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Am. J. Hum. Genet. 75:000–000, 2004
Phylogeography of Y-Chromosome Haplogroup I Reveals Distinct Domains of Prehistoric Gene Flow in Europe
Siiri Rootsi,1,* Chiara Magri,2* Toomas Kivisild,1 Giorgia Benuzzi,2 Hela Help,1Marina Bermisheva,1,3 Ildus Kutuev,1,3 Lovorka Barac´,1,4 Marijana Pericˇic´,1,4 Oleg Balanovsky,1,5Andrey Pshenichnov,1,5 Daniel Dion,1,7 Monica Grobei,1,8 Lev A. Zhivotovsky,6Vincenza Battaglia,2 Alessandro Achilli,2 Nadia Al-Zahery,2 Ju¨ri Parik,1 Roy King,9Cengiz Cinniog˘lu,9 Elsa Khusnutdinova,3 Pavao Rudan,4 Elena Balanovska,5Wolfgang Scheffrahn,7 Maya Simonescu,8 Antonio Brehm,10 Rita Goncalves,10Alexandra Rosa,1,10 Jean-Paul Moisan,11 Andre Chaventre,11 Vladimir Ferak,12 Sandor Fu¨redi,13Peter J. Oefner,14 Peidong Shen,14 Lars Beckman,15 Ilia Mikerezi,16 Rifet Terzic´,17Dragan Primorac,18,19 Anne Cambon-Thomsen,20 Astrida Krumina,21 Antonio Torroni,2Peter A. Underhill,9 A. Silvana Santachiara-Benerecetti,2 Richard Villems,1 and Ornella Semino2
1Department of Evolutionary Biology, University of Tartu and Estonian
Biocentre, Tartu, Estonia; 2Dipartimento di Genetica e Microbiologia,
Universita` di Pavia, Pavia, Italy; 3Institute of Biochemistry and Genetics, Ufa
Research Center, Russian Academy of Sciences, Ufa; 4Institute for
Anthropological Research, Zagreb, Croatia; 5Research Centre for Medical
Genetics, Russian Academy of Medical Sciences, and 6N. I. Vavilov Institute of
General Genetics, Russian Academy of Sciences, Moscow; 7Institute of
Anthropology, University of Zurich-Irchel, Zurich; 8Institute of Cellular
Biology and Pathology “Nicolae Simionescu,” Bucharest, Romania; 9Department of
Genetics, Stanford University, Stanford; 10Human Genetics Laboratory, Center of
Macaronesian Studies, University of Madeira, Madeira, Portugal; 11Laboratoire
Polymorphisme de l’ADN, Faculte´ de Me´decine, Nantes, France; 12Department of Molecular Genetics, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia; 13Institute of Forensic Sciences, Budapest; 14Stanford DNA Sequencing and Technology Center, Palo Alto; 15Gotland University, Visby, Sweden; 16Department of Biology, Faculty of Natural Sciences, Tirana University, Tirana, Albania; 17Department of Biology and Genetics, Medical School Tuzla, Tuzla, Bosnia and Herzegovina; 18Medical School at Split University, Split, Croatia; 19Medical School at Osijek University, Osijek, Croatia; 20Inserm U 558, Epidemiologie et Analyses en Sante´ Publique: Risques, Maladies Chroniques et Handicaps, Faculte de Medecine, Toulouse, France; and 21Medical Academy of Latvia, Riga, Latvia
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 ∼9,000 years ago.
Haplogroup (Hg) I-M170 is a component of the European Y-chromosome gene pool, accounting, on average, for 18% of the total paternal lineages. Its virtual absence elsewhere, including the Near East, suggests that it arose in Europe, likely before the Last Glacial Maximum (LGM) (Semino et al. 2000).
Previous studies revealed that Hg I reached a frequency of ∼40%–50% in two distinct regions—in Nordic populations of Scandinavia and, in southern Europe, around the Dinaric Alps—each showing different background STR modal haplotypes (Semino et al. 2000; Passarino et al. 2002; Barac´ et al. 2003). In addition, subclade I-M26 (Underhill et al. 2000) reaches a very high frequency (∼40%) (Semino et al. 2000; Passarino et al. 2001; Francalacci et al. 2003) in Sardinia, particularly in the “archaic area” (Cappello et al. 1996; Zei et al. 2003), and is associated with the peculiar YCAIIb-11 allele (Ciminelli et al. 1995; Caglia et al. 1997; Quintana-Murci et al. 1999; Malaspina et al. 2000; Scozzari et al. 2001). Overall, these observations suggest that Hg I could have played a central role in the process of human recolonization of Europe from isolated refuge areas after the LGM and suggest the likelihood that a comprehensive phylogeographic study should be able to localize the in situ origin and spread of principal male founders.
In the present study, the M170 ArC transversion, which defines Hg I, was assessed in a total of 7,574 subjects, including 6,095 Y chromosomes from 48 European populations and 1,479 individuals from 12 populations of surrounding regions (the Near East, Macaronesia, Central Asia, and the Caucasus). The results are reported in table 1, together with 407 additional members of Hg I out of 3,859 Y chromosomes extracted from the literature. Of the 1,104 Y chromosomes from the present study (1,060 from European subjects and 44 from the adjacent regions) that showed the derived M170 C-allele, 236, representative of the entire collection, were first examined for all the Hg I mutations known to date—namely, M21, M26, P37, M72, M223, M227, M253, M258, M284, and M307, whose phylogenetic relationships are illustrated in figure 1A. Genotyping was performed in a hierarchical way, and methods are provided in the legend to figure 1. The M258 and M307 mutations were observed in all of the Hg I and I1a Y chromosomes, respectively, whereas the M21, M72, and M284 mutations were not found. Thus, all of these were subsequently omitted in the remainder of the survey. To evaluate the differentiation of the I subclades (fig. 2), 533 Hg I Y chromosomes from 34 population samples were examined for the microsatellites DYS19, DYS388, DYS390, DYS391, DYS392, and DYS393 (Roewer et al. 1992, 1996; Thomas et al. 1998, 1999); 183 of the same chromosomes (from 20 populations) were also genotyped for the DYS389 (Roewer et al. 1996), YCAIIa, and YCAIIb (Mathias et al. 1994) loci; and 128 were also genotyped for the 49a,f system (for a review, see Poloni et al. ). The results obtained were used to construct the network illustrated in figure 2. The STR and 49a,f data are available upon request.
Hg I accounts for more than one-third of paternal lineages in two distinct regions of Europe: among Scandinavian populations and in the northwestern Balkans (table 1; fig. 1B). Relatively high frequencies are also characteristic of some French regions, like Low Normandy and southern France. Interestingly, a lower frequency of haplogroup I distinguished the Baltic-speaking Latvians (7.0%; 90% CI 3.8%–13.2%) from their northern neighbors, the Finnic-speaking Estonians (18.6%; 90% CI 14.6%–23.4%). Similar cases of even more significant frequency change over a short geographic distance occur between the southern Slavic-speaking populations and their adjacent neighbors: namely, the Slovenians versus the northern Italians (38.2%; 99.9% CI 19.5%–60.2% vs. 4.6%; 99.9% CI 1.4%–11.7%), and Macedonians versus Greeks (30.0%; 95% CI 19.1%–43.8% vs.13.8%; 95% CI 10.1%–18.5%).
As reported in table 1 and illustrated in figure 1A, three subhaplogroups, defined by the M253 (I1a), P37 (I1b), and M223 (I1c) markers, account for 95% of the Hg I Y chromosomes, and the remaining subhaplogroups belong to paragroup I*. Subhaplogroup I1a is mostly found in northern Europe, with its highest frequencies in Scandinavian populations, where it accounts for 88%–100% of Norwegian, Swedish, and Saami M170 lineages. I1a has a decreasing gradient from its peak frequency in Scandinavia toward both the Urals and the Atlantic periphery (fig. 1C). Its I1a4 subclade has been found mainly as single observations scattered in eastern and southeastern Europe. Since the Scandinavian Peninsula was completely depopulated during the LGM, two main European refugia, the Iberian Peninsula/southern France and the Ukraine/Central Russian Plain (Dolukhanov 2000), can be considered as possible source regions of Scandinavian I1a chromosomes. Although Hg I occurs in the Ukraine at a higher incidence (22%) than in western Europe (11% in France), the virtual absence in Scandinavia of the most represented eastern European I1b* subclade, together with the higher I1a microsatellite diversity background, point to western Europe as the source of the Scandinavian I1a chromosomes, since the STR diversity of I1a decreases from western to eastern Europe, showing a significant negative correlation (r p 0.63; significance level 0.99) with longitude. In France, I1a is the leading subclade, representing 45% of the Hg I lineages, which, however, occur in a focal rather than clinal pattern. Hg I is more frequent in Low Normandy (I p 23.8%; I1a p 11.9%) and southern France (I p 15.8%; I1a p 5.3%), whereas it has a much lower occurrence in the Poitier and Lyon interior regions (I p 4.0%; I1a p 2.0%). Interestingly, subclade I1a shows a distribution similar to the second PC of the synthetic maps based on classical genetic markers (Cavalli-Sforza et al. 1994) and reveals a significantly positive correlation with mtDNA haplogroups V and U5b (r p 0.47; r p V U5b 0.60; significance level 0.999), which have been suggested to mark a postglacial population expansion from Iberia (Torroni et al. 1998, 2001; Tambets et al. 2004).
A different scenario has to be envisioned for subhaplogroup I1b*, which is the most frequent clade in eastern Europe and the Balkans. It reaches its highest incidences in Croatia (31%) and Bosnia (40%), encompassing almost 80%–90% of I (table 1- not shown). In western Europe, its subclade I1b2 (M26) (fig. 1F) (Semino et al. 2000; Bosch et al. 2001; Capelli et al. 2003; Maca-Meyer et al. 2003) is found at a very low frequency (!5%), except in Sardinia (41%), Castile (19%) (Flores et al., in press), Bearnais (8%), and in the Basques (6%). Although subclade I1b2 and the paragroup I1b* (the latter present at marginal frequencies) co-occur west of the Italian Apennines, only I1b* is present east of the Adriatic. I1b* Y chromosomes rapidly dissipate west of the Balkans—they are virtually absent among Italians, Germans, French, and Swiss (table 1; fig. 1E)—but extend eastward at notable frequencies among Slavic-speaking populations. This finding suggests that, similar to I1a, I1b* also may have expanded from a glacial refuge area. However, this area was most likely located in eastern Europe or the Balkans.
Table 1 is not shown.
In central and eastern Europe, subhaplogroups I1a and I1b
show overlapping frequency gradients, although with opposite post-LGM spreading.
The divergent distributions of I1b2 and I1b* suggest that their separation
occurred before the LGM and that the M26 mutation arose in a I1b Y chromosome
from western Europe, most likely in a population in Iberia/southern France. The
exceptionally high incidence of I1b2 in the archaic zone of Sardinia (Cappello
et al. 1996; Zei et al. 2003) can be explained by the presence of I1b2
chromosomes among the first humans who colonized the island, ∼9,000 years ago,
followed by isolation and genetic drift. The extremely low frequency of I1b2 in
the Scandinavian Peninsula, where the “western European” I1a Y chromosomes
account for the large majority of Hg I, suggests, in addition, that the
ancestral western European population(s), characterized by the M26 mutation,
probably played a minor role in the colonization of that
region. A geographic and genetic subdivision within the broad western refuge area, together with differences in initial sample size, genetic drift, and expansions, could also explain the quite different distribution of Hg I subhaplogroups with respect to the west-east decreasing gradient displayed by R1b, the most frequent subhaplogroup in western Europe.
Figure 1 A, Phylogram of Hg I and its subclades within the context of the superhaplogroup F. Mutation labeling follows theYChromosome Consortium nomenclature (Y Chromosome Consortium 2002; Jobling and Tyler-Smith 2003). Markers M21 and M72 (Underhill et al. 2001) and the three new markers—M258 (a TrC transition at position 123), M284 (ACAAdel at position 105), and M307 (a GrA transversion at position 282)—were examined in a subset of 236 Y chromosomes, representative of the entire collection, by using the DHPLC method. The primers used for the new markers were as follows: F, 5 -tatatagcatatgttaaatgtttaggt-3 and R, 5 -gacttttgaataatttgcatctttc-3 for M258; F, 5 -ggcagttttcatttaagcaga-3 and R, 5 -agcgaaactttcagcacttc-3 for M284; and F, 5 -ttattggcatttcaggaagtg-3 and R, 5 -gggtgaggcaggaaaatagc-3 for M307. When the DHPLC method was not used, M170 was detected as described by Ye et al. (2002); M253 was detected by using published primers (Cinniog˘ lu et al. 2004) and restriction analysis with HincII; P37 was assayed by TaaI digestion using the primers given by YCC (2002); and M223, M26, and the novel M227 (a CrG transversion at position 157) were studied by sequencing using published primers (Underhill et al. 2001) and the primers F, 5 -gagtgccaagctgaggatg-3 and R, 5 -tccttgcagccgctgaggag-3 , respectively. Aminority (n p 67) of widely geographically distributed Hg I Y chromosomes (table 1) not tested for M258 and not harboring derived alleles at the sites M253, P37, and M223 were aggregated into paragroup I*. B–F, Frequency distribution of haplogroup I (B) and its subclades: I1a (C), I1c (D), I1b* (E), and I1b2 (F). Maps were obtained by applying the frequencies from table 1 in Surfer (version 7) software (Golden Software).
The high STR diversity of the I1b* lineages in Bosnia supports the view that the P37 SNP might have been present in the Balkan area before the LGM, as previously proposed by Semino et al. (2000). Diversity h values based on STR haplotypes for I1a are highest near Iberia but vary substantially in different populations (table 2). For I1b*, conversely, the highest h values are in the Balkan populations—among Bosnians (0.93) and Croats (0.85)—coinciding with the area of its frequency peak, but equally high values were also observed for Czechs and Slovaks (0.90). The lowest h values of I1b* were detected among Turks (0.76) and in our Moldavian sample (0.41).
Figure 2 Network of haplogroup I. The network was obtained by using the biallelic markers and six STR loci (DYS19, DYS388, DYS390, DYS391, DYS392, and DYS393) in 533 Hg I chromosomes from 34 populations (Andalusian, Basques [French and Spanish], Bearnais, French [southern France, Low Normandy, Lyon, and Poitier], Swiss, Dutch, Italian [northern Italy, central Italy, Calabria1, Calabria2 of Albanese origin, Apulia, and Sardinia], Croat, Bosnian, Albanian, Macedonian, Moldavian, Gagauz, Greek, Swedish, Norwegian, Saami, Estonian, Polish, Czech, Slovak, Hungarian, Ukrainian, Turkish, and Jewish). The phylogenetic relationships between the 58 microsatellite haplotypes (out of the 156 observed) with frequency 11 were determined by using the program NETWORK 4.0b (Fluxus Engineering Web site). Networks were calculated by the median-joining method ( p 0) (Bandelt et al. 1995), weighting the STR loci according to the average of their relative variability in the haplogroup I subclades and after having processed the data with the reduced-median method. Circles represent microsatellite haplotypes. Unless otherwise indicated by a number on the pie, the area of the circles and the area of the sectors are proportional to the haplotype frequency in the haplogroup (the smallest circle corresponds to two individuals) and in the geographic area indicated by the color. The inset reveals, in more detail, the relationship between I1b2 and I1b* in a subsample of 103 Y chromosomes from 20 populations. The network was determined as described above but, in this case, in addition to the above mentioned six STR loci, the YCAIIa, YCAIIb, and DYS389 microsatellites and the 49a,f system were also considered. Here, the smallest circle of the network corresponds to a single Y chromosome. Very stable YCAII motifs characterize both I1b* (YCAIIa-21/YCAIIb-21) and I1b2 (YCAIIa-21/YCAIIb-11), supporting the hypothesis that single-banded patterns and very short alleles are due to deletion events rather than stepwise mutations.
Subhaplogroup I1c (fig. 1D) covers a wide range in Europe, with the highest frequencies (∼5%–12%) in northwestern Europe and lower frequencies elsewhere. Its geographic and linguistic correlations across the continent were insignificant. However, the 49a,f system and the microsatellites YCAIIa-YCAIIb reveal that I1a and I1c harbor an identical compound haplotype (49a,f Ht12/YCAIIa-21/YCAIIb-19), which is different from those of I1b* (49a,f Ht10/YCAIIa-21/YCAIIb-21) and I1b2 (49a,f Ht12/YCAIIa-21/YCAIIb-11). These results indicate that subhaplogroups I1a and I1c may be part of a single monophyletic clade whose deep biallelic mutations are still undefined and that they probably share a common history of expansion. This scenario is also supported by the high positive correlation between the geographic distributions of I1a and I1c (r p 0.75 when Fennoscandia is excluded; significance level 0.999).
Table 2 - Haplotype Diversity of I1a and I1b*
|Czech and Slovak||.857||.904|
*Ia Haplotype diversity values were calculated according to Nei (1987), using
the STR (DYS19, DYS388, DYS390, DYS391, DYS392, and DYS393) haplotype
frequencies only when more than five Y chromosomes were found to belong to
either I1a or I1b*.
Anatolia is at the easternmost fringe of the spread of haplogroup I, where it is found at higher frequencies in the regions that are geographically closer to Europe (Cinniog ˘ lu et al. 2004). This observation, combined with a low haplotype diversity in Turkey plus exact haplotype matches with Europe, suggests that haplogroup I Y chromosomes in Turkey are due to migrations from Europe, as has been argued for a fraction of the Turkish mtDNAs (Richards et al. 2000).
Table 3. Age Estimates and Divergence Times of Haplogroup I Subclades
|AGE ESTIMATE OR
|HAPLOGROUP I SUBCLADE|
|Time since subclade divergencea||---||15.9 ± 5.2b||10.7 ± 4.8b||9.3 ± 7.6c||14.6 ± 3.8b|
|Age of STR variationd||24.0 ± 7.1||8.8 ± 3.2||7.6 ± 2.7||8.0 ± 4.0||13.2 ± 2.7|
|Time since population divergencee||23.0 ± 7.7f||6.8 ± 1.9g||7.1 ± 2.5||7.9 ± 3.6h||11.2 ± 2.3i|
a The times, in
thousands of years, when the subclades I1a, I1b*, and I1c diverged from I*, as
well as when
I1b2 diverged from I1b*, were estimated by using the TD estimator: T p (D 2V )/2w (Zhivotovsky et al. D 1 0
2001, 2004). Here, D1 is the average squared difference between two alleles sampled from two populations; V0
is the within-population variance in the number of repeats in the ancestral population prior to its subdivision,
estimated as a half square difference between the allele repeat scores at the founder haplotypes; and w is the
effective mutation rate of 0.00069 per locus per 25 years (Zhivotovsky et al. 2004).
b Divergence from I*.
c Divergence from I1b*.
d The age of STR variation of a subclade was estimated as the average squared difference in the number of
repeats between all sampled chromosomes and the founder haplotype, divided by w. Ages of STR variation
within clades I and I1b were estimated by using I* and I1b* Y chromosomes, respectively. This makes them
statistically independent from the STR variation of their subclades, although they could be still biased because
of uncertainties on founder haplotypes.
e The age of population expansion (divergence), estimated with TD, letting V p 0, gives its upper bound. 0
Time since population divergence was analyzed only in populations with a sample size of at least five individuals;
the estimates give an upper bound for the time of population expansion (divergence).
f Since all populations, except the Turks, were represented within I* by fewer than five individuals each, only
two samples were compared: Turks versus “Others.”
g Obtained by comparing Croat, Czech, Estonian, French, Hungarian, Norwegian, Saami, Swedish, Swiss,
Turkish, and Ukrainian populations.
h Since all populations, except the Sardinians, were represented within I1b2 by fewer than five individuals
each, only two samples were compared: Sardinians versus “Others.”
i Because of the small sample size for each separate population, we used five combined samples—namely,
southern European (Albanian, Calabrian, central Italian, Sardinian, southern French), northern European (Norwegian, Swedish, Estonian, Dutch), eastern/central European (Hungarian, Croat, Czech, Slovakian), western/central European (French–Low Normandy, French-Lyon, northern Italian, Swiss), and southern/eastern European (Gagauz, Turkish, Ukrainian).
A temporal interpretation of the phylogeography based on the results of the STR length variation in the individual subhaplogroups of I (Zhivotovsky et al. 2004) is reported in table 3. The age of STR variation for I* was estimated as 24,000 7,100 years, a value that is very close to the population divergence time (23,000 7,700 years). This finding supports the earlier suggestion that haplogroup I originated from a pool of European pre-LGM, middle Upper Paleolithic Y chromosomes (Semino et al. 2000). Our time estimates hint that its initial spread in Europe may be linked to the diffusion of the largely pan-European Gravettian technology ∼28,000–23,000 years ago (Djindjian 2000; Perles 2000). On the other hand, these values represent the lower limit of the age of M170 mutation. The precedent mutation (M89) (fig. 1A) defines the overarching superhaplogroup F, whose representatives span the entire non-African gene pool, likely predating the peopling of Europe (some 40,000–50,000 years ago). Potentially more informative are the estimates of subclade divergence times. Thus, it appears that I1a, I1b, and I1c al diverged from I* in the Late Upper Paleolithic/Mesolithic period (table 3), possibly during the recolonization of Europe after the LGM. However, the expansion phase of I1a and I1b, displaying contrasting phylogeographies, seems to have occurred later, around the early Holocene. Only the less frequent subclade I1c, spread thinly over much of Europe, from Mordvin in the Volga region to southern France (table 1; fig. 1D), shows a somewhat earlier age for its STR variation (table 3), suggesting that the corresponding mutation arose earlier.
In conclusion, although haplogroup I represents only a single piece in the puzzle of European genetic variation, its essential continental specificity and the clearly defined phylogeographic patterns of its subclades contribute uniquely to understanding the human settlement of Europe. Haplogroup I provides an exceptional record of European-specific paternal heritage, including pre-LGM differentiation followed by contraction, isolation, and subsequent post-LGM expansions and spread. Still, the wide CIs in the time estimates dictate caution in definitively linking the phylogeography of this haplogroup with known prehistoric and historic scenarios. Nonetheless, the I1a data in Scandinavia are consistent with a post-LGM recolonization of northwestern Europe from Franco-Cantabria, whereas the expansion of I1b* in the east Adriatic–North Pontic continuum probably reflects demographic processes that began in a refuge area located in that region.
We are grateful to all the donors for providing blood samples and to the people who contributed to their collection. We thank Ille Hilpus and Jaan Lind for technical assistance. We wish to thank the reviewers, whose comments and suggestions helped us to improve the quality of the manuscript. This research was supported by Estonian basic research grant 514 and European Commission Directorate General Research grant ICA1CT20070006 (to R.V.); Estonian basic research grant 5574 (to T.K.); Russian Foundation for Basic Research project numbers 01-04-48487a (to E.K.), 04-06-80260a (to E.B.), and 04-04-49664a (to O.B.); Ministry of Sciences and Technology of Russia (to E.K.); Progetto Finalizzato Consiglio Nazionale della Ricerche (CNR) “Beni Culturali” (to A.S.S.-B.); Progetto MIUR-CNR Genomica Funzionale-Legge 449/97 (to A.T.); Fondo d’Ateneo per la Ricerca dell’Universita` di Pavia (to A.S.S.-B. and A.T.); the Italian Ministry of the University: Progetti Ricerca Interesse Nazionale 2002 and 2003 (to A.T.); National Institutes of Health grant GM28428 (to the Stanford researchers); and Ministry of Science and Technology of the Republic of Croatia project number 0196005 (to P.R.).
Electronic-Database Information: The URL for data presented herein is as follows: Fluxus Engineering, http://www.fluxus-engineering.com/ (for NETWORK 4.0b)
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