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Date Posted: 09:00:24 10/13/02 Sun
Author: Ãàáåëîê
Subject: Ñòàòòÿ
In reply to: Êðîò 's message, "Óêðà¿íà ³ À𳿠(for Habelok)" on 03:11:07 10/11/02 Fri

Îñü ñòàòòÿ, íàæàëü áåç ìàïè òà òàáëèöü, ÿê³ º â pdf, ôàéëàõ.
Öå ç æóðíàëó Ñàºíñ, ÿê º äîñòóï ìîæåòå ïîäèâèòèñÿ â îðèã³íàë³.

The Genetic Legacy of
Paleolithic Homo sapiens
sapiens in Extant Europeans: A
Y Chromosome Perspective
Ornella Semino,1,2*† Giuseppe Passarino,2,3† Peter J. Oefner,4
Alice A. Lin,2 Svetlana Arbuzova,5 Lars E. Beckman,6
Giovanna De Benedictis,3 Paolo Francalacci,7
Anastasia Kouvatsi,8 Svetlana Limborska,9 Mladen Marcikiæ,10
Anna Mika,11 Barbara Mika,12 Dragan Primorac,13
A. Silvana Santachiara-Benerecetti,1 L. Luca Cavalli-Sforza,2
Peter A. Underhill2
A genetic perspective of human history in Europe was derived from 22 binary
markers of the nonrecombining Y chromosome (NRY). Ten lineages account for
.95% of the 1007 European Y chromosomes studied. Geographic distribution
and age estimates of alleles are compatible with two Paleolithic and one
Neolithic migratory episode that have contributed to the modern European
gene pool. A significant correlation between the NRY haplotype data and
principal components based on 95 protein markers was observed, indicating the
effectiveness of NRY binary polymorphisms in the characterization of human
population composition and history.
Various types of evidence suggest that the
present European population arose from the
merging of local Paleolithic groups and Neolithic
farmers arriving from the Near East after
the invention of agriculture in the Fertile Crescent
(1–5). However, the origin of Paleolithic
European groups and their contribution to the
present gene pool have been debated (6, 7).
Assuming no selection, local differentiation occurred
in isolated and small Paleolithic groups
by drift (8, 9). Range expansions and population
convergences, which occurred at the end of
the Paleolithic, were catalyzed by improved
climate and new technologies and spread the
present genetic characteristics to surrounding
areas (8). The smaller effective population size
of the NRY enhances the consequences of drift
and founder effect relative to the autosomes,
making NRY variation a potentially sensitive
index of population composition. Previously,
the distribution of two NRY restriction fragment
length polymorphism (RFLP) markers
suggested Paleolithic and Neolithic contributions
to the European gene pool (10). NRY
binary markers (11) representing unique mutational
events in human history allow a more
comprehensive reconstruction of European genetic
history.
Twenty-two relevant binary markers [4
gathered from the literature and 18 detected
by denaturing high-performance liquid chromatography
(DHPLC) (12)] were genotyped
in 1007 Y chromosomes from 25 different
European and Middle Eastern geographic regions.
More than 95% of the samples studied
could be assigned to haplotypes or clades of
haplotypes defined by just 10 key mutations
(Fig. 1 and Table 1). The frequency distribution
of Y chromosome haplotypes revealed here
defines the basic structure of the male component
of the extant European populations and
provides testimony to population history, including
the Paleolithic period. Two lineages
(those characterized by M173 and M170) appear
to have been present in Europe since Paleolithic
times. The remaining lineages entered
Europe most likely later during independent
migrations from the Middle East and the Urals
as they are found at higher frequencies and with
more variation of linked microsatellites than in
other continents (10–14).
Of the 22 haplotypes that constitute the
phylogeny in Fig. 1 (top), Eu18 and Eu19 characterize
about 50% of the European Y chromosomes.
Although they share M173, the two
haplotypes show contrasting geographic distribution.
The frequency of Eu18 decreases from
west to east, being most frequent in Basques
(Fig. 1, bottom, and Table 1). This lineage
includes the previously described proto-European
lineage that is characterized by the 49a,f
haplotype 15 (10). In contrast, haplotype Eu19,
which is derived from the M173 lineage and is
distinguished by M17, is virtually absent in
Western Europe. Its frequency increases eastward
and reaches a maximum in Poland, Hungary,
and Ukraine, where Eu18 in turn is virtually
absent. Both haplotypes Eu18 and Eu19
share the derived M45 allele. The lineage characterized
by M3, common in Native Americans
1Dipartimento di Genetica e Microbiologia, Universita`
di Pavia, Via Ferrata 1, 27100 Pavia, Italy. 2Department
of Genetics, Stanford University School of Medicine,
300 Pasteur Drive, Stanford, CA 94305–5120,
USA. 3Dipartimento di Biologia Cellulare, Universita`
della Calabria, 87030 Rende, Italy. 4Stanford Genome
Technology Center, 855 California Avenue, Palo Alto,
CA 94304, USA. 5International Medico-Genetic Centre,
Hospital Nol, 57 Artem Str, 340000 Donetsk,
Ukraine. 6Department of Oncology, Pathology and
Medical Genetics, University of Umeå, S-901 85
Umeå, Sweden. 7Dipartimento di Zoologia e Antropologia
Biologica, Universita` di Sassari, Via Regina Margherita,
15, 07100 Sassari, Italy. 8Department of Genetics,
Development and Molecular Biology, Aristotle
University, 54006 Thessaloniki, Macedonia, Greece.
9Institute of Molecular Genetics, Russian Academy of
Sciences, Kurchatov Square, 2, Moscow 123182, Russia.
10Clinical Hospital Center Osijek, Department of
Pathology Medical School, J Huttlera 4, 31000 Osijek,
Croatia. 11Regionalne Centrum Krwiodawstwa i Krwiolecznictwa
w Lublinie–Oddzial w, Zamosciu, ul Legionow
10, 22400 Zamosc, Poland. 12Samodzielny
Publiczny Szpital Wojwodzki im. Papieza Jona Pawla II
w, Zamosciu, ul Legionow 10, 22400 Zamosc, Poland.
13University Hospital Split, Department of Pediatrics,
Laboratory for Clinical and Forensic Genetics, Spine`
iæeva 1, 21000 Split, Croatia.
*To whom correspondence should be addressed. Email:
semino@ipvgen.univp.it
†These authors contributed equally to this work.
R E P O R T S
www.sciencemag.org SCIENCE VOL 290 10 NOVEMBER 2000 1155
(12) and a few Siberian populations (15), is also
a derivative of M45. This observation suggests
that M173 is an ancient Eurasiatic marker that
was brought by or arose in the group of Homo
sapiens sapiens who entered Europe and diffused
from east to west about 40,000 to 35,000
years ago (16, 17), spreading the Aurignac
culture. This culture also appeared almost simultaneously
in Siberia (17), from which some
groups eventually migrated to the Americas.
We interpret the differentiation and the distribution
of haplotypes Eu18 and Eu19 as signatures
of expansions from isolated population
nuclei in the Iberian peninsula and the present
Ukraine, following the Last Glacial Maximum
(LGM). In fact, during this glacial period
(20,000 to 13,000 years ago), human groups
were forced to vacate Central Europe, with the
exception of a refuge in the northern Balkans
(16). Similar discrete patterns of the flora and
fauna in Europe have been attributed to glaciation-
modulated isolation followed by dispersal
from climatic sanctuaries (18). This scenario is
also supported by the finding that the maximum
variation for microsatellites linked to Eu19 is
found in Ukraine (19). In turn, the maximum
variation for microsatellites linked to 49a,f
Ht15 and its derivatives (and then to the Eu18
lineage) is in the Iberian peninsula (19). This is
consistent with the diffusion of M173-marked
Eu18 from its refuge after the LGM, in agreement
with mitochondrial DNA (mtDNA) haplogroup
V and some of the H lineages (20).
Haplotype Eu19 has been also observed at substantial
frequency in northern India and Pakistan
(12) as well as in Central Asia (12). Its
spread may have been magnified by the expansion
of the Yamnaia culture from the “Kurgan
culture” area (present-day southern Ukraine)
into Europe and eastward, resulting in the
spread of the Indo-European language (21). An
alternative hypothesis of a Middle Eastern origin
of Indo-European languages was proposed
on the basis of archaeological data (3).
We estimated the age of M173 by using
the variation of three microsatellites, namely
DYS19, YCAIIa, and YCAIIb (22). Although
an estimate of ;30,000 years for
M173 must be interpreted cautiously (23), it
is consistent with our hypothesis that M173
marks the Aurignac settlement in Europe or,
at least, predates the LGM.
The polymorphism M170 represents another
putative Paleolithic mutation whose age has
been estimated to be ;22,000 years (22, 23).
With the exception of idiosyncratic distributions
indicative of recent gene flow, M170 is
confined to Europe (Eu7). The mutation is most
frequent in central Eastern Europe and also
occurs in Basques and Sardinians that have
accumulated a subsequent mutation (M26) that
distinguishes Eu8. The closest phylogenetic
predecessor is the M89 mutation, from which
the most important Middle Eastern lineages
originated. We propose that M170 originated in
Europe in descendants of men that arrived from
the Middle East 20,000 to 25,000 years ago,
who have been associated with the Gravettian
culture (16). This migration may have coincided
with that of mtDNA haplogroup H to Europe.
It has been suggested that Gravettian and
Aurignac groups coexisted for a few thousand
years, maintaining their identities despite occasional
contacts. During the LGM, Western Europe
was isolated from Central Europe, where
an Epi-Gravettian culture persisted in the area
of present-day Austria, the Czech Republic, and
the northern Balkans (16). After climatic improvement,
this culture spread north and east
(16). This finding is supported by the present
Eu7 haplotype distribution. In this scenario,
haplotype Eu8 would have originated in the
western Paleolithic population during the LGM,
Fig. 1. (Top) Maximum parsimony phylogeny of the NRY markers found in Europe and elsewhere.
YAP (32), TAT (14), RPS4 [5 RPS4YC711T (33)], and 4064 [5 SRY4064 (34)] were previously
described. The remaining polymorphisms were identified with DHPLC (11, 12, 27) and are deposited
in the National Center for BioTechnology Information (NCBI) dbSNP database (www.ncbi.nlm.
nih.gov/SNP). The phylogeny is rooted with the use of great ape sequences. (Bottom) The 19
haplotypes observed (Table 1) were pooled into six classes represented by different colors: Yellow
indicates haplotype Eu4; blue includes Eu7 and Eu8, which both involve the M170 mutation; red
groups three separate haplotypes for reasons explained in the text; pink includes haplotypes Eu13
and Eu14, which both involve the TAT mutation; and green indicates Eu18 and purple indicates
Eu19, which despite sharing the M173 mutation are distinguished because they represent a distinct
dichotomy in European phylogeography. The other nine observed haplotypes, which catalog the
remaining ,5% of the total samples, are shown as black dashed lines and are represented in the
white sector of relevant pie charts. Three haplotypes, Eu2, Eu5, and Eu21, were not detected. The
pie sectors are proportional to the relative frequencies of haplotypes or clades in each population.
The two Basque samples have been pooled.
R E P O R T S
10 NOVEMBER 2000 VOL 290 SCIENCE www.sciencemag.org 1156
as local differentiation of the M170 lineage.
The frequency and the distribution of haplogroup
H across Europe support gene flow between
Gravettian and Western European Aurignac
groups and suggest differential gender migratory
phenomena (24).
The cline of frequencies for haplotypes
marked by M35 (Eu4), M172 (Eu9), M89
(Eu10), and M201 (Eu11) decreases from the
Middle East into Europe. Haplotype Eu4 is
phylogenetically distinct from the other three
and defines most European YAP1 chromosomes.
The Eu4 haplotype appears to correspond
to the previously reported Ht-4, defined
by the absence of M2 (25). Comparative genotyping
with the Y chromosome RFLPs 49a,f
and 12f2 [(10) and citations therein] revealed
that Eu9 and Eu10 share the 12f2-derived 8Kb
allele, whereas Eu11 has the ancestral 12f2-
10Kb allele. Haplotypes Eu9, Eu10, and
Eu11share the 49a,f haplotype 8 or its derivatives,
which are not observed in any of the other
16 Eu haplotypes (19), suggesting a shared
common ancestry. Thus, we have displayed the
combined frequencies of haplotypes Eu9, Eu10,
and Eu11 in Fig. 1. By correlation between
Ht-4 ' Eu4 and 12f2-8Kb ' Eu9 and Eu10,
the origin of these lineages has been estimated
to be about 15,000 to 20,000 years ago (13). A
similar date (17,000 years ago) for Eu11 has
been estimated (22, 23). The molecular age of a
mutation and its corresponding haplotype must
predate the demographic migratory event it
marks. The age estimates of these haplotypes,
especially considering their approximation (22,
23), cannot distinguish whether they came to
Europe before or after the LGM. However, the
decreasing clinal pattern of haplotypes Eu4,
Eu9, Eu10, and Eu11 from the Middle East to
Europe would not be compatible with the localization
of peoples carrying these Y chromosomes
to refuges during the LGM. If these
haplotypes were present in Europe before the
LGM, we would expect to see a differentiation
between the European and Middle Eastern lineages
because of temporal and spatial isolation.
Unpublished data from a 49a,f system and seven
short tandem repeats (STRs) in a large sample
of these NRY haplotypes from Europe and
the Middle East (19) have revealed that almost
all the compound haplotypes observed in Europe
were included in the smaller sample of the
Middle East (19). A similar result was observed
for mtDNA haplogroup J, which, although considered
Paleolithic, is believed to have been
introduced to Europe during the Neolithic (6).
These observations suggest that the four NRY
haplotypes, as well as mtDNA haplogroup J,
had sufficient time to differentiate in the Middle
East and then migrate toward Europe in sufficiently
large numbers to account for most of
the existing variation. Therefore, haplotypes
Eu4, Eu9, Eu10, and Eu11 represent the male
contribution of a demic diffusion of farmers
from the Middle East to Europe. The contribution
of the Neolithic farmers to the European
gene pool seems to be more pronounced along
the Mediterranean coast than in Central Europe.
This is evident from Fig. 2, in which we have
plotted the frequencies of haplotypes Eu4, Eu9,
Eu10, and Eu11 against the geographic distances
from the Middle East for each population.
The regression line accounting for
Mediterranean populations has a slope that is
significantly different from the other populations,
indicating that the diffusion of Neolithic
farmers affected Southern more than
Central Europe.
Table 1. Frequencies (in percent) of the haplotypes found in the examined European populations.
Population† n
Haplotypes*
Eu1 Eu3 Eu4 Eu6 Eu7 Eu8 Eu9 Eu10 Eu11 Eu12 Eu13 Eu14 Eu15 Eu16 Eu17 Eu18 Eu19 Eu20 Eu21
Andalusian 29 10.3 3.4 6.9 3.4 6.9 3.4 65.5
Spanish
Basque 45 2.2 2.2 4.4 2.2 88.9
French
Basque 22 9.1 4.5 86.4
Catalan 24 4.2 4.2 4.2 8.3 79.2
French 23 8.7 17.4 13.0 4.3 52.2 4.3
Dutch 27 3.7 22.2 70.4 3.7
German 16 6.2 37.5 50.0 6.2
Czech and
Slovakian 45 2.2 15.6 8.9 4.4 2.2 2.2 2.2 35.6 26.7
Centralnorthern
Italian 50 2.0 8.0 14.0 10.0 62.0 4.0
Calabrian 37 2.7 13.5 21.6 10.8 8.0 2.7 5.4 32.4 2.7
Sardinian 77 1.3 10.4 1.3 2.6 35.1 5.2 5.2 14.2 1.3 22.1 1.3
Croatian 58 6.9 44.8 5.2 1.7 1.7 10.3 29.3
Albanian 51 2.0 21.6 19.6 23.5 4.0 2.0 17.6 9.8
Greek 76 1.3 22.4 1.3 7.9 21.0 1.3 2.6 1.3 1.3 27.6 11.8
Macedonian 20 15.0 20.0 15.0 5.0 10.0 35.0
Polish 55 3.6 23.6 16.4 56.4
Hungarian 45 8.9 11.1 2.2 2.2 2.2 13.3 60.0
Ukrainian 50 4.0 18.0 6.0 4.0 2.0 6.0 2.0 2.0 54.0 2.0
Georgian 63 33.3 3.2 30.1 1.6 1.6 1.6 14.3 7.9 6.3
Turkish 30 3.3 13.3 3.3 40.0 3.3 6.6 3.3 3.3 3.3 3.3 6.6 6.6 3.3
Lebanese 31 25.8 3.2 3.2 29.0 16.1 3.2 3.2 6.4 9.7
Syrian 20 10.0 10.0 5.0 15.0 30.0 5.0 15.0 10.0
Saami 24 41.7 41.7 8.3 8.3
Udmurt 43 4.7 7.0 4.7 2.3 27.9 4.6 11.6 37.2
Mari 46 4.3 6.5 4.3 65.2 6.5 13.0
Total 1007
*The haplotypes are defined by the following markers and the respective derived alleles: Eu1, M13-C; Eu3, YAP1, 4064-A; Eu4, YAP1, 4064-A, M35-C; Eu6, RPS4-T; Eu7, M89-T, M170-C;
Eu8, M89-T, M170-C, M26-A; Eu9, M89-T, M172-G; Eu10, M89-T; Eu11, M89-T, M201-T; Eu12, M89-T, M69-C; Eu13, M89-T, M9-G, TAT-C; Eu14, M89-T, M9-G, TAT-C, M178-T; Eu15,
M89-T, M9-G, M70-C; Eu16, M89-T, M9-G; Eu17, M89-T, M9-G, M11-G; Eu18, M89-T, M9-G, M45-A, M173-C; Eu19, M89-T, M9-G, M45-A, M173-C, M17(delG); Eu20, M89-T, M9-G,
M45-A; Eu21, M89-T, M9-G, M45-A, M124-T. Haplotypes Eu2, Eu5, and Eu22 were not observed. †Several samples were previously described (10, 11, 28). Samples not previously
examined included 23 French, 16 Germans, 39 northern Italians, 45 Sardinians, 58 Croats, 20 Macedonians from northern Greece, 55 Poles, 50 Ukrainians, 20 Syrians, 24 Saami, 43
Udmurts, and 46 Mari.
R E P O R T S
www.sciencemag.org SCIENCE VOL 290 10 NOVEMBER 2000 1157
While allelotyping M35 by DHPLC, we
found a previously unknown mutation, M178,
in 95% of all TAT chromosomes. The latter has
been reported to be ;4000 years old and marks
a recent Uralic migration confined to Northern
Europe (14). Neither TAT nor M178 was detected
in Hungary, where a Uralic language is
spoken.
The first two principal components (PC)
derived from the data in Table 1 are shown in
Fig. 3. The Udmurts, Mari, and Saami were
excluded because they monopolized the first
PC and compressed the rest of the variation
because of their high TAT/M178 frequency. In
the plot, it is possible to see three clusters of
distinct geography and culture. The first comprises
Basques and Western Europeans, the second
Middle Eastern, and the third Eastern European
populations from Croatia, Ukraine,
Hungary, and Poland. These three geographic
clusters correspond to the major glacial refuges
and to the region of origin of the farmers’
expansion.
The most comprehensive previous survey of
the European gene pool has been the PC analysis
of 95 autosomal protein polymorphisms (5,
8). We compared the frequency distribution of
the major Eu Y chromosome haplotypes with
the first three PCs of Europe (Table 2). Because
Sardinians were not included in the original PC
analysis because of their pronounced outlier
phylogenetic status (5), they were also excluded
in our correlation analysis. The first PC, which
was proposed to reflect the diffusion of Neolithic
farmers (5, 8), correlates with Eu4, Eu9,
Eu10, and Eu11. The second PC, whose meaning
has never been fully assessed (5, 8), is
correlated with the spread of Eu18 from Spain
toward Central Europe and, on the opposite
pole, with the spread of Uralic TAT/M178
(Eu13 and Eu14). The third PC, the meaning
of which has been debated (3, 5, 8), correlates
to the M17 mutation (Eu19). The concordance
of protein-based PC and NRY data
suggests that migration, more than natural
selection, has influenced the pattern of NRY
variation observed.
Analyses of mtDNA sequence variation in
European populations have been conducted (6,
20). These data suggest that the gene pool has
;80% Paleolithic and ;20% Neolithic ancestry.
Our data support this observation because
haplotypes Eu4, Eu9, Eu10, and Eu11 account
for ;22% of European Y chromosomes. Thus,
the mtDNA and Y data corroborate the previous
observation that the first PC of the 95
classical polymorphisms accounts for ;28% of
the overall genetic variation (5, 6). However,
some differences exist between the mtDNA and
Y data pertaining to the putative Paleolithic
components. It has been proposed that mtDNA
haplogroup U5 arrived from the Middle East
45,000 years ago (6, 26). We did not detect any
corresponding Y haplotypes. Furthermore,
most European mtDNA lineages, which account
for 60 to 70% of the variation in Europe,
have been interpreted as having arrived from
the Middle East during the Paleolithic about
25,000 years ago (6). Correspondingly, ;20%
of contemporary Y lineages characterized by
the M170 mutation derive from deep phylogenetic
M89 ancestry, consistent with a Middle
Eastern Paleolithic heritage. Moreover, the remaining
;50% of Y lineages associated with
the M173 mutation indicate a major influence
Fig. 2. Abscissa: distances in thousands of kilometers of each population from the average of the
two Middle Eastern populations (Lebanese and Syrians). Ordinate: logarithm of relative frequencies
of Neolithic markers (sum of Eu4, Eu9, Eu10, and Eu11) in the Mediterranean and non-Mediterranean
populations. The Middle Eastern point ( X 5 0) was considered for both series of points. The
two regression lines are significantly different (P , 0.01).
Fig. 3. PC analysis of
data in Table 1. The
first PC accounts for
46.24% of the variance,
whereas the second
accounts for
34.69%.
Table 2. Correlation between the first three PCs based on autosomal protein markers (5) and the
frequency of the major European Y chromosome haplotypes.
Eu4 Eu91Eu101Eu11 Eu7 Eu18 Eu131Eu14 Eu19
PC1 (28%)† 0.6806** 0.7939** 20.4450* 20.3004 20.3644 20.1673
PC2 (22%)† 20.1415 0.0626 0.0594 20.6967** 0.7570** 0.2074
PC3 (11%)† 20.3385 20.1248 0.0924 20.3836 0.0438 0.7270**
*P , 0.05. **P , 0.001. †Portion of variation accounted for by each PC based on autosomal protein markers (5).
R E P O R T S
10 NOVEMBER 2000 VOL 290 SCIENCE www.sciencemag.org 1158
on the extant gene pool from Central Asia
;30,000 years ago. In contrast, Central Asian
mtDNA 16223/C haplogroups (I, X, and W)
account for only ;7% of the contemporary
composition (26). These discrepancies may be
due in part to the apparent more recent molecular
age of Y chromosomes relative to other
loci (27), suggesting more rapid replacement of
previous Y chromosomes. Gender-based differential
migratory demographic behaviors will
also influence the observed patterns of mtDNA
and Y variation (24).
The previously categorized Sardinians,
Basques, and Saami outliers (5) share basically
the same Y binary components of the
other Europeans. Their peculiar position with
respect to frequency is probably a consequence
of genetic drift and isolation. In addition,
our analysis highlights the expansion
of the Epi-Gravettian population from the
northern Balkans.
Almost all of the European Y chromosomes
analyzed in the present study belong to
10 lineages characterized by simple biallelic
mutations. Furthermore, a substantial portion
of the European gene pool appears to be of
Upper Paleolithic origin, but it was relocated
after the end of the LGM, when most of
Europe was repopulated (16).
References and Notes

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