Ornella Semino

Distinctive Paleo-Indian migration routes from Beringia marked by two rare mtDNA haplogroups.

BACKGROUND It is widely accepted that the ancestors of Native Americans arrived in the New World via Beringia approximately 10 to 30 thousand years ago (kya). However, the arrival time(s), number of expansion events, and migration routes into the Western Hemisphere remain controversial because linguistic, archaeological, and genetic evidence have not yet provided coherent answers. Notably, most of the genetic evidence has been acquired from the analysis of the common pan-American mitochondrial DNA (mtDNA) haplogroups. In this study, we have instead identified and analyzed mtDNAs belonging to two rare Native American haplogroups named D4h3 and X2a. RESULTS Phylogeographic analyses at the highest level of molecular resolution (69 entire mitochondrial genomes) reveal that two almost concomitant paths of migration from Beringia led to the Paleo-Indian dispersal approximately 15-17 kya. Haplogroup D4h3 spread into the Americas along the Pacific coast, whereas X2a entered through the ice-free corridor between the Laurentide and Cordilleran ice sheets. The examination of an additional 276 entire mtDNA sequences provides similar entry times for all common Native American haplogroups, thus indicating at least a dual origin for Paleo- Indians. CONCLUSIONS A dual origin for the first Americans is a striking novelty from the genetic point of view, and it makes plausible a scenario positing that within a rather short period of time, there may have been several entries into the Americas from a dynamically changing Beringian source. Moreover, this implies that most probably more than one language family was carried along with the Paleo-Indians.

Genetic evidence of an early exit of Homo sapiens sapiens from Africa through eastern Africa.

The out-of-Africa scenario has hitherto provided little evidence for the precise route by which modern humans left Africa. Two major routes of dispersal have been hypothesized: one through North Africa into the Levant, documented by fossil remains, and one through Ethiopia along South Asia, for which little, if any, evidence exists. Mitochondrial DNA (mtDNA) can be used to trace maternal ancestry. The geographic distribution and variation of mtDNAs can be highly informative in defining potential range expansions and migration routes in the distant past. The mitochondrial haplogroup M, first regarded as an ancient marker of East-Asian origin, has been found at high frequency in India and Ethiopia, raising the question of its origin. (A haplogroup is a group of haplotypes that share some sequence variations.) Its variation and geographical distribution suggest that Asian haplogroup M separated from eastern-African haplogroup M more than 50,000 years ago. Two other variants (489C and 10873C) also support a single origin of haplogroup M in Africa. These findings, together with the virtual absence of haplogroup M in the Levant and its high frequency in the South-Arabian peninsula, render M the first genetic indicator for the hypothesized exit route from Africa through eastern Africa/western India. This was possibly the only successful early dispersal event of modern humans out of Africa.

The molecular dissection of mtDNA haplogroup H confirms that the Franco-Cantabrian glacial refuge was a major source for the European gene pool.

Complete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup--by far the most common in Europe--is subdivided into numerous subhaplogroups, with at least 15 of them (H1-H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast--a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (~11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ~15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event.

Origin, Diffusion, and Differentiation of Y-Chromosome Haplogroups E and J: Inferences on the Neolithization of Europe and Later Migratory Events in the Mediterranean Area

The phylogeography of Y-chromosome haplogroups E (Hg E) and J (Hg J) was investigated in >2400 subjects from 29 populations, mainly from Europe and the Mediterranean area but also from Africa and Asia. The observed 501 Hg E and 445 Hg J samples were subtyped using 36 binary markers and eight microsatellite loci. Spatial patterns reveal that (1). the two sister clades, J-M267 and J-M172, are distributed differentially within the Near East, North Africa, and Europe; (2). J-M267 was spread by two temporally distinct migratory episodes, the most recent one probably associated with the diffusion of Arab people; (3). E-M81 is typical of Berbers, and its presence in Iberia and Sicily is due to recent gene flow from North Africa; (4). J-M172(xM12) distribution is consistent with a Levantine/Anatolian dispersal route to southeastern Europe and may reflect the spread of Anatolian farmers; and (5). E-M78 (for which microsatellite data suggest an eastern African origin) and, to a lesser extent, J-M12(M102) lineages would trace the subsequent diffusion of people from the southern Balkans to the west. A 7%-22% contribution of Y chromosomes from Greece to southern Italy was estimated by admixture analysis.

Excavating Y-chromosome haplotype strata in Anatolia

Analysis of 89 biallelic polymorphisms in 523 Turkish Y chromosomes revealed 52 distinct haplotypes with considerable haplogroup substructure, as exemplified by their respective levels of accumulated diversity at ten short tandem repeat (STR) loci. The major components (haplogroups E3b, G, J, I, L, N, K2, and R1; 94.1%) are shared with European and neighboring Near Eastern populations and contrast with only a minor share of haplogroups related to Central Asian (C, Q and O; 3.4%), Indian (H, R2; 1.5%) and African (A, E3*, E3a; 1%) affinity. The expansion times for 20 haplogroup assemblages was estimated from associated STR diversity. This comprehensive characterization of Y-chromosome heritage addresses many multifaceted aspects of Anatolian prehistory, including: (1) the most frequent haplogroup, J, splits into two sub-clades, one of which (J2) shows decreasing variances with increasing latitude, compatible with a northward expansion; (2) haplogroups G1 and L show affinities with south Caucasus populations in their geographic distribution as well as STR motifs; (3) frequency of haplogroup I, which originated in Europe, declines with increasing longitude, indicating gene flow arriving from Europe; (4) conversely, haplogroup G2 radiates towards Europe; (5) haplogroup E3b3 displays a latitudinal correlation with decreasing frequency northward; (6) haplogroup R1b3 emanates from Turkey towards Southeast Europe and Caucasia and; (7) high resolution SNP analysis provides evidence of a detectable yet weak signal (<9%) of recent paternal gene flow from Central Asia. The variety of Turkish haplotypes is witness to Turkey being both an important source and recipient of gene flow.

Where West Meets East: The Complex mtDNA Landscape of the Southwest and Central Asian Corridor

The southwestern and Central Asian corridor has played a pivotal role in the history of humankind, witnessing numerous waves of migration of different peoples at different times. To evaluate the effects of these population movements on the current genetic landscape of the Iranian plateau, the Indus Valley, and Central Asia, we have analyzed 910 mitochondrial DNAs (mtDNAs) from 23 populations of the region. This study has allowed a refinement of the phylogenetic relationships of some lineages and the identification of new haplogroups in the southwestern and Central Asian mtDNA tree. Both lineage geographical distribution and spatial analysis of molecular variance showed that populations located west of the Indus Valley mainly harbor mtDNAs of western Eurasian origin, whereas those inhabiting the Indo-Gangetic region and Central Asia present substantial proportions of lineages that can be allocated to three different genetic components of western Eurasian, eastern Eurasian, and south Asian origin. In addition to the overall composite picture of lineage clusters of different origin, we observed a number of deep-rooting lineages, whose relative clustering and coalescent ages suggest an autochthonous origin in the southwestern Asian corridor during the Pleistocene. The comparison with Y-chromosome data revealed a highly complex genetic and demographic history of the region, which includes sexually asymmetrical mating patterns, founder effects, and female-specific traces of the East African slave trade.

Phylogeography of Y-Chromosome Haplogroup I Reveals Distinct Domains of Prehistoric Gene Flow in Europe

To investigate which aspects of contemporary human Y-chromosome variation in Europe are characteristic of primary colonization, late-glacial expansions from refuge areas, Neolithic dispersals, or more recent events of gene flow, we have analyzed, in detail, haplogroup I (Hg I), the only major clade of the Y phylogeny that is widespread over Europe but virtually absent elsewhere. The analysis of 1,104 Hg I Y chromosomes, which were identified in the survey of 7,574 males from 60 population samples, revealed several subclades with distinct geographic distributions. Subclade I1a accounts for most of Hg I in Scandinavia, with a rapidly decreasing frequency toward both the East European Plain and the Atlantic fringe, but microsatellite diversity reveals that France could be the source region of the early spread of both I1a and the less common I1c. Also, I1b*, which extends from the eastern Adriatic to eastern Europe and declines noticeably toward the southern Balkans and abruptly toward the periphery of northern Italy, probably diffused after the Last Glacial Maximum from a homeland in eastern Europe or the Balkans. In contrast, I1b2 most likely arose in southern France/Iberia. Similarly to the other subclades, it underwent a postglacial expansion and marked the human colonization of Sardinia approximately 9,000 years ago.

New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing

The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.

The genome-wide structure of the Jewish people

Contemporary Jews comprise an aggregate of ethno-religious communities whose worldwide members identify with each other through various shared religious, historical and cultural traditions. Historical evidence suggests common origins in the Middle East, followed by migrations leading to the establishment of communities of Jews in Europe, Africa and Asia, in what is termed the Jewish Diaspora. This complex demographic history imposes special challenges in attempting to address the genetic structure of the Jewish people. Although many genetic studies have shed light on Jewish origins and on diseases prevalent among Jewish communities, including studies focusing on uniparentally and biparentally inherited markers, genome-wide patterns of variation across the vast geographic span of Jewish Diaspora communities and their respective neighbours have yet to be addressed. Here we use high-density bead arrays to genotype individuals from 14 Jewish Diaspora communities and compare these patterns of genome-wide diversity with those from 69 Old World non-Jewish populations, of which 25 have not previously been reported. These samples were carefully chosen to provide comprehensive comparisons between Jewish and non-Jewish populations in the Diaspora, as well as with non-Jewish populations from the Middle East and north Africa. Principal component and structure-like analyses identify previously unrecognized genetic substructure within the Middle East. Most Jewish samples form a remarkably tight subcluster that overlies Druze and Cypriot samples but not samples from other Levantine populations or paired Diaspora host populations. In contrast, Ethiopian Jews (Beta Israel) and Indian Jews (Bene Israel and Cochini) cluster with neighbouring autochthonous populations in Ethiopia and western India, respectively, despite a clear paternal link between the Bene Israel and the Levant. These results cast light on the variegated genetic architecture of the Middle East, and trace the origins of most Jewish Diaspora communities to the Levant.

The Archaeogenetics of Europe

A new timescale has recently been established for human mitochondrial DNA (mtDNA) lineages, making mtDNA at present the most informative genetic marker system for studying European prehistory. Here, we review the new chronology and compare mtDNA with Y-chromosome patterns, in order to summarize what we have learnt from archaeogenetics concerning five episodes over the past 50,000 years which significantly contributed to the settlement history of Europe: the pioneer colonisation of the Upper Palaeolithic, the Late Glacial re-colonisation of the continent from southern refugia after the Last Glacial Maximum, the postglacial re-colonization of deserted areas after the Younger Dryas cold snap, the arrival of Near Easterners with an incipient Neolithic package, and the small-scale migrations along continent-wide economic exchange networks beginning with the Copper Age. The available data from uniparental genetic systems have already transformed our view of the prehistory of Europe, but our knowledge of these processes remains limited. Nevertheless, their legacy remains as sedimentary layers in the gene pool of modern Europeans, and our understanding of them will improve substantially when more mtDNAs are completely sequenced, the Y chromosome more thoroughly analysed, and haplotype blocks of the autosomal genome become amenable to phylogeographic studies.