The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event
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Abstract
Both
the extent and location of the maternal ancestral deme from which the
Ashkenazi Jewry arose remain obscure. Here, using complete sequences of
the maternally inherited mitochondrial DNA (mtDNA), we show that close
to one-half of Ashkenazi Jews, estimated at 8,000,000 people, can be
traced back to only 4 women carrying distinct mtDNAs that are virtually
absent in other populations, with the important exception of low
frequencies among non-Ashkenazi Jews. We conclude that four founding
mtDNAs, likely of Near Eastern ancestry, underwent major expansion(s) in
Europe within the past millennium.
The
founder effect was originally defined as “the establishment of a new
population by a few original founders (in an extreme case, by a single
fertilized female) which carry only a small fraction of the total
genetic variation of the parental population” (Mayr 1963).
Since then, DNA variation studies in human populations—particularly
those employing the mtDNA and the male-specific portion of the Y
chromosome (MSY)—have proven invaluable for generating models of the
evolution of modern humans (Cavalli-Sforza and Feldman 2003).
Recent progress in the analysis of complete mtDNA genomes, combined
with the growing number of samples in existing databases, provides a
sophisticated tool to dissect microevolutionary processes, such as
founding events, in individual haplogroups (Hgs) and populations (Ingman
et al. 2000; Achilli et al. 2004, 2005; Loogväli et al. 2004; Palanichamy et al. 2004; Macaulay et al. 2005; Thangaraj et al. 2005).
The
term “Ashkenazi” refers to Jews of mainly central and eastern European
ancestry, in contrast to those of Iberian (Sephardic), Near Eastern, or
North African origin (Ostrer 2001).
Most historical records indicate that the founding of the Ashkenazi
Jewry took place in the Rhine Basin, followed by a dramatic expansion
into eastern Europe. However, both the origin and size of the maternal
ancestral deme remain obscure. Two features have made the Ashkenazi
Jewish population an excellent candidate for genetic studies. First, its
unique, well-documented overall demography is consistent with several
founding events, repeated bottlenecks, and dramatic expansions, from an
estimated number of ∼25,000 in 1300 a.d. to >8,500,000 around the turn of the 20th century (DellaPergola 2001; Ostrer 2001).
Second, the unusual accumulation of >20 recessive disorders
restricted to this population and the proposed possible explanations for
this phenomenon have fueled a long-standing and lively debate between
theories favoring heterozygote advantage and theories postulating drift
of rare disease-causing alleles during the rapid population expansion
that followed the founding event (Diamond 1994; Risch et al. 1995; Ostrer 2001).
The published genetic data addressing the question of a founding event
in the maternal history of Ashkenazi Jews (Torroni et al. 1996; Thomas et al. 2002; Behar et al. 2004) are partially discordant, with some studies detecting a strong founder event (Torroni et al. 1996; Behar et al. 2004) and others reaching the conclusion that there is little evidence for such an event (Thomas et al. 2002). In particular, our recent analysis of HVS-I sequences (Behar et al. 2004),
extended herein to a larger fraction of the control-region
(16024–00300) variation in Ashkenazi Jews, has yielded a broad range of
Hgs well known to be prevalent and shared between Europe and the Near
East and, therefore, not informative in determining the geographic
origin of the population ancestral to contemporary Ashkenazi Jews (tables 1 and and2).2).
Despite the presence of the entire range of west Eurasian Hgs in the
Ashkenazi mtDNA pool, Hg frequencies clearly deviated from those
reported elsewhere for west Eurasian populations. This deviation was due
to a striking overrepresentation of Hgs K and N1b. However, since
common Hgs cover large geographic areas and comprise numerous lineages
that usually coalesced tens of thousands of years ago, monitoring their
general frequencies does not effectively allow determination of the real
number of ancestral maternal lineages that gave rise to the present-day
diversity in a population. Therefore, although in previous studies the
elevated frequencies of mtDNA Hgs K and N1b in Ashkenazi Jews suggested a
maternal founding event (Torroni et al. 1996; Behar et al. 2004),
the number of lineages within these Hgs, their putative origin, and
their level of restriction to Ashkenazi Jews remain to be resolved. To
this end, in the current study, using complete mtDNA sequence analysis,
we identified the founding lineages of Ashkenazi Hgs K and N1b and
contrasted their variation against a global set of mtDNAs belonging to
the same Hgs. On the basis of these data, we infer the actual number, as
well as the temporal and geographic origin, of these maternal founders.
Control-Region Sequences and Hg Affiliation of Ashkenazi mtDNAs[Note]
Control-Region Haplotypes of Ashkenazi Hg K mtDNAs[Note]
We
initially generated a maximum parsimony tree of 121 complete mtDNA
sequences belonging to Hg K. The tree encompassed 28 novel and 93
previously reported mtDNAs (fig. 1 and table 3). The sequencing procedure and phylogeny construction were performed as described in appendix A.
Of the 28 novel samples, 13 were from Ashkenazi Jews, and 15 were
selected from non-Ashkenazi Jews and non-Jewish Near Eastern
populations. Samples for complete mtDNA sequencing were chosen to
include the widest possible range of Hg K internal variation, on the
basis of sequence analysis of the mtDNA control region. Figure 1 shows that Hg K splits at its root into two primary branches, K1 and K2. All 789 Hg K mtDNAs reported herein (table 4)
were designated as either “K1” or “K2” (89% and 11%, respectively),
revealing no additional branching at the root of K. Subhaplogroup
(subHg) K2 is subdivided into two subsequent major branches labeled
“K2a” and “K2b,” whereas K1 splits into three branches—K1a, K1b, and
K1c—that are defined by positions 497, 5913, and 498del, respectively.
All but one of the K1 mtDNAs reported in this study belong to one of
these three branches. SubHg K1a encompassed most subbranches and is also
the dominant branch in our sample set, encompassing 80% of all Hg K
mtDNAs. The 13 Ashkenazi complete mtDNAs clustered into three distinct
branches in the phylogeny: K1a1b1a, K1a9, and K2a2a (fig. 1).
Source and Ethnic Origin of the 121 Complete mtDNA Sequences
Hg K Database[Note]
K1a1b1a
is marked by two coding-region transitions, 10978 and 12954, and
includes 14 of the 121 complete sequences. Seven of these are reported
for the first time herein and are from Ashkenazi subjects, whereas the
other seven were reported elsewhere as forming a specific cluster termed
“K1a” (Herrnstadt et al. 2002).
The ethnicities or religious affiliations of these seven subjects are
not available, but they were all collected in the United States and
shared the control-region mutations with the Ashkenazi samples. Since
the majority of contemporary Ashkenazi Jews reside in the United States,
it is possible that this cluster represents a sample set of Ashkenazi
Jews, though we have no way to confirm or refute this.
K1a9
mtDNAs are marked only by the control-region transition 16524 but lack
the diagnostic mutations of the other K1a2 through K1a8 subHgs (fig. 1).
Six samples belong to this lineage—four of which, from Ashkenazi Jews,
are reported herein for the first time. The other two mtDNAs were
reported elsewhere, and the same considerations noted for subHg K1a1b1a,
with respect to the ethnic or religious affiliation, also apply
(Herrnstadt et al. 2002).
K2a2a mtDNAs are marked by three coding-region transitions: 9254,
11348, and 11914. Three mtDNAs belong to this lineage, two of which are
from Ashkenazi individuals and are reported herein for the first time.
The third mtDNA was reported elsewhere in the same U.S. data set
(Herrnstadt et al. 2002).
After
the delineation of the Hg K topology and in a search for clues
regarding the possible origin of the Ashkenazi lineages, 789 Hg K mtDNAs
of a global set of 13,359 samples (tables 5 and and6)6)
were hierarchically screened for polymorphisms relevant to include or
exclude the samples from the three Ashkenazi K subbranches—K1a1b1a,
K1a9, and K2a2a. The position of the three dominant Ashkenazi founding
sequences within the phylogenetic tree of 789 Hg K genomes is
illustrated in figure 2. Of the 182 Ashkenazi Hg K mtDNAs, 179 could be readily assigned to K1a1b1a, K1a9, or K2a2a (table 6),
demonstrating that virtually all Hg K genomes present in the Ashkenazi
Jews belong to these three distinct monophyletic clades and, in turn,
comprise 30% of all Ashkenazi maternal lineages. Of 123 K1a1b1a mtDNAs (fig. 2 and table 6),
122 were from Jews—113 of Ashkenazi and 9 of Spanish-exile ancestry (6
Bulgarian, 2 Italian, and 1 Turkish). The only non-Jewish K1a1b1a mtDNA
that shared the HVS-I haplotype 16223-16224-16234-16311 with the
Ashkenazi Jews was found in a subject from Hmelnitski, a Ukrainian town
with a major Jewish settlement until the Second World War. As for K1a9,
48 of the 789 K mtDNAs were members of this subHg (fig. 2 and table 6),
and 47 were from Jews—41 Ashkenazi, 4 Spanish exile (2 Bulgarian, 1
former Yugoslavian, and 1 from Turkey), 1 from Iraq, and 1 from Syria. A
subHg K1a9 mtDNA was found in one Hungarian of unidentified ethnic or
religious affiliation. Finally, 28 (25 Ashkenazi Jews, 1 Bulgarian Jew, 1
Georgian Jew, and 1 Azerbaijani Jew) of the 789 K samples belonged to
subHg K2a2a (fig. 2 and table 6). This subHg and its parental Hg were not found in any of 11,452 non-Jewish samples.
The location of the three Ashkenazi lineages (light blue)
belonging to Hg K in a global set of complete K sequences. For the
network construction, first, a topology network encompassing the 91
branches found in the total set of 121 complete K sequences ...
Description of the Populations
SubHg Affiliation of the 789 mtDNAs Belonging to K[Note]
The
same principles were followed to investigate the high incidence of Hg
N1b in Ashkenazi Jews. Hg N1b is virtually absent in Europeans but
appears at frequencies of ∼3% or higher in those from Levant, Arabia,
and Egypt (Richards et al. 2003; Kivisild et al. 2004;
unpublished results of Tartu and Haifa groups). This Hg is defined by
the transversion C16176G, relative to the revised Cambridge Reference
Sequence (rCRS) (Andrews et al. 1999),
and is reported in all non-Jewish Near Eastern N1b mtDNAs. However, all
but one of the Ashkenazi N1b mtDNAs were found to harbor a C→A
transversion at nucleotide position 16176. To assess whether this was
another Ashkenazi founding lineage, we followed the same approach
applied to Hg K. We randomly chose two mtDNAs for complete sequencing
and identified several shared mutations that were absent in a previously
reported N1b complete sequence (Maca-Meyer et al. 2001) (fig. 3).
We then examined nucleotide positions 11928 and 12092—sites of two of
the private mutations—in 82 N1b mtDNAs that were available to us (table 7).
Fifty-six of the 57 Ashkenazi Jews, the Spanish-exile Jews, and the
Moroccan Jew, who shared 16176A, could be assigned to this same lineage.
The single Ashkenazi and all other mtDNAs with 16176G did not harbor
the mutations at 11928 and 12092. Curiously, the 16176A transversion
probably occurred twice in the phylogeny of N1b. Indeed, we have found
lineages with 16176A in Slavic-speaking populations both in the Balkans
and in Ukraine, but these possessed HVS-I mutations different from those
present among the Jews, and they did not harbor the mutations at 11928
and 12092; thus, they are clearly phylogenetically distinct from N1b
genomes of the Ashkenazi Jews.
N1b Haplotypes in Jews and Near Eastern Non-Jews[Note]
In
total, we have identified four Ashkenazi founding lineages, three
within Hg K and one in Hg N1b, deriving from only four ancestral women
and accounting for fully 40% of the mtDNAs of the current Ashkenazi
population (∼8,000,000 people). The most dominant of these lineages,
K1a1b1a, encompasses 62% of the Ashkenazi K mtDNAs, which translates
into 19.4% of contemporary Ashkenazi Jews, or ∼1,700,000 people. The
second most common lineage is within Hg N1b and corresponds to an
additional 800,000 people. We compared the pattern of lineage
distribution seen in Ashkenazi Jews with a global database of ∼30,000
mtDNAs, 13,359 of which are from populations in which Hg K and N1b are
present (table 6),
and we could not detect anything similar. For instance, in European
populations, the closest the existing literature offers is the database
of 192 complete Finnish mtDNA sequences (Finnila et al. 2001).
Though these mtDNAs were nonrandomly selected from a larger
control-region database of nearly 500 individuals living in a
north-central region of Finland, a typical, frequently derived,
phylogenetically recent lineage comprises merely 3%–4% of the total. In
the study of Coble et al. (2004),
the entire mtDNA sequences of 241 individuals matching 1 of the 18 most
common control-region haplotypes in European Caucasian populations were
determined. The frequency of these 18 haplotypes was found to account
for only 20.8% of the European Caucasian mtDNAs—a very significant
difference compared with the Ashkenazi Jews, for which four complete
sequence haplotypes comprise 42% of the mtDNAs. Furthermore, even mtDNAs
with the same control-region motif were rarely found to completely
match at the coding-region level, with an average coding-region mismatch
of 6.2 mutations observed within the 241 completely sequenced mtDNAs.
This would correspond to an approximate average date of 15,000–16,000
years ago for the most recent common ancestor, under the same
assumptions used to calculate the coalescence of the Ashkenazi lineages
(see below). Therefore, in contrast to Thomas et al. (2002),
we conclude that a significant founding event is, indeed, readily
evident in the maternal history of Ashkenazi Jews. Thomas et al. (2002)
based their analysis on a portion of the HVS-I region (nucleotide
positions 16093–16383) from 78 subjects and, in contrast to Torroni et
al. (1996) and Behar et al. (2004),
reported that the most frequent sequence found in their Ashkenazi
sample (their “modal haplotype”) is identical to the HVS-I sequence of
the so-called rCRS, with a frequency not significantly different from
that observed among their European host populations. However, it is now
well established that the rCRS sequence in HVS-I can be found in several
different Hgs—H, HV, pre-HV, U, and a paraphyletic group R*. Thus,
although the inference by Thomas et al. (2002)
soundly emanates from the results of their limited sample size and
subfragment analysis, the conclusion reached is not borne out with the
use of control-region analysis in a larger sample set. Moreover, even
under the improbable assumption that all rCRS mtDNAs studied by Thomas
et al. (2002)
belonged to Hg H, additional genealogical resolution is not provided,
since such a motif can be found in a diverse variety of subclades of Hg
H, many of which diverged from a common ancestor >10,000 years ago
(Finnila et al. 2001; Herrnstadt et al. 2002; Achilli et al. 2004; Loogväli et al. 2004; Pereira et al. 2005),
a time frame uninformative for studying recent ancestries in general
and the founding of the Ashkenazi population in particular. Complete
sequencing of Ashkenazi mtDNA genomes with the rCRS sequence motif in
their HVS-I region, as demonstrated for Hg K and N1b in the current
study, would be a straightforward approach to reveal additional maternal
founder lineages among such mtDNAs.
The coalescence
time for each of the four lineages was calculated independently in two
ways: from HVS-I and from the entire coding-region sequence (table 8).
When we analyzed the coding-region data, we used only the information
obtained from the novel complete mtDNA genomes in which Ashkenazi
ancestry was firmly established (table 1).
Historical records suggest the establishment of the Ashkenazi
population during the 7th and 8th centuries in the Rhine valley by a few
migrating families arriving from northern Italy (Ostrer 2001).
The estimated number of Ashkenazi Jews in the 12th and 13th centuries
is 25,000, a number sufficient to keep allelic frequencies largely in
balance against random genetic drift within ∼30–40 generations.
Therefore, the demographic history suggests that the crucial founder
events are likely to have occurred sometime before the 12th century,
whereas the expansion phase of Ashkenazi Jewry in Europe, with its ups
and downs, has lasted more than a millennium. Our coalescence analysis
is in agreement with this assumption, since the expansion time
calculations for the four Ashkenazi lineages point to the past 20
centuries and are close to the historical founding period of the
Ashkenazi population. It should be noted that, despite relatively large
SDs, the coalescence time estimates for the four maternal founder
Ashkenazi lineages are at least an order of magnitude lower than those
obtained for the corresponding parental clades, which clearly signals a
recent beginning of their expansion.
Coalescence Ages of the Four Major Ashkenazi mtDNA Lineages
There
are two fundamental questions with respect to the geographic origin of
the Ashkenazi founding lineages. First, were these lineages a part of
the mtDNA pool of a population ancestral to Ashkenazi Jews in the Near
East, or were they established within the Ashkenazi Jews later in
Europe, as a result of introgression from European or Eurasian groups?
Second, where did these lineages expand? The observed global pattern of
distribution renders very unlikely the possibility that the four
aforementioned founder lineages entered the Ashkenazi mtDNA pool via
gene flow from a European host population. For example, in databases of
HVS-I sequences of British, Irish, German, French, or Italian subjects,
these Ashkenazi sample founder lineage sequences were not observed
(Baasner et al. 1998; Lutz et al. 1998; Pfeiffer et al. 2001).
Furthermore, the non-Ashkenazi Jewish populations sharing the Ashkenazi
mtDNA Hg K lineages turn out to be from Jewish communities that trace
their origins to the expulsion from Spain in 1492. Either a shared
ancestral origin of the two groups or, alternatively, a postexile
admixture between neighboring Ashkenazi and Spanish-exile Jewish
populations may explain the sharing of these maternal lineages. However,
the very presence of the Ashkenazi founding lineages, albeit at low
frequencies, in North African, Near Eastern, and Caucasian Jews,
supports a common Levantine ancestry. The maternal subclade from which
the Ashkenazi mtDNA lineage K2a2a arose was not found in any other of
the populations reported herein (table 6).
The Ashkenazi K1a9 and K1a1b1a lineages were not found in non-Jews,
with the exception of the former in a single Hungarian and the latter in
a single Ukrainian, both of unknown ethnicity. However, it is of
interest that K1a1b1a sister lineages, which share with it a common
ancestry at the internal nodal level of subclade K1a1b1 (fig. 2), can be found in Portugal, Italy, France, Morocco, and Tunisia (table 6).
This reveals that this particular limb of the Hg K phylogenetic tree is
of a wider Mediterranean presence and origin. Likewise, the
distribution of Hg N1b in southwestern Asia and North Africa (Rando et
al. 1998; Richards et al. 2000)
supports a Near Eastern, rather than a European, origin for this Hg. It
is noteworthy that our extensive sample set from the Caucasus (table 5)
does not offer any hint that the four dominant Ashkenazi mtDNA lineages
might have arrived from this region. However, it can be concluded that,
irrespective of where exactly the mutations defining these Ashkenazi
lineages arose, their expansion clearly took place during the time
period of the sojourn of the Ashkenazi population in Europe.
It
is important to note that, although our findings clarify the restricted
nature of mtDNA lineage diversity carried by Ashkenazi Jewry and
provide evidence of a founder event specifically for the matrilineal
ancestry, some questions remain unsolved and could be the focus of
future studies. First, our findings are not sufficient to answer
questions about the extent and location of the ancestral deme from which
Ashkenazi Jewry, as a population, arose. It is possible that, for the
MSY and autosomal loci, different patterns might be observed. Second,
our findings cannot provide a quantitative assessment of the Ashkenazi
population bottleneck, because the fraction of the ancestral maternal
deme represented by the four particular founding lineages that we have
identified cannot be determined. Third, the effects on the nuclear
genome of the maternal founding event, whose mtDNA population genetic
imprint we have observed, is influenced by other parameters, such as
admixture, recombination events, and paternal contribution, that have
occurred through the generations. The quantitative contribution of each
of these parameters is not known, and these are likely to result in a
different pattern for the nuclear genome, compared with that of mtDNA.
Nevertheless, the analysis of mtDNA sequence variation enables the
detailed and quantitative elucidation of a maternal founder event, which
cannot be inferred from analysis of other genomic regions.
In
conclusion, the present study highlights the importance of a combined
phylogenetic/phylogeographic strategy that includes complete mtDNA
sequence analysis to accurately portray maternal founding events and to
infer conclusions relevant to both shared ancestries and
population-level effects that shaped the mtDNA gene pool in a given
population. In the Ashkenazi Jews, this approach enabled us to
reconstruct a detailed phylogenetic tree for the major Ashkenazi Hgs K
and N1b, allowing the detection of a small set of only four individual
female ancestors, likely from a Hebrew/Levantine mtDNA pool, whose
descendants lived in Europe and carried forward their particular mtDNA
variants to 3,500,000 individuals in a time frame of <2 millennia.
This founding event(s), established here as a dominant mechanism in the
genetic maternal history of the Ashkenazi Jews, is a vivid example of
the founder effect originally described by Mayr (1963) 4 decades ago.
Acknowledgments
We
thank the individuals who provided samples for this study, the National
Laboratory for the Genetics of Israeli Populations, which also provided
samples, and Vered Friedman and Guennady Yudkovsky for technical
assistance. This research was supported in part by Israeli Science
Foundation grants (to K.S.), the Annie Chutick Endowment and Technion
(to K.S.), the Estonian Science Foundation (to E.M. and T.K.), European
Union Framework Programme Genemill and Genera grants (to R.V.), the
Consiglio Nazionale della Ricerche–Ministro dell'Istruzione
dell'Univerita e della Ricerca (CNR-MIUR) Genomica Funzionale-Legge
449/97 (to A.T.), the Fondo Investimenti Ricerca di Base 2001 (to A.T.),
the Progetti Ricerca Interesse Nazionale 2005 (to A.T.), the National
Science Foundation (to N.H.), and Programa Operacional Ciência,
Tecnologia e Inovação (to A. Amorim).
Appendix A: Methods
Sampling
A
total of 583 Ashkenazi Jewish and 1,111 non-Ashkenazi Jewish samples
were analyzed for mtDNA Hg-specific markers, identifying 186 and 63
samples, respectively, belonging to Hg K (HVS-I data for 565 of the
Ashkenazi samples have been reported elsewhere [Behar et al. 2004]).
Of the 186 samples found among Ashkenazi Jews and the 63 Hg K samples
found among non-Ashkenazi Jews, 182 and 62, respectively, were available
for further genotyping. Next, we identified Hg K samples in all
population sample collections available from the laboratories in Haifa,
Tartu, Pavia, Porto, and Paris, and we reported only populations in
which Hg K samples were found and available for further genotyping. We
evaluated a total of 11,452 samples from 67 populations and identified
636 Hg K samples, 545 of which were available for further genotyping. Table 5
details the total number of samples available from each population, the
number of Hg K samples within each population, the number of Hg K
samples from each population that were technically available for
genotyping in this study, the reporting laboratory, and the first study
in which the samples were reported (Bermisheva et al. 2002; Behar et al. 2004; Pereira et al. 2004; Quintana-Murci et al. 2004).
We then examined the same data set of Jewish samples described above
for the presence of Hg N1b samples and identified a total of 57 and 11
Hg N1b samples in Ashkenazi and non-Ashkenazi Jews, respectively. We
also reported the results of 14 Hg N1b samples found in the same Druze,
Palestinian, and Bedouin samples included in the sample set described
above (table 5),
and we compared the Ashkenazi N1b Hg mtDNAs with the unpublished
database of 8,644 Caucasian, European, Near and Middle Eastern, and
North African subjects included in this study and available in Tartu (table 5).
All samples reported herein were derived from blood, buccal swab, or
blood cell samples that were collected with informed consent, in
accordance with procedures approved by institutional human subjects
review committees in their respective locations. All subjects reported
the birthplace of their mothers, grandmothers, and, in most cases,
great-grandmothers.
Control-Region Sequencing
Sequences
of the control region were determined from position 16024 to 00300, by
use of the ABI Prism Dye Terminator cycle-sequencing protocols developed
by Applied Biosystems (Perkin-Elmer). Control-region sequence data were
used to define haplotypes within the Hgs. The control-region
information reported from Haifa and Paris extends from 16024 to 00300.
The control-region information reported from Tartu spans from 16024 to
16400, corresponding to HVS-I. The control-region information reported
from Pavia extends from 16024 to at least 00200 and, in most cases, up
to 00300. The control-region information reported from Porto extends
from 16024 to 16365 and from 00072 to 00340. The hypervariable positions
16182 and 16183 in HVS-I and the indels at positions 00309 and 00315 in
HVS-II were excluded from the analysis (tables 1 and and44).
Complete mtDNA Sequencing
DNA was amplified using 18 primers to yield nine overlapping fragments, as reported elsewhere (Taylor et al. 2001).
After purification, the nine fragments were sequenced by means of 56
internal primers to obtain the complete mtDNA genome. Sequencing was
performed on a 3100 DNA Analyzer (Applied Biosystems), and the resulting
sequences were analyzed with the SEQUENCHER software. Mutations were
scored relative to the rCRS (Andrews et al. 1999). The novel 28 Hg K and 2 N1b complete mtDNA sequences reported herein have been submitted to GenBank (accession numbers DQ301789-DQ301818).
Quality control was assured as follows: first, each base pair was
determined once with a forward and once with a reverse primer; second,
any ambiguous base call was tested by additional and independent PCR and
sequencing reactions; and third, all sequences were examined by two
independent investigators.
Hg Labeling
All Hg K samples reported herein harbored the diagnostic marker G9055A, as confirmed by the RFLP reaction −9052HaeII.
Diagnostic markers for genotyping subclades of Hg K were selected on
the basis of the analyses of the complete mtDNA sequences. Positions
295, 497, 498, 1189, 4561, 7927, 8697, 8703, 8790, 9254, 9647, 9716,
10398, 11025, 11914, 13117, 11470, 11485, 15924, 10978, and 12954 were
obtained by direct sequencing. Positions 1189, 5913, 9716, 10398, and
11914 were obtained by direct sequencing or by means of RFLPs +1186RsaI, +5913HaeIII, +9714BsaI, +10398DdeI, and −11914TaiI or −11911HpyCH4IV, respectively. All Hg N1b samples reported herein harbored the diagnostic marker T10238C, as confirmed by +10237HphI.
Two diagnostic positions, 11928 and 12092, derived from the complete
mtDNA sequences analysis of the two Hg N1b samples, were examined by
direct sequencing in all Jewish, Druze, Palestinian, and Bedouin
samples.
Nomenclature
We followed a consensus Hg nomenclature scheme (Richards et al. 1998). Numbers 1–16569 refer to the position of the mutation in the rCRS (Andrews et al. 1999).
We use the term “lineage” to denote a cluster of related, evolving
haplotypes within an Hg. Note that haplotypes and lineages can relate to
HVS-I, to the control region, or to the complete mtDNA sequence data.
Nomenclature within Hg K has been the subject of some ambiguity because
of the recycling of the designation “K1a” (Herrnstadt et al. 2002; Palanichamy et al. 2004). We followed the definitions of both publications for “K1” and “K2.” We followed Palanichamy et al. (2004)
for the definitions of “K1a,” “K1a1,” “K1a2,” “K1b,” “K1c,” and “K2a”
and corrected in this article a few inaccuracies reported for the
samples labeled “SF#153” and “CH#365.” Herrnstadt et al. (2002)
used the designation of “K1a” for one subHg of K. To avoid confusion
and because this lineage was found to be highly important in the current
study, we specifically note that we assigned to this lineage the more
detailed designation “K1a1b1a.”
Web Resources
Accession numbers and URLs for data presented herein are as follows:
Fluxus Engineering Web site, http://www.fluxus-engineering.com/
GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for the complete mtDNA sequences [accession numbers DQ301789–DQ301818])
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