splicing.

"Using new tools for genome editing and brain organoid models for neural function, these mutations are obvious and important targets for experimental studies to determine what was selected in our human ancestors after divergence from our most closely related, extinct relatives," the authors wrote.

There were other surprises, too. Along with Neanderthal sequences that were traced back to mixing between Neanderthals and modern human populations outside of Africa, the ARG approach pointed to several bouts of Denisovan admixture involving Denisovans from multiple populations. And specific archaic hominin haplotype blocks not found in human populations from other parts of the world appeared to be somewhat enriched in certain human populations.

"We find support for the hypothesis that Denisovan-like ancestry is the result of multiple introgression events from different source populations," the authors wrote. "We also detect an excess of Neanderthal and Denisovan haplotype blocks unique to South Asian genomes."

They noted that the discovery of additional archaic representatives in the future may provide a better look at the historical interactions between specific archaic hominin and modern human populations, including the group of Denisovans that contributed ancestry to some present-day human populations.