Journal of Human Genetics
https://doi.org/10.1038/s10038-020-00898-3

ARTICLE

Genome-wide SNP data of Izumo and Makurazaki populations
support inner-dual structure model for origin of Yamato people
Timothy Jinam1,2 Yosuke Kawai 3 Yoichiro Kamatani 4,5 Shunro Sonoda6 Kanro Makisumi6
Hideya Sameshima6 Katsushi Tokunaga3 Naruya Saitou1,2,7,8
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Received: 4 June 2020 / Revised: 2 December 2020 / Accepted: 20 December 2020
© The Author(s) 2021. This article is published with open access

Abstract
The “Dual Structure” model on the formation of the modern Japanese population assumes that the indigenous huntergathering population (symbolized as Jomon people) admixed with rice-farming population (symbolized as Yayoi people)
who migrated from the Asian continent after the Yayoi period started. The Jomon component remained high both in Ainu
and Okinawa people who mainly reside in northern and southern Japan, respectively, while the Yayoi component is higher inthe mainland Japanese (Yamato people). The model has been well supported by genetic data, but the Yamato population was
mostly represented by people from Tokyo area. We generated new genome-wide SNP data using Japonica Array for 45
individuals in Izumo City of Shimane Prefecture and for 72 individuals in Makurazaki City of Kagoshima Prefecture in
Southern Kyushu, and compared these data with those of other human populations in East Asia, including BioBank Japandata. Using principal component analysis, phylogenetic network, and f4 tests, we found that Izumo, Makurazaki, andTohoku populations are slightly differentiated from Kanto (including Tokyo), Tokai, and Kinki regions. These results
suggest the substructure within Mainland Japanese maybe caused by multiple migration events from the Asian continent
following the Jomon period, and we propose a modiﬁed version of “Dual Structure” model called the “Inner-Dual
Structure” model.

Introduction

These authors contributed equally: Timothy Jinam, Yosuke Kawai
Supplementary information The online version of this article (https://doi.org/10.1038/s10038-020-00898-3) contains supplementarymaterial, which is available to authorized users.
* Naruya Saitou
saitounr@nig.ac.jp
1

2

Population Genetics Laboratory, National Institute of Genetics,
Yata 1111, Mishima 411-8540, Japan
Department of Genetics, School of Life Science, Graduate
University for Advanced Studies (SOKENDAI), Yata 1111,
Mishima 411-8540, Japan

3

Genome Medical Science Project, National Center for Global
Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 1628655, Japan

4

Department of Computational Biology and Medical Sciences,
Graduate School of Frontier Sciences, The University of Tokyo, 46-1 Shirokane-dai, Minato-ku 108-8639, JapanThe Japanese Archipelago spans more than 2000 km from
north to south. This Archipelago was called “Yaponesia” bywriter Toshio Shimao in early 1960s [1], by connecting“Yapo” (Japan in Latin) and “nesia” (islands in Latin).
Yaponesia can be divided into three geographical areas:
Northern Yaponesia, Central Yaponesia, and Southern
5

Laboratory for Statistical and Translational Genetics, RIKEN
Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho,
Tsurumi-ku, Yokohama 230-0045, Japan

6

The Makurazaki City Medical Association, 102-1, Kotobuki-cho,
Makurazaki-shi 898-0062, Japan

7

Faculty of Medicine, University of the Ryukyus, 207 Uehara,
Nishihara-cho 903-0215, Japan

8

Department of Biological Sciences, Graduate School of Science,
the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1138655, JapanT. Jinam et al.

Fig. 2 Re-drawing of the dual structure model from Hanihara [5]Fig. 1 Geographical map of Yaponesia. The different regions arecolor-coded and numbered to correspond to Fig. 3

Yaponesia (Fig. 1). Northern Yaponesia consists of Hokkaido (sometimes Sakhalin and Kuril Islands may also be
included [2]), Central Yaponesia consists of Honshu, Shikoku, and Kyushu, and Southern Yaponesia consists of theislands in Okinawa prefecture, also known as Ryukyu
Islands. Besides people from Okinawa and the Ainu from
Hokkaido, people who inhabit the Japanese Archipelago
can be referred to as Yamato people.
Regarding the formation of Yaponesians (Japanese), vonBaelz [3] ﬁrst pointed out common features in Ainu andOkinawan people as early as 1911. This view was later
supported by many researchers, and renamed by Yamaguchi[4] and Hanihara [5] as the “Dual Structure” model. Thismodel has often been invoked to explain the genetic
diversity of people from the Japanese Archipelago, which
has been inhabited by humans long before the Jomon period(16,000–3,000 years before present, BP [6, 7]). According
to the model, rice agriculturists (symbolically called“Yayoi” people) migrated from the Asian Continent during
the Yayoi period (10th century B.C.–3rd century A.D. [7]).
They admixed with the indigenous hunter-gatherers (symbolically called “Jomon” people), resulting in the current
Japanese population. Figure 2 shows the “Dual Structure”
model based on Hanihara [5]. This model also posits that
Ainu people from Hokkaido in the north and Okinawa
people from the southernmost islands have the much higher
proportion of Jomon ancestry compared to Yamato people.
Initially conceived from craniometric data, the model now
has a strong support from our genome-wide SNP data [8].
However, most genetic data of Yamato people were from
Tokyo and its surrounding Kanto region. There have beenreports of substructure within Japanese people using
genome-wide SNPs [9, 10] and HLA alleles [11, 12].
Nonetheless, some regions in Japan are under-represented
in population genetics studies. We therefore generated new
genome-wide SNP data from people in Izumo, Shimane

Prefecture and Makurazaki, Kagoshima Prefecture, andtogether with data from other parts of Japan, we tested
whether the “Dual Structure” model still applies to these
populations.

Materials and methods
A total of 90 and 72 individuals from Izumo City of Shimane Prefecture and Makurazaki City of Kagoshima Prefecture, respectively (see Fig. 1), were recruited forthis study.
It should be noted that individuals from Izumo were
sampled in two periods and at different locations. We ﬁrst
collected blood samples at Department of Human Genetics,
School of Medicine, the University of Tokyo in 2013 from
21 individuals who grew up in Izumo City and were at thattime residents of Tokyo Area. Most of their grandparents
also grew up in Izumo area. These data on 21 individuals
were reported by Saitou and Jinam [13] as a preliminary
study. We later collected saliva samples at the Archeological Museum of Kojindani, Izumo City in 2014 from 69
individuals. In total, only 51 DNA samples from Izumo
contained enough good-quality DNA for genotyping.
As for the Makurazaki population, blood samples werecollected from 72 individuals in 2015 at Makurazaki City
with the help of the Makurazaki City Medical Association,
and all 72 individual DNA samples were used for this study.
Four grandparents of all these 72 individuals collected in
Makurazaki grew up in the Southern Satsuma region. Boththe Izumo and Makurazaki samples were genotyped using
the Japonica array [14]. After ﬁltering out SNPs based on
genotyping call rate (<95%) and the Hardy-Weinberg
equilibrium (p < 1 × 10−10), a total of 625,177 autosomal
SNPs remained. Cryptic relatedness within each population
was checked using KING software [15]. Six individuals
from Izumo and eight from Makurazaki with up to 3rd
degree relations (kinship coefﬁcient more than 0.06) were

Genome-wide SNP data of Izumo and Makurazaki populations support inner-dual structure model for origin. . .

omitted from further analysis. Therefore, 45 and 64 genome-wide SNP data for Izumo and Makurazaki, respectively, were used for subsequent data analyzes.
The Japonica-array SNP data for Izumo and Makurazaki
were then merged with the following datasets: (1) BioBank
Japan (BBJ) [16, 17] genome-wide SNP data (922,511
sites); (2) Affymetrix 6.0 micro-array data (641,314 SNP
sites) of 20 Ainu, 35 Okinawa, 50 Yamato (mostly from
Kanto region) [8], and 42 Chinese Han in Beijing (CHB)[18] individuals; (3) high-coverage whole genome data of
88 Koreans from the Korean Personal Genome Project [19];(4) high-coverage whole genome data of Asian populations(CHB, Southern Han Chinese, Chinese Dai from China,
Kinh from Vietnam) from the 1000 genomes project [20].
The BioBank Japan dataset (BBJ) [17] consisted of
182,546 individuals treated at hospitals in seven regions inJapan: Hokkaido, Tohoku, Kanto-Koshinetsu (Kanto forshort), Tokai-Hokuriku (Tokai for short), Kinki, Kyushu,
and Okinawa (Fig. 1). The genotyping data obtained by
SNP array was downloaded from Japanese genotypephenotype archive on the approval of NBDC Data AccessCommittee (JGA Accession ID: JGAD000123). The genotype data were converted into VCF format.
Whole genome sequence data were analyzed by the
workﬂow recommended by the GATK best practice. We
retrieved the mapped-read data in CRAM format for Asian
population from the 1000 Genomes project (https://www.
internationalgenome.org/). For Korean population, raw
reads in fastq format were retrieved from The Personal
Genome Project Korea (http://opengenome.net/Main_Page). The raw reads were then mapped to GRCh38 reference sequence by bwa-mem in order to consolidate with
1000 Genomes project data. Variant discovery was performed using the HaplotypeCaller algorithm implemented
in GATK4.1 to perform joint calling. Joint calling was
performed by GVCFtyper algorithm implemented in sentieon package [21] for computational efﬁciency. This program yields results compatible with GATK’s GenomicsDB
and genotypeGVCFs programs. Each variant was scoredusing the VQSR algorithm to ﬁlter the variants. We applied
VQSR by valCal and ApplyVarCal program of sentieon
package. The HapMap and International 1000 GenomesOmni2.5 sites, the high-conﬁdence SNPs of 1000-G sites,
and the dbSNP151 sites are used as true datasets, training
datasets, and known datasets, respectively. SNPs that passed the 99.9% sensitivity ﬁlter by VQSR were used for
subsequent analyzes. The ﬁltered genotype data in VCF
were then merged with SNP array data of the BBJ, Izumo,
and Makurazaki datasets by the merge function implemented in bcftools. SNPs that are missing in either dataset,minor allele frequency <1%, call rate <3%, or statisticallysigniﬁcant deviation from Hardy-Weinberg equilibrium (pvalue < 0.00001) were ﬁltered out. In total 106,237 SNPs

remained. For the subsequent analyzes that require theindependence of nearby SNPs, the linkage disequilibrium(LD)-based SNP pruning were performed by PLINK1.9[22] with “--indep-pairwise 500 50 0.1”. We obtained
39,331 LD independent SNPs. After excluding duplicate
samples and those with cryptic relatedness by KING, theprincipal component analysis (PCA) was performed using
PLINK1.9 to remove outlier samples. The number of BBJ
samples remaining after this step was 169,169. To reduce
computation times for subsequent analyzes, we decided tofurther trim down the BBJ dataset. First, the mean values of
the top 10 principal component values were calculated foreach region, and the deviation of the principal component
values from the mean were assessed for each sample by
Euclidean distance. The top 1000 samples with the smallest
Euclidean distances were selected from each region andused for subsequent analyses.
PCA was again performed using the trimmed down BBJ
dataset using PLINK1.9, and Admixture [23] was used foradmixture analysis. f4 test implemented in treemix [24] wasused to test for gene ﬂow between populations. GBR(British in England and Scotland) population from the 1000
Genomes dataset was used as outgroup for the f4 test.
Phylogenetic analysis of populations was conducted using
the neighbor-joining method [25] and Neighbor-Net [26]for phylogenetic tree and network construction, respectively. Pairwise Fst distances between populations calculated in smartpca [27] was used for tree and network
construction.

Results
We ﬁrst conducted PCA under various combinations of
populations. Supplementary Fig. 1 shows that Makurazaki
and Izumo cluster with Yamato when PCA was performed
with Ainu, Okinawan, and CHB. Next, PCA was performed
using Izumo, Makurazaki, BBJ, Korean, and 1,000 genomes project data (Fig. 3). A total of 106,237 SNP sites
were used for this PCA. Non-Japanese individuals are
represented by gray dots and the detailed positions areshown in Supplementary Fig. 2, while the nine Yaponesian
populations (see Fig. 1 for their geographical locations) are
shown as different colors in each panel. The left mostcluster in each panel is made up of Okinawa (9) individuals,
Yamato individuals in the middle cluster, while other continental Asians are located on the right side. Individuals
from Hokkaido (1), Kanto (3), and Tokai (4) are distributedin the center of Yamato cluster, while Tohoku (2) and Kinki(5) individuals are slightly deviated from the central cluster.
Interestingly, individuals sampled from Kyushu (7) arelocated both in Okinawa and Yamato clusters (shown as A
and B, respectively). These Kyushu individuals who are

T. Jinam et al.

Fig. 5 Neighbor-Net network from pairwise Fst distances between
populations. A Network when all populations were included; B Network after Ainu was omitted; C Magniﬁed view of reticulations
involving Yamato people

Fig. 3 Principal component analysis (PCA) plots of individuals fromvarious regions in Japan corresponding to Fig. 1 map. Non-Japaneseindividuals are indicated by gray dots. Two major clusters wereobserved in the BioBank Japan Kyushu cohort, labeled A and B,
respectively

Fig. 4 Admixture analysis for k (number of ancestral components) =9. For clarity, only 100 randomly selected individuals from eachregion of the BioBank Japan dataset are included in this ﬁgure

within the Okinawa cluster (referred to as “Kyushu-A”
hereafter) might have been sampled from islands that are
geographically close to the Okinawa but are included
administratively in Kagoshima prefecture of Kyushu. For
BBJ data, geographical location of samples reﬂect thelocations of hospitals where the patients were recruitedfrom. In contrast, we collected DNA from Izumo and
Makurazaki individuals only if all four grandparents wereresidents of their respective regions, a similar strategy
employed in a study of British populations [28]. Makurazaki is located at the southern tip of Kyushu (see Fig. 1)
and Fig. 3 shows that individuals of this city are locatedslightly nearer to the Okinawa cluster.
The results of admixture analysis [23] when k (number ofancestral components) equals to nine is shown in Fig. 4. Cross
validation errors for other values k are shown in Supplementary Fig. 3. The main ancestry components in Yaponesians (more than 10%) are indicated in brown, light blue anddark green colored ancestry components. The light blue

ancestry component is highest in northern East Asians (CHB
and Koreans) and on average 17% in Yaponesians except forindividuals belonging to Okinawa and Kyushu-A. Anotherancestry component (brown) is present at 42% in Yamato and
25% in Koreans but very low in Okinawa, Kyushu-A, andother Asian populations. The dark green ancestry component
is highest in Okinawans, and Yamato populations consistently
have this component, whereas the yellow ancestry component
is highest among Kyushu-A population.
An unrooted tree was constructed using the neighborjoining method [25] based on Fst distances between populations (Supplementary Fig. 4). Populations are located more orless in a linear fashion; Okinawa/Kyushu-A cluster on the left
and the CHB/Korean cluster at the right. Yamato people arein the center, with Kinki being the closest to the CHB/Koreancluster. We also constructed phylogenetic networks using
Neighbor-Net method [26] focusing on Yaponesians andKorean/CHB (Fig. 5) and their relationship with other continental Asians (Supplementary Fig. 5). Because the Ainu
population is very distant from the remaining populations(Fig. 5A), they were omitted from the subsequent network(Fig. 5B). Now Okinawa and Kyushu-A populations formed
one cluster, and the remaining seven Yaponesian populations(shown in light blue background in Fig. 5B) are locatedbetween this cluster and the Korean-CHB cluster. Figure 5cshows the phylogenetic relationship of these seven Yaponesian populations. It should be noted that BBJ data for Fig. 5
were sampled in a different way than that for the remaining
ﬁgures; 100 individuals were randomly chosen from sevenpopulations of BioBank. This sampling difference probably
caused the change of the Tohoku population; either somewhat
closer to Izumo in Fig. 5C or almost identical to JPT in
Supplementary Fig. 5. Makurazaki is the closest to the Okinawa and Kyushu-A cluster (indicated by splits labeled b, c,and d), followed by Izumo as shown by split a. Okinawa,
Kyushu-A, and Tohoku are separated from the remaining nine
populations by split e.

Genome-wide SNP data of Izumo and Makurazaki populations support inner-dual structure model for origin. . .
Table 1 f4 test for gene ﬂow
xf4

Std. error

Z-scoref4(GBR, CHB; Okinawa, x)
Hokkaido

0.00124

5.07E−05

24.49

Tohoku0.00111

4.79E−05

23.16

Kanto

0.00124

5.06E−05

24.48

Tokai

0.00127

5.17E−05

24.58

Kinki

0.00143

5.44E−05

26.20*

Izumo

0.00100

7.12E−05

14.08

Kyushu-A

0.00003

2.16E−05

1.16

Kyushu-B

0.00124

4.94E−05

25.12

Makurazaki

0.00111

5.82E−05

19.05

f4(GBR, x; Izumo, Kinki)
Hokkaido

0.00008

4.89E−05

1.58

Tohoku0.00005

4.92E−05

0.97

Kanto

0.00007

4.90E−05

1.44

Tokai

0.00009

4.89E−05

1.74−0.00008

5.14E−05−1.63

Kyushu-B

0.00009

4.89E−05

1.78

Makurazaki−0.00003

5.00E−05−0.69

Okinawa−0.00008

5.12E−05−1.64*

Kyushu-A

f4(GBR, x; Kinki, Makurazaki)
Hokkaido−0.00015

4.28E−05−3.49

Tohoku−0.00013

4.29E−05

−3.03

Kanto

−0.00014

4.28E−05

−3.33

Tokai

−0.00015

4.28E−05

−3.46

Izumo

−0.00002

4.50E−05−0.41

Kyushu-A

0.00020

4.44E−05

4.45

Kyushu-B−0.00010

4.27E−05−2.35

Okinawa

0.00022

4.38E−05

4.92**Most signiﬁcant Z-scores

The results of f4 test for gene ﬂow are listed in Table 1.
To test if there is gene ﬂow between Yaponesians andcontinental Asians, we tested f4(GBR, CHB; Okinawa, x)
where x is the test population. Consistent with PCA, phylogenetic trees and network, Kinki showed the highest Zscore (26.2) among the Yamato populations. Similarly, f4(GBR,CHB;x1,x2) where x1 and x2 are non-Okinawan
Yaponesians also showed evidence of gene ﬂow between
Kinki and CHB (Supplementary Table). For example, mostsigniﬁcant Z-scores were observed for f4(GBR,CHB;
Kanto, Kinki), Z-score: 24.7. We also tested f4(GBR, x;
Izumo, Kinki) to test if there is gene ﬂow involving Izumo.
Negative f4 values indicative of gene ﬂow was observed for
Okinawa, Kyushu-A, and Makurazaki, although the Zscores are relatively low. This was repeated with Makurazaki instead of Izumo using f4(GBR, x; Kinki, Makurazaki), and results suggest presence of gene ﬂow between
Makurazaki and Okinawa or Kyushu-A. Gene ﬂow between

Okinawa and Kyushu-A was further supported by f4(GBR,
Okinawa; x1, x2) where x1 and x2 are non-Okinawa
Yaponesians (Supplmenentary Table).

Discussion
We generated genome-wide SNP data for Izumo in the Sanin region and Makurazaki in the southern Kyushu region(see Fig. 1) using Japonica array. The genetic location of
Makurazaki population in the PCA plot (Fig. 3) and phylogenetic network (Fig. 5) is more or less similar to thegeographical location of this city, namely, between Okinawa and the mainland. This is supported by f4(GBR, x;
Kinki, Makurazaki) test showing Makurazaki having moregene ﬂow with Okinawa and Kyushu-A than with otherYamato.
Geographically, Izumo city is facing the sea between
Yaponesia and Continental East Asia (Fig. 1). The distanceto the Korean Peninsula is ~350 km, and it was expectedthat Izumo people may be closer to continental Asians.
However, f4 test showed that the Kinki population is theclosest to continental Asians (f4(GBR, CHB; Okinawa, x)).
This is supported by another study using genome-wide
SNPs [29]. Interestingly, Izumo population has higher
genetic afﬁnity to Okinawa and Kyushu than to otherpopulations in Honshu, as suggested by f4(GBR, x; Izumo,
Kinki). This discrepancy suggests an existence of somegene ﬂow events that are different from usually expectedisolation by distance [30].
Yamaguchi-Kabata et al. [9] analyzed genome-wide SNP
data of 7,000 Japanese collected from seven geographicalregions (Hokkaido, Tohoku, Kanto, Tokai, Kinki, Kyushu,
and Okinawa) as part of the BBJ Project. They found thetwo clear clusters called Hondo and Ryukyu, which we also
observed (Fig. 3). We also conﬁrmed region speciﬁc characteristics discovered by Yamaguchi-Kabata et al. [9] andlater conﬁrmed by Okada et al. [31] in which Hokkaido,
Kanto, and Tokai area individuals are more or less genetically similar, whereas Tohoku individuals are slightly differentiated from those three regions people based on PCA,
network and f4 tests. We also conﬁrm that Kinki people are
the closest to continental Asians as reported by YamaguchiKabata et al. [9] and Watanabe et al. [29]. Kinki area
includes Nara and Kyoto, past capitals of Japan and thus has
a history of human migration from the Asian continent.
These results and HLA data [11] prompted Saitou [32] topropose the three-migration model. Later, Saitou and Jinam[13] and Saitou [2] proposed the “Inner-Dual Structure”
model of Yaponesians, shown in Fig. 6. After the initial
peopling of the Japanese Archipelago by the ancestors ofJomon and possibly including the paleolithic period people(ﬁrst migration), there were possibly two (or more) human

T. Jinam et al.

Fig. 6 Representation of “Inner-Dual Structure” model

migrations from the Asian continent. Although the timing of
this event is not yet determined, these people may haveoccupied coastal areas of the main island Honshu (“Periphery” in Fig. 6). Then the third migration from the continent mostly involved movement between the AsianContinent and six areas (Hakata in northern Kyushu, Osaka,
Kyoto, Nara in Kinki, Kamakura, and Edo-Tokyo in Kanto;
shown in gray circles in Fig. 6). These “Central Axis” areas
were historically the cultural and political centers in
Yaponesia, and are assumed to attract many new migrants
from continental East Asia.
Two additional data also supported the “Inner-Dual
Structure” model according to Saitou [2]; ﬁve mtDNA
haplogroup frequency data of 18,641 Yaponesians sampledfrom all the 47 prefectures provided by Genesis Healthcare(see Supplementary Fig. 6; taken from Fig 52 of Saitou [2])and ABO blood group allele frequency data of 46 prefectures except for Okinawa by Fujita et al. [33] and those
for Okinawa Prefecture [34, 35] (see Supplementary Fig. 7;
taken from Figure 53 of Saitou [2]). We divided the 47
prefectures into 26 peripheral (shown in blue) and 21 central axis (shown in red) in both data. In Supplementary
Fig. 6, Principal Component 1 broadly separates peripheral(right side) and central axis (left side) populations. This bias
is statistically signiﬁcant at the 1% level using Fisher’s
exact test (see the upper right 2 × 2 table of Supplementary
Fig. 6). The frequency plot of alleles A and B of the ABO
blood group (Supplementary Fig. 7) tend to group peripheral prefectures (shown in blue) to the lower left of the
diagonal dotted line, and this bias is also statistically signiﬁcant at the 1% level using Fisher’s exact test (see theupper right 2 × 2 table of Supplementary Fig. 7).
Recently, HLA data for all 47 prefectures were analyzed[12], and a phylogenetic relationship of 15 regions was shown.
Interestingly, populations in northern Kyushu and southern
Kanto are phylogenetically closer to continental Asian populations, whereas northern Tohoku, Shikoku and Okinawa
formed one cluster. These patterns are compatible with the“Inner-Dual Structure” model shown in Fig. 6. However, Sanin (belonging to Periphery in Fig. 6) and San-yo (belonging toCentral Axis in Fig. 6) populations in Chugoku region are
clustered in the phylogenetic tree of Hashimito et al. [12].
The “Inner-Dual Structure” model might explain why
people in the Central Axis region appear closely related in
the PCA and network analyzes, whereas people from the
Periphery such as Makurazaki, Izumo, or Tohoku were lessgenetically inﬂuenced by the more recent migrations.
However it is still not clear when those new and old
migrants came to Yaponesia. Overall, these results appear to
support the “Inner-Dual Structure” model, however otherexplanations such as very recent migrations might contribute to the observed patterns. The addition of samples
from under-represented regions in Japan together withwhole genome sequence data is needed to properly decipher
the genetic make-up of Yaponesians.
Acknowledgements The authors would like to thank the following
people and organizations: the people in Izumo and Makurazaki cities
who kindly donated their DNA to this study; Mr. Yoshinori Okagaki
and Tokyo Izumo Furusato Kai, Mr. Daisetsu Fujioka and Izumo City
Kojindani Museum, Makurazaki City Medical Doctors Association,
and Asian DNA Repository Consortium. This study was supported by
SOKENDAI Cooperative Research grant on modern human evolution,
MEXT Grant-in-aid for Scientiﬁc Research on Innovative Areas“Yaponesian Genome” (grant number 18H05505), cooperative
research of the Inter-University Research Institutions (grant number IURIC18P01), and a cooperative research with Genesis Healthcare.

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References
1. Shimao T. Thoughts on Yaponesia (in Japanese). Tokyo: Ashi
Shobo; 1977.
2. Saitou N. Origin of Japanese based on nuclear DNA data analyses(in Japanese). Tokyo: Kawade Shobo Shinsha; 2017.
3. von Baelz E. Die Riu-Kiu-Insulaner, die Aino und andere
kaukasier-ahnliche Reste in Ostasien (in German). Korres Bl
Dtsch Ges Anthr Ethnol Urgesch. 1911;42:187–91.

Genome-wide SNP data of Izumo and Makurazaki populations support inner-dual structure model for origin. . .
4. Yamaguchi B. Face and body of Japanese (in Japanese). Tokyo:
PHP Institute; 1986.
5. Hanihara K. Dual structure model for the population history of theJapanese. Jpn Rev. 1991;2:1–33.
6. Imamura K. Prehistoric Japan: new perspectives on insular east
asia. Honolulu: University of Hawaii Press; 1996.
7. Fujio S. History of Yapoi period (in Japanese). Tokyo: Kodansha;
2015.
8. Jinam T, Nishida N, Hirai M, Kawamura S, Oota H, Umetsu K.
Japanese Archipelago Human Population Genetics Consortiumet al. The history of human populations in the Japanese Archipelago inferred from genome-wide SNP data with a specialreference to the Ainu and the Ryukyuan populations. J Hum
Genet. 2012;57:787–95.
9. Yamaguchi-Kabata Y, Nakazono K, Takahashi A, Saito S, Hosono N, Kubo M, et al. Japanese population structure, based on snp
genotypes from 7003 individuals compared to other ethnic groups:
effects on population-based association studies. Am J Hum Genet.
2008;83:445–56.
10. Takeuchi F, Katsuya T, Kimura R, Nabika T, Isomura M, Ohkubo
T, et al. The ﬁne-scale genetic structure and evolution of theJapanese population. PLoS One. 2017;12:e0185487.
11. Nakaoka H, Mitsunaga S, Hosomichi K, Shyh-yuh L, Sawamoto
T, Fujiwara T, et al. Detection of ancestry informative HLA allelesconﬁrms the admixed origins of Japanese population. PLoS One.
2013;8(4):e60793.
12. Hashimoto S, Nakajima F, Imanishi T, Kawai Y, Kato K, Kimura
T, et al. Implications of HLA diversity among regions for bonemarrow donor searches in Japan. HLA 2020;96:1–19.
13. Saitou N, Jinam TA. Language diversity of the Japanese Archipelago and its relationship with human DNA diversity. Man India.
2017;97:205–28.
14. Kawai Y, Mimori T, Kojima K, Nariai N, Danjoh I, Saito R, et al.
Japonica array: improved genotype imputation by designing a
population-speciﬁc SNP array with 1070 Japanese individuals. J
Hum Genet. 2015;60:581–7.
15. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen
WM. Robust relationship inference in genome-wide association
studies. Bioinformatics. 2010;26:2867–73.
16. Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y,
Ikeda M, et al. Genome-wide association study identiﬁes 112 newloci for body mass index in the Japanese population. Nat Genet.
2017;49:1458–67.
17. Nagai A, Hirata M, Kamatani Y, Muto K, Matsuda K, Kiyohara
Y, et al. Overview of the BioBank Japan Project: study design and
proﬁle. J Epidemiol. 2017;27(3S):S2–8.
18. Belmont JW, Boudreau A, Leal SM, Hardenbol P, Pasternak S,
Wheeler DA, et al. A haplotype map of the human genome.
Nature 2005;437:1299–320.

19. Jeon S, Bhak Y, Choi Y, Jeon Y, Kim S, Jang J, et al. Korean
Genome Project: 1094 Korean personal genomes with clinicalinformation. Sci Adv. 2020;6:eaaz7835. 1
20. Clarke L, Fairley S, Zheng-Bradley X, Streeter I, Perry E, Lowy
E, et al. The international Genome sample resource (IGSR): aworldwide collection of genome variation incorporating the 1000
Genomes Project data. Nucleic Acids Res. 2016;45:D854–9.
21. Freed D, Aldana R, Weber J, Edwards J. The Sentieon Genomics Tools—A fast and accurate solution to variant calling from next-generation
sequence data. bioRxiv; 2017. https://doi.org/10.1101/115717
22. Chang CC, Chow CC, Tellier LCAM, Vattikuti S, Purcell SM,
Lee JJ. Second-generation PLINK: rising to the challenge of larger
and richer datasets. Gigascience. 2015;4:1.
23. Alexander DH, Novembre J, Lange K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res.
2009;19:1655–64.
24. Pickrell JK, Pritchard JK. Inference of population splits andmixtures from genome-wide allele frequency data. PLoS Genet.
2012;8:e1002967.
25. Saitou N, Nei M. The neighbor-joining method: a new method forreconstructing phylogenetic trees. Mol Biol Evol. 1987;4:406–25.
26. Bryant D, Moulton V. Neighbor-net: an agglomerative method forthe construction of phylogenetic networks. Mol Biol Evol.
2004;21:255–65.
27. Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet. 2006;2:2074–93.
28. Leslie S, Winney B, Hellenthal G, Davison D, Boumertit A, Day
T, et al. The ﬁne-scale genetic structure of the British population.
Nature. 2015;519:309–14.
29. Watanabe Y, Isshiki M, Ohashi J. Prefecture level population structure of the Japanese based on SNP genotypes of 11,069 individuals. J
Hum Genet. 2020. https://doi.org/10.1038/s10038-020-00847-0.
30. Wright S. Isolation by distance. Genetics. 1943;28:114–38.
31. Okada Y, Momozawa Y, Sakaue S, Kanai M, Ishigaki K,
Akiyama M, et al. Deep whole-genome sequencing reveals recent
selection signatures linked to evolution and disease risk of Japanese. Nat Commun. 2018;9:1631.
32. Saitou N. History of Japanese Archipelago people. (in Japanese).
Tokyo: Iwanami Shoten; 2015.
33. Fujita N, Tanimura T, Tanaka K. The distribution of the ABO
blood groups in Japan. Jpn J Hum Genet. 1978;23:63–109.
34. Nakajima H, Ohkura K, Inafuku S, Ogura Y, Koyama T, Hori F,
et al. The distribution of several serological and biochemical traits
in east Asia. II. The distribution of ABO, MNSs, Q, Lewis, Rh,
Kell, Duffy and Kidd blood groups in Ryukyu. Japan. Jpn J Hum
Genet. 1967;12:29–37.
35. Misawa S, Ohno N, Ishimoto G, Omoto K. The distribution ofgenetic markers in blood samples from Okinawa, the Ryukyus. J
Anthropol Soc Nippon. 1974;82:135–43.