Neanderthal ancestry through time: Insights from genomes of ancient and present-day humans

Abstract: INTRODUCTION
Gene flow from Neanderthals has shaped genetic and phenotypic variation in modern humans. Most non-Africans living today derive ~1 to 2% of their ancestry from Neanderthals. Across the genome, some genomic regions harbor a high frequency of Neanderthal variants and are identified as “candidates of adaptive introgression,” whereas others are devoid of any Neanderthal ancestry and are referred to as “deserts.” However, the timing and evolutionary processes, for example, genetic drift or natural selection, that have shaped the landscape of Neanderthal ancestry remain elusive. Most of the previous studies have focused on genomes of present-day individuals, where separating the effects of past demography and selection is challenging. Ancient DNA analyses have transformed research into human evolutionary history by enabling the direct observation of genetic variation patterns that existed in the past.
RATIONALE
In this study, we analyzed genomic data from 59 ancient individuals sampled between 45,000 and 2200 years before present and 275 diverse present-day individuals to study the evolutionary history of Neanderthal ancestry throughout time. We examined the frequency, length, and distribution of Neanderthal ancestry segments over time to answer the following questions: (i) How is Neanderthal ancestry shared among individuals, by geography and time? (ii) When did Neanderthal gene flow occur and for how long did it last? and (iii) What is the functional legacy of Neanderthal ancestry in modern humans?
RESULTS
We generated a catalog of Neanderthal ancestry in ancient and present-day modern humans and found that the majority of the Neanderthal ancestry segments are shared across populations and that the sharing of Neanderthal ancestry segments mirrors the population structure among non-Africans. The comparison with sequenced Neanderthals, for example, Vindija, Altai, and Chagyrskaya, suggests that the gene flow occurred from a single or multiple closely related Neanderthal groups. By contrast, the earliest modern humans—Oase, Ust’-Ishim, Zlatý kun, and Bacho Kiro—possess substantial unique Neanderthal ancestry and a distinct matching profile to the sequenced Neanderthals, indicating that some Neanderthal ancestry in these early individuals is not shared with modern humans after 40,000 years.
By studying the distribution and lengths of the Neanderthal ancestry segments in ancient individuals, we found evidence for a single extended period of Neanderthal gene flow that occurred ~47,000 years ago and lasted for ~7000 years. This is consistent with archaeological evidence for the potential overlap of early modern humans and Neanderthals in Europe.
Finally, we examined the frequency of Neanderthal ancestry across the genome and over time. We uncovered new candidates of adaptive introgression, including regions that were immediately adaptive for modern humans and some that became adaptive more recently from introgressed standing variation. Most Neanderthal deserts—on the autosomes and the X chromosome—were formed rapidly after the gene flow and were also evident in the earliest modern human genomes. Notably, the X chromosome exhibits a nonuniform and nonrandom distribution of Neanderthal ancestry, with large Neanderthal ancestry deserts overlapping previously identified signals of sweeps in non-Africans.
CONCLUSION
Our study provides insights into the complex history of Neanderthal gene flow into modern humans. We found strong support for a single extended period of Neanderthal gene flow into the common ancestors of all non-Africans that occurred between 50,500 and 43,500 years ago. These dates provide a lower bound for the timing of the out-of-Africa migration and settlement of regions outside Africa. The majority of natural selection—positive and negative—on Neanderthal ancestry happened very quickly after the gene flow and left clear signals in the genetic diversity of the earliest modern humans outside Africa