|
|
Post by Admin on Jul 12, 2024 6:34:57 GMT
New research shows that recurrent episodes of gene flow, beginning 250,000 to 200,000 years ago, affected the genomes and biology of both modern humans and Neanderthals, and estimates that Neanderthals have 2.5 to 3.7% human ancestry. “This is the first time that geneticists have identified multiple waves of modern human-Neanderthal admixture,” said Southeast University’s Professor Liming Li. “We now know that for the vast majority of human history, we’ve had a history of contact between modern humans and Neanderthals,” added Princeton University’s Professor Joshua Akey. “The hominins who are our most direct ancestors split from the Neanderthal family tree about 600,000 years ago, then evolved our modern physical characteristics about 250,000 years ago.” “From then until the Neanderthals disappeared — that is, for about 200,000 years — modern humans have been interacting with Neanderthal populations.”  Using genomes from 2,000 living humans as well as three Neanderthals and one Denisovan, the researchers mapped the gene flow between the hominin groups over the past quarter-million years. They used a genetic tool they designed a few years ago called IBDmix, which uses machine learning techniques to decode the genome. Scientists previously depended on comparing human genomes against a reference population of modern humans believed to have little or no Neanderthal or Denisovan DNA. The study authors have established that even those referenced groups, who live thousands of miles south of the Neanderthal caves, have trace amounts of Neanderthal DNA, probably carried south by voyagers (or their descendants). With IBDmix, they identified a first wave of contact about 200,000-250,000 years ago, another wave 100,000-120,000 years ago, and the largest one about 50,000-60,000 years ago. That contrasts sharply with previous genetic data. “To date, most genetic data suggests that modern humans evolved in Africa 250,000 years ago, stayed put for the next 200,000 years, and then decided to disperse out of Africa 50,000 years ago and go on to people the rest of the world,” Professor Akey said. “Our models show that there wasn’t a long period of stasis, but that shortly after modern humans arose, we’ve been migrating out of Africa and coming back to Africa, too.” “To me, this story is about dispersal, that modern humans have been moving around and encountering Neanderthals and Denisovans much more than we previously recognized.” Recurrent gene flow between Neanderthals and modern humans over the past 200,000 years www.science.org/doi/10.1126/science.adi1768 |
|
|
|
Post by Admin on Jul 14, 2024 1:01:31 GMT
Our understanding of admixture between humans and Neanderthals has changed dramatically over the past decade and a half. Once thought not to have occurred at all, there is now ample evidence for gene flow from Neanderthals to humans and vice versa. Li et al. used a new framework to model the increasingly complex dynamics of introgression between humans and Neanderthals and the ramifications for both populations. They identified regions of human ancestry in Neanderthals, estimated population sizes for Neanderthals were about 20% lower than previously thought, and proposed the possibility of two pulses of gene flow from humans to Neanderthals. This study comprehensively synthesizes our current knowledge of hominin admixture. —Corinne N. Simonti
Structured Abstract
INTRODUCTION
For much of modern human history, we were only one of several different groups of hominins that existed. Studies of ancient and modern DNA have shown that admixture occurred multiple times among different hominin lineages, including between the ancestors of modern humans and Neanderthals. A number of methods have been developed to identify Neanderthal-introgressed sequences in the DNA of modern humans, which have provided insight into how admixture with Neanderthals shaped the biology and evolution of modern human genomes. Although gene flow from an early modern human population to Neanderthals has been described, the consequences of admixture on the Neanderthal genome have received comparatively less attention.
RATIONALE
A better understanding of how admixture with modern humans influenced patterns of Neanderthal genomic variation may provide insights into hominin evolutionary history. For example, DNA sequences inherited from modern human ancestors in Neanderthals can be used to test hypotheses on the frequency, magnitude, and timing of admixture and the population genetics characteristics of Neanderthals. Introgressed modern human sequences in Neanderthals can also be used to refine estimates of Neanderthal ancestry in contemporary individuals. We developed a simple framework to investigate introgressed human sequences in Neanderthals that is predicated on the expectation that sequences inherited from modern human ancestors would be, on average, more genetically diverse and would result in local increases in heterozygosity across the Neanderthal genome.
RESULTS
We first used a method referred to as IBDmix to identify introgressed Neanderthal sequences in 2000 modern humans sequenced by the 1000 Genomes Project. We found that sequences identified by IBDmix as Neanderthal in African individuals from the 1000 Genomes Project are significantly enriched in regions of high heterozygosity in the Neanderthal genome, whereas no such enrichment is observed with sequences detected as introgressed in non-African individuals. We show that these patterns are caused by gene flow from modern humans to Neanderthals and estimate that the Vindija and Altai Neanderthal genomes have 53.9 Mb (2.5%) and 80.0 Mb (3.7%) of human-introgressed sequences, respectively. We leverage human-introgressed sequences in Neanderthals to revise estimates of the amount of Neanderthal-introgressed sequences in modern humans. Additionally, we show that human-introgressed sequences cause Neanderthal population size to be overestimated and that accounting for their effects decrease estimates of Neanderthal population size by ~20%. Finally, we found evidence for two distinct epochs of human gene flow into Neanderthals.
CONCLUSION
Our results provide insights into the history of admixture between modern humans and Neanderthals, show that gene flow had substantial impacts on patterns of modern human and Neanderthal genomic variation, and show that accounting for human-introgressed sequences in Neanderthals enables more-accurate inferences of admixture and its consequences in both Neanderthals and modern humans. More generally, the smaller estimated population size and inferred admixture dynamics are consistent with a Neanderthal population that was decreasing in size over time and was ultimately being absorbed into the modern human gene pool.
|
|
|
|
Post by Admin on Jul 17, 2024 2:18:23 GMT
Studies of ancient DNA have shown that admixture among modern humans (Homo sapiens), Neanderthals, and Denisovans has played a prominent role in hominin evolutionary history (1). Although genetic data from Neanderthal and Denisovan individuals continue to accumulate (2–10), inferences of gene flow among hominin lineages have largely focused on high-coverage, whole-genome sequence (WGS) data from three Neanderthals and one Denisovan (3–6). The Vindija (4) and Chagyrskaya (5) Neanderthals were excavated from the Vindija cave in Croatia and the Chagyrskaya cave in the Altai Mountains, respectively, whereas the Altai Neanderthal (also referred to as Denisova 5) (3) and the Denisovan hominin (also named Denisova 3) (6) were both excavated from the Denisova Cave in the Altai Mountains. These genomes combined with WGS data from thousands of modern humans have revealed a network of interactions—including gene flow—between modern humans and Neanderthals (2, 3, 11), between modern humans and two distinct Denisovan populations (12), and between Neanderthals and Denisovans (3, 13), including an F1 hybrid who had a Neanderthal mother and Denisovan father (10). In modern humans, non-African individuals derive ~2% of their genome from Neanderthal ancestors (2), and individuals of Melanesian and Australian aboriginal ancestry can trace an additional 2 to 5% of their genome to Denisovan ancestors, with the highest levels in certain Philippine groups (14). In addition to estimates of admixture proportions, numerous approaches have been developed to identify the specific DNA sequences in the genomes of modern humans that were inherited from Neanderthals and Denisovans (15–17). The resulting catalogs of introgressed sequences have enabled their functional, phenotypic, and evolutionary consequences to be studied (18–23). For example, analyses of Neanderthal-introgressed sequences in modern humans have shown that they were targets of both purifying and positive selection (24–26), have facilitated the development of more-refined admixture models (24, 27–30), and have enabled insights into the phenotypic legacy of admixture (23). In contrast to the detailed studies of how admixture with Neanderthals affected the genomes of modern humans, comparatively little is known about the consequences that admixture had on the Neanderthal genome. Several studies have shown evidence of modern human ancestry in the Neanderthal genome (31–33) as a result of admixture that predates the out-of-Africa dispersal of ~60 thousand years ago (ka) (11, 34), to which contemporary non-Africans can trace the majority of their ancestry (35–38). Thus, admixture between modern humans and Neanderthals has occurred at least twice, with one admixture resulting in modern human–to-Neanderthal (H→N) gene flow ~250 to 200 ka and the other admixture resulting in Neanderthal-to–modern human (N→H) gene flow ~60 to 50 ka (39) (Fig. 1A). The signal of modern human–to-Neanderthal gene flow was initially detected in the Altai Neanderthal (31) but was also subsequently found in the Vindija (32), which suggests that admixture occurred before the divergence of these two lineages (Fig. 1A).  Fig. 1. Neanderthal-introgressed sequences identified in African individuals are associated with regions of high heterozygosity in the Neanderthal genome. (A) Schematic of modern human–to-Neanderthal (H→N) and Neanderthal-to–modern human (N→H) gene flow. Red and blue lines represent modern human and Neanderthal lineages, respectively. AFR, EUR, and EAS denote African, European, and East Asian, respectively. (B) Schematic showing how H→N admixture can lead to regions of high heterozygosity in the Neanderthal genome and calls of introgressed Neanderthal sequence in modern humans. Two Neanderthal, AFR, and EUR chromosomes are shown. Red segments in Neanderthal chromosomes denote modern human–introgressed sequences due to H→N gene flow. Black segments represent IBDmix-called introgressed Neanderthal sequences in modern humans due to a mixture of H→N and N→H gene flow. H→N admixture can result in local increases of heterozygosity, whereas N→H admixture does not. The bar plot shows the amount of introgressed sequence identified in EUR and AFR samples when the entire genome is analyzed (unmasked) or when loci in the human genome that overlap high-heterozygosity regions in the Neanderthal genome (gray rectangles) are removed from the analysis (masked). (C) Genome-wide distribution of heterozygosity calculated in nonoverlapping 100-kb windows across the Altai Neanderthal genome. Solid and dashed lines represent the 99th percentile and average heterozygosity, respectively. (D) Proportion of windows in the Altai Neanderthal genome that overlap AFR (purple) and non-AFR (light blue) calls of introgressed Neanderthal sequences as a function of heterozygosity in the Neanderthal genome. The x axis represents the percentile of heterozygosity for analyzed windows. Heterozygosity of windows decreases from left to right. (E) Heterozygosity in regions of the Altai Neanderthal and Denisovan genomes that overlap IBDmix calls of introgressed Neanderthal sequence in Africans and non-Africans. The dashed line represents the genome-wide average heterozygosity of Altai. |
|
|
|
Post by Admin on Jul 19, 2024 2:32:21 GMT
Expected characteristics of human-introgressed sequences in Neanderthals Our approach for investigating modern human–to-Neanderthal gene flow is predicated on two observations made in previous studies of hominin admixture. First, our framework takes advantage of the well-known differences in Ne between modern humans and Neanderthals (3–5). Second, our approach derives power from the fact that both H→N and N→H gene flow make substantial contributions to the signal of Neanderthal-introgressed sequences identified in African individuals (33), whereas the signal of Neanderthal-introgressed sequences detected in non-African individuals is primarily the result of N→H admixture (2, 33). Given these observations, we hypothesized that introgressed modern human sequences in Neanderthal genomes would result in local increases in levels of heterozygosity (Fig. 1, B and C) given the larger Ne of modern humans compared with that of Neanderthals. If true, we would expect regions of high heterozygosity in the Neanderthal genome to overlap sequences identified as Neanderthal in African individuals more often compared with sequences identified as Neanderthal in non-African individuals (Fig. 1B). We would further expect that when regions of high heterozygosity in the Neanderthal genome are masked, the amount of detected introgressed sequence would decrease more in Africans compared with non-Africans (because the signal from H→N admixture is attenuated, which preferentially affects African individuals; Fig. 1B). Below, we evaluate these predicted features using empirical data. Regions of high heterozygosity in Neanderthal genomes are enriched for introgressed modern human sequences To assess the relationship between Neanderthal heterozygosity and the probability of calling introgressed Neanderthal sequences in Africans and non-Africans, we applied IBDmix (33) to 2000 individuals from the 1000 Genomes Project (40). IBDmix detects introgressed sequences by identifying segments in a test genome that are shared identical by descent with an archaic reference genome. To mitigate false positives, a minimum segment size threshold is used, which we previously specified in units of physical distance (33). In this work, we extended IBDmix to also allow segment sizes to be measured in units of genetic distance, which results in a lower false discovery rate (FDR) while maintaining the same power compared with physical distance–based thresholds (41) (fig. S1). Using a minimum segment size threshold of 0.05 centimorgans (cM), we identified 92.4, 85.5, and 84.3 gigabases (Gb) of introgressed Neanderthal sequence across all 2000 individuals using the Vindija Neanderthal (4), Altai Neanderthal (3), and Chagyrskaya Neanderthal (5) as the archaic reference genome, respectively (table S1). IBDmix calls in African individuals were significantly enriched at locations of the human genome that overlap regions of high heterozygosity in the Neanderthal genome compared with those in non-African individuals (Fig. 1D). For example, 60% of windows in the top fifth percentile of high-heterozygosity regions in the Altai genome overlapped calls of Neanderthal-introgressed sequence in Africans compared with only 23% of windows in non-Africans (Fig. 1D). Similar patterns were observed with the Vindija and Chagyrskaya genomes (fig. S2). Furthermore, Neanderthal heterozygosity in regions that overlap calls of introgressed sequence in Africans is 8.6 times as high relative to Neanderthal heterozygosity in regions that overlap introgressed sequence in non-Africans (Fig. 1E). As a control, we compared levels of heterozygosity in the same regions of the Denisovan genome and only observed a 1.3-fold difference in heterozygosity between Africans and non-Africans (Fig. 1E). In addition, Kuhlwilm et al. (31) have reported 162 regions of the Altai Neanderthal genome that had elevated heterozygosity and were putatively introgressed from modern humans, of which 130 overlap our high-heterozygosity regions, which is significantly more than expected by chance . Collectively, these observations demonstrate that regions of high heterozygosity in the Neanderthal genome are enriched for modern human–introgressed sequences. |
|
|
|
Post by Admin on Jul 24, 2024 20:16:03 GMT
Decomposing IBDmix calls into their component sources Genomic segments that IBDmix detects as Neanderthal introgressed are potentially a mixture of sequences derived from both H→N and N→H gene flow. Thus, to specifically investigate the characteristics of modern human–to-Neanderthal gene flow, it is necessary to distinguish between these two component sources. To this end, we evaluated whether the summary statistics RInd and RPop (41) could distinguish between IBDmix calls of introgressed sequence attributable to H→N or N→H gene flow. RInd is the ratio of the average number of introgressed base pairs per individual called by IBDmix in Africans relative to Europeans, and RPop is the ratio of the number of base pairs of the reference modern human genome covered by one or more IBDmix calls in Africans relative to that in Europeans (41, 42). We estimated RInd and RPop using each of the five African populations and Europeans from the 1000 Genomes Project (40) and evaluated their relationship with levels of heterozygosity in the Neanderthal genome (41). Both RInd and RPop are higher for LWK (Luhya in Webuye, Kenya) and GWD (Gambian in Western Division, The Gambia) compared with MSL (Mende in Sierra Leone), YRI (Yoruba in Ibadan, Nigeria), and ESN (Esan in Nigeria), which suggests that they have higher amounts of introgressed Neanderthal sequence (Fig. 2A). Despite the quantitative differences in RInd and RPop among African populations, they all qualitatively show the same pattern as a function of heterozygosity in the Neanderthal genome.  |
|
