An X-linked haplotype of Neandertal origin is present among all non-African populations

Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.     

X-Linked MTMR8 Diversity and Evolutionary History of Sub-Saharan Populations

The genetic diversity within an 11 kb segment of the MTMR8 gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary humans originated from a single population or as an amalgamation of different populations separated by years of independent evolution, thus suggesting a greater antiquity of our species than generally assumed. While the oldest sub-Saharan lineages, ∼500 thousand years, are found among Khoe-San from southern-Africa, a distinct haplotype found among Biaka is likely due to admixture from an even older population. An East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where MTMR8 is located. This and similar sweeps in four other regions of the X chromosome, documented in the literature, effectively reduced genetic diversity of non-African chromosomes and therefore may have exacerbated the effect of the demographic bottleneck usually ascribed to the out of Africa migration. Our data is suggestive, however, that a bottleneck, occurred in Africa before range expansion.     

Spatial and temporal distribution of the neutral polymorphisms in the last ZFX intron: analysis of the haplotype structure and genealogy.

With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.     

Haplotypes in the dystrophin DNA segment point to a mosaic origin of modern human diversity

Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one T(n) microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotypes in 1,343 chromosomes from around the world. Although a classical out-of-Africa topology was observed in trees based on the variant frequencies, the tree of haplotype sequences reveals three lineages accounting for present-day diversity. The proportion of new recombinants and the diversity of the T(n) microsatellite were used to estimate the age of haplotype lineages and the time of colonization events. The lineage that underwent the great expansion originated in Africa prior to the Upper Paleolithic (27,000-56,000 years ago). A second group, of structurally distinct haplotypes that occupy a central position on the tree, has never left Africa. The third lineage is represented by the haplotype that lies closest to the root, is virtually absent in Africa, and appears older than the recent out-of-Africa expansion. We propose that this lineage could have left Africa before the expansion (as early as 160,000 years ago) and admixed, outside of Africa, with the expanding lineage. Contemporary human diversity, although dominated by the recently expanded African lineage, thus represents a mosaic of different contributions.     

Out of Africa and the evolution of human behavior

Twenty‐one years ago, a landmark exploration of mitochondrial DNA diversity popularized the idea of a recent African origin for all living humans. 1 The ancestral African population was estimated to have existed 200 ka (thousands of years ago) plus or minus a few tens of thousands of years. A corollary was that at some later date the fully modern African descendants of that population expanded to swamp or replace the Neanderthals and other nonmodern Eurasians. The basic concept soon became known as “Out of Africa,” after the Academy Award winning film (1985) that took its title, in turn, from Isak Dinesen's classic autobiography (1937). Many subsequent genetic analyses, including those of Ingman and coworkers 2 and Underhill and coworkers, 3 have reaffirmed the fundamental Out of Africa model. The fossil and archeological records also support it strongly. The fossil record implies that anatomically modern or near‐modern humans were present in Africa by 150 ka; the fossil and archeological records together indicate that modern Africans expanded to Eurasia beginning about 50 ka.     

Deep divergences of human gene trees and models of human origins

Two competing hypotheses are at the forefront of the debate on modern human origins. In the first scenario, known as the recent Out-of-Africa hypothesis, modern humans arose in Africa about 100,000-200,000 years ago and spread throughout the world by replacing the local archaic human populations. By contrast, the second hypothesis posits substantial gene flow between archaic and emerging modern humans. In the last two decades, the young time estimates--between 100,000 and 200,000 years--of the most recent common ancestors for the mitochondrion and the Y chromosome provided evidence in favor of a recent African origin of modern humans. However, the presence of very old lineages for autosomal and X-linked genes has often been claimed to be incompatible with a simple, single origin of modern humans. Through the analysis of a public DNA sequence database, we find, similar to previous estimates, that the common ancestors of autosomal and X-linked genes are indeed very old, living, on average, respectively, 1,500,000 and 1,000,000 years ago. However, contrary to previous conclusions, we find that these deep gene genealogies are consistent with the Out-of-Africa scenario provided that the ancestral effective population size was approximately 14,000 individuals. We show that an ancient bottleneck in the Middle Pleistocene, possibly arising from an ancestral structured population, can reconcile the contradictory findings from the mitochondrion on the one hand, with the autosomes and the X chromosome on the other hand.     

The Date of Interbreeding between Neandertals and Modern Humans

Comparisons of DNA sequences between Neandertals and present-day humans have shown that Neandertals share more genetic variants with non-Africans than with Africans. This could be due to interbreeding between Neandertals and modern humans when the two groups met subsequent to the emergence of modern humans outside Africa. However, it could also be due to population structure that antedates the origin of Neandertal ancestors in Africa. We measure the extent of linkage disequilibrium (LD) in the genomes of present-day Europeans and find that the last gene flow from Neandertals (or their relatives) into Europeans likely occurred 37,000–86,000 years before the present (BP), and most likely 47,000–65,000 years ago. This supports the recent interbreeding hypothesis and suggests that interbreeding may have occurred when modern humans carrying Upper Paleolithic technologies encountered Neandertals as they expanded out of Africa.     

Assessing DNA sequence variations in human ESTs in a phylogenetic context using high-density oligonucleotide arrays

We have analyzed human genomic diversity in 32 individuals representing four continental populations of Homo sapiens in the context of four ape species. We used DNA resequencing chips covering 898 expressed sequence tags (ESTs), corresponding to 109 kb of sequence. Based on the intra-species data, the neutral hypothesis could not be rejected. However, the mutation rate was two times lower than typically observed in functionally unconstrained genomic segments, suggesting a certain level of selection. The worldwide diversity (297 segregating sites and nucleotide diversity of 0.054%) was partitioned among continents, with the greatest amount of variation observed in the African sample. The long-term effective population size of the human population was estimated at 13,000; a similar figure was obtained for the African sample and a 20% lower estimate was obtained for the other continents. Africans also differed in having a higher number of continental-specific polymorphisms contributing to the higher average nucleotide diversity. These results are consistent with the existence of two distinct lineages of modern humans: amalgamation of these lineages in Africa led to the higher present-day diversity on that continent, whereas colonization of other continents by one of them gave the effect of a population bottleneck.     

史前古人类之间的基因交流及对当今现代人的影响

古DNA实验技术及高通量测序技术的出现和发展,使得直接从古老化石中进行遗传物质的提取及测序成为可能,与古人类相关的基因组学研究因此取得了一系列突破性进展,已灭绝的古老型人类(如:尼安德特人和丹尼索瓦人)与非洲以外现代人之间基因的相互影响已被诸多证据所证实。研究表明,在史前时期,早期现代人向非洲以外地区扩散时,遭遇到了现已灭绝的古老型人类,他们在同一时空内长期共存,并发生了基因交流,有一部分古老型人类基因因此流向了现代人,有些基因一直流传至今,对当今现代人的基因组成产生重大影响;此外,不同古老型人类之间也存在基因交流;而早期现代人也对部分古老型人类的基因组成造成了影响。化石与古DNA信息的证据均表明,史前各种人类之间的基因交流在多个地区发生多次,他们的基因交流共同构建了当今现代人的基因库,并在生理机能、形态和疾病发生率等方面对现代人造成了深远的影响。     

Estimating divergence time with the use of microsatellite genetic distances: impacts of population growth and gene flow

Genetic distances play an important role in estimating divergence time of bifurcated populations. However, they can be greatly affected by demographic processes, such as migration and population dynamics, which complicate their interpretation. For example, the widely used distance for microsatellite loci, (deltamu)2, assumes constant population size, no gene flow, and mutation-drift equilibrium. It is shown here that (deltamu)2 strongly underestimates divergence time if populations are growing and/or connected by gene flow. In recent publications, the average estimate of divergence time between African and non-African populations obtained by using (deltamu)2 is about 34,000 years, although archaeological data show a much earlier presence of modern humans out of Africa. I introduce a different estimator of population separation time based on microsatellite statistics, T(D), that does not assume mutation-drift equilibrium, is independent of population dynamics in the absence of gene flow, and is robust to weak migration flow for growing populations. However, it requires a knowledge of the variance in the number of repeats at the beginning of population separation, V(0). One way to overcome this problem is to find minimal and maximal bounds for the variance and thus obtain the earliest and latest bounds for divergence time (this is not a confidence interval, and it simply reflects an uncertainty about the value of V(0) in an ancestral population). Another way to avoid the uncertainty is to choose from among present populations a reference whose variation is presumably close to what it might have been in an ancestral population. A different approach for using T(D) is to estimate the time difference between adjacent nodes on a phylogenetic population tree. Using data on variation at autosomal short tandem repeat loci with di-, tri-, and tetranucleotide repeats in worldwide populations, T(D) gives an estimate of 57,000 years for the separation of the out-of-Africa branch of modern humans from Africans based on the value of V(0) in the Southern American Indian populations; the earliest bound for this event has been estimated to be about 135,000 years. The data also suggest that the Asian and European populations diverged from each other about 20,000 years, after the occurrence of the out-of-Africa branch.     

Out of Africa with regional interbreeding? Modern human origins

A central issue in paleoanthropology is whether modern humans emerged in a single geographic area and subsequently replaced the preexisting people in other areas. Although the study of human mitochondrial DNAs supported this single-origin and complete-replacement model, a recent paper(1) argues that humans expanded out of Africa more than once and regionally interbred. However, both the genetic antiquity and the impact of the African contribution to modern Homo sapiens are so great as to view Africa as a central place of human evolution. Despite the possibility that out-of-Africa H. sapiens interbred with other populations, this evidence is more consistent with the uniregional hypothesis than the multiregional hypothesis of modern human origins.     

DNA polymorphism in a worldwide sample of human X chromosomes

DNA sequence data from humans can provide insight into the history of modern humans and the genetic variability in human populations. We report here a study of human DNA sequence variation at an X-linked noncoding region of 10,346 bp. The sample consists of 62 X chromosomes from Africa, Europe, and Asia. Forty-four polymorphic sites were found among the 62 sequences, resulting in 23 different haplotypes. Statistical analyses of the data led to the following inferences. (1) There is strong evidence of human population expansion in the relatively recent past, and this population expansion has had a significant effect on the pattern of polymorphism at this locus. (2) Non-African populations were unlikely to have been derived from a very small number of African lineages. (3) There was considerable geographic subdivision in the ancient human population, which could be an important reason why many studies failed to detect population expansion. (4) The long-term effective population size of humans is between 12,000 and 15,000. And (5) a non-African specific variant was found at a frequency of 35% in non-Africans, an estimate supported by the genotyping of additional 80 non-African and 106 African X chromosomes. This variant could have arisen in Eurasia more than 140,000 years ago, predating the emergence of modern humans. Moreover, this haplotype and all other haplotypes coalesced to the most recent common ancestor of the sample, which was estimated to be older than 490,000 years. Therefore, this region may have a long history in Eurasia.     

Deletion polymorphism in the human COL1A2 gene: genetic evidence of a non-African population whose descendants spread to all continents

We report the frequencies of a deletion polymorphism at the alpha 2 (1) collagen gene (COL1A2) and argue that this distribution has major implications for understanding the evolution of modern humans immediately after their exodus from sub-Saharan Africa as well as their subsequent spread to all continents. The high frequency of the deletion in non-African populations and its complete absence in sub-Saharan African groups suggest that the deletion event occurred just before or shortly after modern humans left Africa. The deletion probably arose shortly after the African exodus in a group whose descendants were among the ancestors of all contemporary populations, except for sub-Saharan Africans. This, of course, does not imply that there was a single migration out of Africa. The GM immunoglobulin haplotype GM*A,X G displays a similar distribution to that for the COL1A2 deletion, and these 2 polymorphisms suggest that the exodus from Africa may not have been a rapid dispersion to all other regions of the world. Instead, it may have involved a period of time for the savanna-derived gene pool to adapt to novel selective agents, such as bacteria, viruses, and/or environmental xenobiotics found in both animal and plant foods in their new environment. In this context these polymorphisms are indicators of the evolution that occurred before the diaspora of these populations to the current distribution of modern peoples.     

A predominantly indigenous paternal heritage for the Austronesian-speaking peoples of insular Southeast Asia and Oceania

Modern humans reached Southeast Asia and Oceania in one of the first dispersals out of Africa. The resulting temporal overlap of modern and archaic humans-and the apparent morphological continuity between them-has led to claims of gene flow between Homo sapiens and H. erectus. Much more recently, an agricultural technology from mainland Asia spread into the region, possibly in association with Austronesian languages. Using detailed genealogical study of Y chromosome variation, we show that the majority of current Austronesian speakers trace their paternal heritage to Pleistocene settlers in the region, as opposed to more-recent agricultural immigrants. A fraction of the paternal heritage, however, appears to be associated with more-recent immigrants from northern populations. We also show that the northern Neolithic component is very unevenly dispersed through the region, with a higher contribution in Southeast Asia and a nearly complete absence in Melanesia. Contrary to claims of gene flow (under regional continuity) between H. erectus and H. sapiens, we found no ancestral Y chromosome lineages in a set of 1,209 samples. The finding excludes the possibility that early hominids contributed significantly to the paternal heritage of the region.     

Archaic lineages in the history of modern humans

An important question in the ongoing debate on the origin of Homo sapiens is whether modern human populations issued from a single lineage or whether several, independently evolving lineages contributed to their genetic makeup. We analyzed haplotypes composed of 35 polymorphisms from a segment of the dystrophin gene. We find that the bulk of a worldwide sample of 868 chromosomes represents haplotypes shared by different continental groups. The remaining chromosomes carry haplotypes specific for the continents or for local populations. The haplotypes specific for non-Africans can be derived from the most frequent ones through simple recombination or a mutation. In contrast, chromosomes specific for sub-Saharan Africans represent a distinct group, as shown by principal component analysis, maximum likelihood tree, structural comparison, and summary statistics. We propose that African chromosomes descend from at least two lineages that have been evolving separately for a period of time. One of them underwent range expansion colonizing different continents, including Africa, where it mixed with another, local lineage represented today by a large fraction of African-specific haplotypes. Genetic admixture involving archaic lineages appears therefore to have occurred within Africa rather than outside this continent, explaining greater diversity of sub-Saharan populations observed in a variety of genetic systems.     

Paleogenomics of archaic hominins

In order to understand the genetic basis for the evolutionary success of modern humans, it is necessary to compare their genetic makeup to that of closely related species. Unfortunately, our closest living relatives, the chimpanzees, are evolutionarily quite distant. With the advent of ancient DNA study and more recently paleogenomics - the study of the genomes of ancient organisms - it has become possible to compare human genomes to those of much more closely related groups. Our closest known relatives are the Neanderthals, which evolved and lived in Europe and Western Asia, from about 600,000 years ago until their disappearance around 30,000 years ago following the expansion of anatomically modern humans into their range. The closely related Denisovans are only known by virtue of their DNA, which has been extracted from bone fragments dating around 30,000 to 50,000 years ago found in a single Siberian cave. Analyses of Neanderthal and Denisovan nuclear and mitochondrial genomes have revealed surprising insights into these archaic humans as well as our own species. The genomes provide a preliminary catalogue of derived amino acids that are specific to all extant modern humans, thus offering insights into the functional differences between the three lineages. In addition, the genomes provide evidence of gene flow between the three lineages after anatomically modern humans left Africa, drastically changing our view of human evolution.     

Did a discrete event 200,000-100,000 years ago produce modern humans?

Scenarios for modern human origins are often predicated on the assumption that modern humans arose 200,000-100,000 years ago in Africa. This assumption implies that something ‘special’ happened at this point in time in Africa, such as the speciation that produced Homo sapiens, a severe bottleneck in human population size, or a combination of the two. The common thread is that after the divergence of the modern human and Neandertal evolutionary lineages ∼400,000 years ago, there was another discrete event near in time to the Middle-Late Pleistocene boundary that produced modern humans. Alternatively, modern human origins could have been a lengthy process that lasted from the divergence of the modern human and Neandertal evolutionary lineages to the expansion of modern humans out of Africa, and nothing out of the ordinary happened 200,000-100,000 years ago in Africa.Three pieces of biological (fossil morphology and DNA sequences) evidence are typically cited in support of discrete event models. First, living human mitochondrial DNA haplotypes coalesce ∼200,000 years ago. Second, fossil specimens that are usually classified as ‘anatomically modern’ seem to appear shortly afterward in the African fossil record. Third, it is argued that these anatomically modern fossils are morphologically quite different from the fossils that preceded them.Here I use theory from population and quantitative genetics to show that lengthy process models are also consistent with current biological evidence. That this class of models is a viable option has implications for how modern human origins is conceptualized.     

Age of the Association between Helicobacter pylori and Man

When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43–56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya.     

The Expansion of mtDNA Haplogroup L3 within and out of Africa

Although fossil remains show that anatomically modern humans dispersed out of Africa into the Near East ～100 to 130 ka, genetic evidence from extant populations has suggested that non-Africans descend primarily from a single successful later migration. Within the human mitochondrial DNA (mtDNA) tree, haplogroup L3 encompasses not only many sub-Saharan Africans but also all ancient non-African lineages, and its age therefore provides an upper bound for the dispersal out of Africa. An analysis of 369 complete African L3 sequences places this maximum at ～70 ka, virtually ruling out a successful exit before 74 ka, the date of the Toba volcanic supereruption in Sumatra. The similarity of the age of L3 to its two non-African daughter haplogroups, M and N, suggests that the same process was likely responsible for both the L3 expansion in Eastern Africa and the dispersal of a small group of modern humans out of Africa to settle the rest of the world. The timing of the expansion of L3 suggests a link to improved climatic conditions after ～70 ka in Eastern and Central Africa rather than to symbolically mediated behavior, which evidently arose considerably earlier. The L3 mtDNA pool within Africa suggests a migration from Eastern Africa to Central Africa ～60 to 35 ka and major migrations in the immediate postglacial again linked to climate. The largest population size increase seen in the L3 data is 3-4 ka in Central Africa, corresponding to Bantu expansions, leading diverse L3 lineages to spread into Eastern and Southern Africa in the last 3-2 ka.