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Ancient DNA Analysis Elucidates Split of Denisovan, Neanderthal Y Chromosome Lineages

NEW YORK – Through an analysis of ancient Denisovan and Neanderthal DNA samples, researchers in Europe, the US, and China have found that the Y chromosomes of Denisovans split around 700,000 years ago from a Y chromosome lineage that was shared by Neanderthals and modern humans, which diverged from each other around 370,000 years ago.

In a paper published on Thursday in Science, the researchers wrote that the phylogenetic relationships of archaic and modern human Y chromosomes differed from the population relationships inferred from the autosomal genomes, and mirrored mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals.

"We speculate that given the important role of the Y chromosome in reproduction and fertility, the lower evolutionary fitness of Neanderthal Y chromosomes might have caused natural selection to favor the Y chromosomes from early modern humans, eventually leading to their replacement," Martin Petr, a researcher at the Max Planck Institute for Evolutionary Anthropology and first author on the study, said in a statement.

There's a lack of comprehensive research on the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female, the investigators noted. Neanderthals discovered at the Sima de los Huesos site in Spain, which are about 400,000 years old, were shown to carry mitochondrial genomes related to Denisovan mtDNA, suggesting that Neanderthals originally carried a Denisovan-like mtDNA, which was later completely replaced through ancient gene flow from an early lineage related to modern humans.

The Y chromosomes of Neanderthals and Denisovans would provide an additional source of information about population splits and gene flow events between archaic and modern humans or populations related to them, but none of the male Neanderthals or Denisovans studied to date have yielded sufficient amounts of DNA to allow comprehensive studies of archaic human Y chromosomes, the researchers said.

Previous genetic studies have identified two male Denisovans named Denisova 4 (55,000 to 84,000 years old) and Denisova 8 (106,000 to 136,000 years old), and two male late Neanderthals named Spy 94a (38,000 to 39,000 years old) and Mezmaiskaya 2 (43,000 to 45,000 years old). To enrich for Y chromosome DNA from these individuals, the researchers performed hybridization capture using probes they designed to target about 6.9 megabases of the non-recombining portion of the human Y chromosome. They used a capture array designed for modern human Y chromosomes to obtain coverage of about 560 kilobases of the Y chromosome from the El Sidrón 1253 Neanderthal, which had been analyzed in previous studies.

Their analyses determined that the Denisovan Y chromosomes formed a separate lineage that split before Neanderthal and modern human Y chromosomes diverged from each other, unlike the rest of the nuclear genome, which puts Denisovans and Neanderthals as sister groups to modern humans. The two Denisovan Y chromosomes split from the modern human lineage around 700,000 years ago, whereas the three Neanderthal Y chromosomes split from it about 370,000 years ago.

In another analysis, the researchers explored the introgression of modern human Y chromosomes into Neanderthals. Owing to their low effective population size and the reduced efficacy of purifying selection, Neanderthals have accumulated an excess of deleterious variation compared with modern humans, and it has been suggested that introgressed DNA from humans was not neutral. The researchers simulated introgression of modern human Y chromosomes into the Neanderthal population in a single pulse and varied the contribution between 1 percent and 10 percent. They then traced the frequency of the introgressed modern human Y chromosomes in Neanderthals over the course of 100,000 years and calculated how much lower the fitness of an average Neanderthal Y chromosome was compared with an average modern human Y chromosome, using all linked deleterious mutations on each simulated chromosome.

Assuming 5 percent gene flow from modern humans, for example, they found that even a 1 percent reduction in Neanderthal Y chromosome fitness increased the probability of replacement after 50,000 years to about 25 percent, and a 2 percent reduction in fitness increased this probability to about 50 percent.

The researchers refrained from making predictions about the specific process of replacement, because they lacked information about the frequencies of introgressed Y chromosomes in older Neanderthals, potential sex bias in the gene flow, and the fitness effects of single-nucleotide and structural variants on the Y chromosome. However, they said, their models served as a proof-of-principle demonstration that even a simple difference in the efficacy of purifying selection between two lineages can markedly affect introgression dynamics of non-recombining, uniparental DNA.

"We conclude that the Y chromosomes of late Neanderthals represent an extinct lineage closely related to modern human Y chromosomes that introgressed into Neanderthals between about 370,000 and about 100,000 years ago," the authors wrote. "The presence of this Y chromosome lineage in all late Neanderthals makes it unlikely that genetic changes that accumulated in Neanderthal and modern human Y chromosomes before the introgression led to incompatibilities between these groups."

In a related Perspective in Science on Thursday, Aarhus University researcher Mikkel Heide Schierup said that the new study solves important questions about Neanderthal evolutionary history, but also brings up some new ones.

For example, a rapid and total replacement of both the Y chromosome and mitochondrial genome seems like too much of a coincidence to be driven by chance alone, he wrote, especially given the relatively small contribution of Homo sapiens to the Neanderthal nuclear genome. But while some form of natural selection must have contributed to this event, it's completely unclear what that selection event was, Schierup said, adding that "because both the Y chromosome and mitochondrion are inherited as non-recombining units, it is exceedingly difficult to locate targets of natural selection on them."