American Indian Prehistory as Written in the Mitochondrial DNA:

A Review
Author(s) :Douglas C. Wallace and Antonio Torroni
Source: Human Biology, 81(5/6):509-521. 2009.
Published By: Wayne State University Press
DOI: http://dx.doi.org/10.3378/027.081.0602
URL: http://www.bioone.org/doi/full/10.3378/027.081.0602

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American Indian Prehistory as Written in the

Mitochondrial DNA: A Review
douglas c. wallace1 and antonio torroni1
Abstract Native Americans have been divided into three linguistic groups:
the reasonably well-defined Eskaleut and Nadene of northern North America
and the highly heterogeneous Amerind of North, Central, and South America. The heterogeneity of the Amerinds has been proposed to be the result
of either multiple independent migrations or a single ancient migration with
extensive in situ radiation. To investigate the origin and interrelationship of
the American Indians, we examined the mitochondrial DNA (mtDNA) variation in 87 Amerinds (Pima, Maya, and Ticuna of North, Central, and South
America, respectively), 80 Nadene (Dogrib and Tlingit of northwest North
America and Navajo of the southwest North America), and 153 Asians from 7
diverse populations. American Indian mtDNAs were found to be directly descended from five founding Asian mtDNAs and to cluster into four lineages,
each characterized by a different rare Asian mtDNA marker. Lineage A is
defined by a HaeIII site gain at np 663, lineage B by a 9-bp deletion between
the COII and tRNALys genes, lineage C by a HincII site loss at np 13259,
and lineage D by an AluI site loss at np 5176. The North, Central, and South
America Amerinds were found to harbor all four lineages, demonstrating that
the Amerinds originated from a common ancestral genetic stock. The genetic
variation of three of the four Amerind lineages (A, C, and D) was similar with
a mean value of 0.084%, whereas the sequence variation in the fourth lineage
(B) was much lower, raising the possibility of an independent arrival. By
contrast, the Nadene mtDNAs were predominantly from lineage A, with 27%
of them having a Nadene-specific RsaI site loss at np 16329. The accumulated Nadene variation was only 0.021%. These results demonstrate that the
Amerind mtDNAs arose from one or maybe two Asian migrations that were
distinct from the migration of the Nadene and that the Amerind populations
are about four times older than the Nadene.

Questions about Native American Prehistory

When Columbus contacted the Americas in 1492, Native American occupation stretched from the Bering Strait to Tierra del Fuego. These native populations
encompassed extraordinary linguistic and cultural diversity, which has fueled extensive debate on their interrelationships and origins.

Center for Genetics and Molecular Medicine, Emory University, Atlanta, GA 30322.

Human Biology, June 1992, v. 64, no. 3, pp. 403416.

Copyright 1992 Wayne State University Press, Detroit, Michigan 48202

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Traditional anthropological analysis has confirmed that American Indians
came from Asia, probably crossing the Bering land bridge when it was exposed
during an episode of glaciation (Crawford and Enciso 1983; Fladmark 1983;
Laughlin and Wolf 1979; Matson et al. 1968; Schell and Blumberg 1988; Turner
1983, 1987; Williams et al. 1985). Linguistic and genetic analysis has divided
the Native Americans into three major groups: Eskaleut, Nadene, and Amerind
(Cavalli-Sforza et al. 1988; Greenberg 1987; Neel 1978; Neel and Thompson
1978; Szathmary 1984, 1991). The first two groups are well defined, with the
Eskaleut encompassing the Eskimos and the Aleuts of the Arctic and the Nadene
including the Athapaskans, Tlingits, Haida, and Eyaks of northwestern North
America. The homogeneity of these linguistic groups has led to the hypothesis
that they represent two separate waves of migration that arrived about 5000 and
9000 years or more before present. By contrast, the Amerind group, composed of
the American Indians from North, Central, and South America, shows extensive
linguistic diversity. This diversity has been proposed to be the result of the amalgamation of multiple independent migrations with different linguistic traditions
or of a single ancient migration that has undergone extensive linguistic radiation
(Greenberg et al. 1986).
Archeological evidence on the timing of ancestral American Indian migrations is also ambiguous. The oldest skeletal remains and Clovis lithic artifacts have
yielded dates between 13,000 and 14,000 years b.p. (Nelson et al. 1986; Taylor et
al. 1985). By contrast, excavations at the Meadowcroft Rock Shelter in Pennsylvania (Adovasio et al. 1983), the Boqueiro site in Pedra Furada in Brazil (Guidon
and Delibrias 1986), and the Monte Verde site in Chile (Dillehay and Collins 1988)
have yielded evidence of human occupation dating back to 33,000 years b.p., although the authenticity of these sites continues to be debated (Marshall1990).
These observations generate a number of questions. How many Asian migrations occurred? When did the ancestral American Indians arrive? And what
is the relationship between the Amerinds and the Nadene? Recently, molecular
anthropology has begun to provide new insights into these questions. One particularly productive approach has been the analysis of mitochondrial DNA (mtDNA)
variation.

mtDNA Variation and Human Origins

mtDNA has several unique features that make it ideal for studying ancient
human migrations. mtDNA is a small circular molecule of 16,569 nucleotide pairs
(np). It is present in 30005000 copies per cell (Shuster et al. 1988), making it easy
to analyze. mtDNA is maternally inherited (Case and Wallace 1981; Giles et al.
1980) and never recombines (Schurr et al. 1990). Therefore it evolves by the sequential accumulation of mutations along radiating female lineages (Johnson et al.
1983). Finally, its sequence evolves about 10 times faster than nuclear DNA (Brown
et al. 1979, 1982; Miyata et al. 1982; Neckelmann et al. 1987; Wallace et al. 1987),
permitting distinctions to be made between even closely related populations.

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The mtDNA codes for 13 polypeptides of mitochondrial respiratory complexes and for the rRNA and tRNA genes for mitochondrial protein synthesis
(Shoffner and Wallace 1990). These coding regions evolve at a rate of 24% per
million years (Cann et al. 1987; Stoneking et al. 1990) with the replacement mutation rate being 1.8 109 substitutions per site per year (SSY) (0.19% per million
years), whereas the synonymous mutation rate is 32.3 109 SSY (3.2% per million years) (Wallace et al. 1987). The noncoding D-loop sequence evolves much
faster, 8.4% per million years (Greenberg et al. 1983; Horai and Hayasaka 1990;
Vigilant et al. 1989). Thus analysis of various regions of the mtDNA can provide
information on different time scales (Di Rienzo and Wilson 1991; Stoneking et al.
1991; Vigilant et al. 1991).
Sequence variation of the mtDNA can be efficiently surveyed through restriction fragment length polymorphisms (RFLPs). Restriction fragment variants are detected by gel electrophoresis, and each restriction site gain or loss is
equivalent to a single nucleotide substitution. One efficient procedure for analyzing RFLPs is to digest blood cell DNAs, resolve the fragments on agarose gels,
and detect the fragments by Southern blotting and hybridization with radioactive mtDNA probes (Blanc et al. 1983; Denaro et al. 1981; Johnson et al. 1983;
Wallace 1983). Six highly informative (core) restriction endonucleases (HpaI,
BamHI, HaeII, MspI, AvaII, and HincII) have been used to survey the variation
of 3065 individuals from 62 geographic samples. This survey has detected 149
haplotypes encompassing 81 polymorphic sites (Blanc et al. 1983; Bonn-Tamir
et al. 1986; Brega, Gardella et al. 1986; Brega, Scozzari et al. 1986; Denaro et al.
1981; Johnson et al. 1983; Merriwether et al. 1991; Santachiara-Benerecetti et al.
1988; Semino et al. 1989, 1991; Scozzari et al. 1988; Torroni et al. 1990).
These studies have revealed four principles of human mtDNA evolution. First, mtDNA mutations accumulate sequentially along radiating maternal
lineages. Second, mtDNA variation correlates highly with the ethnic and geographic origin of the samples, because new mutations occurred concurrently with
the migration of female lineages into new geographic regions. Third, all human
mtDNAs are components of a single mtDNA lineage, indicating a single origin.
Fourth, the mtDNA tree and hence our species are very young. The average age
of the ethnic groups is about 100,000 years b.p., and the overall lineal age is about
twice that, with the greatest mtDNA diversity found in Africa. If we assume that
the evolutionary rate of the mtDNA is constant, then the origin of the mtDNA tree
and hence of Homo sapiens must be Africa. These principles were first reported
by Johnson et al. (1983) and have subsequently been confirmed (Cann et al. 1987;
Merriwether et al. 1991; Vigilant et al. 1991).

mtDNA Variation in American Indians

The high correlation between mtDNA variation and ethnic and geographic
origin suggested that mtDNA variation might be valuable for determining the
number and origin of ancient Asian migrations to the Americas. This has proven

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to be the case. It is now known that the Amerinds are a coherent genetic group
that originated from a common ancestral genetic stock and that the Nadene are a
separate group that arrived in the Americas much later.
The first evidence that the Amerinds represent a genetically homogeneous
population came from analyzing the mtDNAs of the Pima and Papago of the
southwestern United States. RFLP analysis using the six core restriction endonucleases revealed that the mtDNAs of the Pima and Papago were much less
variable than those of Asians but harbored certain rare Asian variants at high
frequencies. An individual restriction pattern generated by one restriction endonuclease is called a morph, and analysis with HpaI, BamHI, HpaII, and AvaII
revealed that the Pima and Papago harbored only the most common Asian morph.
Analysis with HaeII revealed somewhat greater variation, with about 8% of the
Pima and Papago mtDNAs having variants found at low frequencies in Asians and
Europeans. However, analysis with HincII revealed that an extraordinary 41% of
the Pima and Papago harbor the rare Asian variant HincII morph 6 and that an additional 3% had an American Indianspecific derivative, HincII morph 9 (Wallace
et al. 1985). HincII morph 2 is the most common morph in Asians (Blanc et al.
1983) and was found in 55% of the Pima and Papago. The loss of restriction site
e at np 13259 converts HincII morph 2 to morph 6, a mutation that presumably
occurred in Asia. The subsequent loss of the adjacent site c at np 13634 results
in HincII morph 9 and occurred in the Americas (Wallace et al. 1985) (Figure 1).
Because HincII morph 6 has been found in only 2% of Asian mtDNAs and not in
European or African mtDNAs (Blanc et al. 1983), these results confirm the Asian
origin of the Amerinds. In addition, the over 20-fold increase in the frequency of
HincII morph 6 mtDNAs indicates that a major bottleneck occurred during the
transition from the Asians to the southwestern Amerinds.
The genetic bottleneck was shown to have occurred before the radiation of
the ancestral Amerinds by analyzing Central American Maya and South American Ticuna mtDNAs. Like the Pima and Papago, the Maya and the Ticuna were
monomorphic for HpaI and BamHI and showed only modest variation for MspI/
HpaII, HaeII, and AvaII. However, HincII was again polymorphic with 11% of the
Mayan mtDNAs and 42% of the Ticuna mtDNAs being HincII morph 6. Hence all
the Amerinds harbored the same rare Asian marker at a high frequency, confirming that they descended from a common stock (Schurr et al. 1990).
The genetic association of all Amerinds was further substantiated by analysis of an Asian-specific 9-bp intergenic deletion between the COII and tRNALys
genes (Cann and Wilson 1983; Wrischnik et al. 1987). This variant identifies an
mtDNA lineage that is different from that associated with HincII morph 6. Analysis of Amerind mtDNAs revealed that 45% of the Pima mtDNAs and 22% of
the Maya mtDNAs contain this morph (Schurr et al. 1990; Torroni et al. 1992).
Although the Ticuna do not harbor this mtDNA, many other Central and South
American tribes do (unpublished data). Hence the COII/tRNALys deletion defines
a second Asian mtDNA lineage shared with Amerinds and confirms the common
origin of these populations (Schurr et al. 1990).

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Figure 1. Restriction endonuclease fragment patterns of HincII morphs 2, 6, and 9. Uppercase letters correspond to fragments found in the circular map of the most common morph, HincII
morph 2. Lowercase letters indicate positions of site losses converting morph 2 to morph 6
(e + d) and morph 6 to morph 9 (f). Reprinted from Wallace et al. (1985) with permission.

To clarify the relationship between Asian and American Indian mtDNAs,

we analyzed 153 Asian mtDNAs and 167 American Indian mtDNAs using polymerase chain reaction (PCR) amplification of the mtDNA in 9 overlapping segments and digestion of each segment with 14 restriction endonucleases (AluI,
AvaII, DdeI, HaeIII, HhaI, Hinfl, HpaI, HpaII, MboI, RsaI, TaqI, BamHI, HaeII,
and HincII). The Asian samples included 14 Malaysian Chinese, 32 Malaysian
Senoi, 14 Malays, 32 Borneans, 28 Vietnamese, 20 Han Chinese from Taiwan,
and 13 Koreans (Ballinger et al. 1992). The Americans Indians included 87 Amerinds (30 Pima, 27 Maya, 28 Ticuna, 1 Pomo, and 1 Hopi) and 80 Nadene (2
Tlingit, 30 Dogrib, and 48 Navajo) (Torroni et al. 1992).
The Asians were found to harbor extensive mtDNA variation, including
106 haplotypes encompassing 191 polymorphic restriction site (Ballinger et al.
1992). The COII/tRNALys deletion was found to have occurred more than once.
However, most of the mtDNAs associated with the deletion were derived from a
single ancient event and have closely related haplotypes. The highest Asian frequency (40%) of this deletion lineage is in the Han Chinese of Taiwan. This suggests that this mtDNA lineage arose in southeast China (Ballinger et al. 1992). Its
frequency then declines along the southern Asian coast and increases again into

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Table 1.

Mitochondrial DNA Haplotype Distribution in Nadene and Amerindsa

mtDNA
Lineage A

Population N

Nadene
Dogrib 30 19
Tlingit
2 1
Navajo 48 11
Amerinds
Hopi
1
Pima
30
Pomo
1
Maya
27 5
Ticuna 28
Total
167 36

7
1
13

Lineage
8

1
0

1
1

1
2

1
4

1
5

1
6

1
7

1
8

11

5
2
2

2
2 21

1
9

2
0

1
3

2
2

2
1 2
1 11

1 21

Modified from Torroni et al. (1992).

a. We define a lineage as a set of mtDNAs related to each other by shared common and unique mutations not observed in other mtDNAs. We define a haplotype as a distinct association of restriction
endonuclease site polymorphisms for 14 enzymes within 1 mtDNA genome.

the Pacific, where it approaches fixation, being present in 93% of Polynesians

(Ballinger et al. 1992; Hertzberg et al. 1989; Stoneking et al. 1990). American
Indian deletion mtDNAs are also derived from this lineage, the deletion accompanying migrants who colonized both the Americas and the Pacific. The Vietnamese have the greatest intragroup mtDNA variation (0.236%), indicating that
they are the oldest population. They also have the highest frequency of mtDNAs
that are HpaI/HincII morph 1 (Ballinger et al. 1992), an mtDNA morph previously proposed to identify a founding Asian mtDNA lineage (Blanc et al. 1983).
Hence most Asian mtDNA variation centers around southeastern China, suggesting that this is where the Asian population originated. Two additional ancient
mtDNA restriction site polymorphisms were found to divide all Asian haplotypes
into two groups: a DdeI site at np 10394 and an overlapping AluI site at np 10397
(Ballinger et al. 1992).
Compared with the Asian mtDNAs, American Indian mtDNAs show substantially less variation, with 50 haplotypes (Table 1) encompassing 68 polymorphic sites (Torroni et al. 1992). All the American Indian mtDNA haplotypes
separated into four discrete lineages (A, B, C, and D) (Figure 2), and each lineage
was founded by mtDNA haplotypes (1, 9, 13, 43, and 44) that were either closely
related to or identical with haplotypes found in Asia (Ballinger et al. 1992; Torroni et al. 1992). Lineages A and B differ from lineages C and D in that the former
lack the Asian DdeI np 10394 and AluI np 10397 sites. Furthermore, each lineage
is defined by a specific Asian polymorphism: lineage A by an HaeIII site gain at

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Haplotype
B

Lineage C

Lineage D

2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 5
1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0

2
1
1 2 1 1 3

1 1 1 5

3 1 1
1

1 1

1 1
1
3 2 3
4 1 4 2 3
1 1 2 1 1 3 1 1 2 1 1 1 1 1 5 1 3 1 1 3 2 3 2 5 1 4 2 3 1 1

np 663, lineage B by the 9-bp deletion, lineage C by the HincII site loss at np
13259 (HincII morph 6), and lineage D by an AluI site loss at np 5176. Beyond
the founding haplotypes (9, 13, 43, and 44), all the mtDNAs of these lineages
are American Indian specific, indicating that they arose after the separation of
these lineages from Asians. The Amerinds (Figure 2, filled circles) encompass all
four lineages, and the Amerind intracluster mtDNA variation of three of these is
similar (0.071% for lineage A, 0.102% for lineage C, and 0.073% for lineage D).
This suggests that their founding haplotypes became isolated at approximately
the same time. The weighted-average intracluster variation of these lineages is
0.084%. Assuming an mtDNA evolutionary rate of 24% per million years, these
lineages would be between 21,000 and 42,000 years old (Torroni et al. 1992).
The Nadene mtDNAs (Figure 2, open circles) were much less variable than
those of the Amerinds. The Tlingit and Dogrib mtDNAs of Alaska and Canada
all fall into cluster A, defined by the HaeIII np 663 site gain, and only four haplotypes (Torroni et al. 1992) were observed (Table 1). Furthermore, haplotypes
5 and 6 carried a distinctive RsaI site loss at np 16329, which provides a unique
marker for Nadene mtDNAs. The Navajo mtDNA also contained haplotypes 1, 5,
and 9, confirming their affinity with the northwestern Nadene. However, the Navajo mtDNA also contained six deletion haplotypes (Table 1, Figure 2). Because
the ancestors of the Navajo and the Apache migrated through the Great Plains to
the southwestern United States about 1000 years ago, a reasonable hypothesis
is that these deletion mtDNAs were acquired by the Navajo through admixture
with Amerinds of the southwestern United States (Torroni et al. 1992). Consistent with the limited number of haplotypes, the Nadene mtDNA diversity was
only 0.021%, about one-fourth that of the Amerinds. This means that the Nadene

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mtDNA lineage is 525010,500 years old (Torroni et al. 1992), a time range consistent with estimates from linguistic diversity (Greenberg 1987).
The relationship of lineage B to the Amerinds is less clear. Its sequence
divergence is 0.038%, a value greater than that of Nadene lineage A and lower
than those calculated for the rest of the Amerind lineages. This result raises the
possibility that the individuals carrying the founding haplotype of lineage B arrived in the Americas in a separate migration that occurred after the first migration
and before the migration of the ancestral Nadene. As these migrants moved south,
they would have mixed with the descendants of the original settlers.
These studies lead to the conclusion that all modern Amerinds essentially
derived from a common ancestral genetic stock. Four of the founding mtDNA
haplotypes (1, 9, 43, and 44) arrived with the first human migrants in the Americas. Possibly, haplotype 13, the founding haplotype of the 9-bp deletion lineage,
arrived independently and more recently. These results confirm the hypothesis that
the diversity of the Amerind linguistic group was essentially generated through radiation from a single founding language (Greenberg 1987; Greenberg et al. 1986).
They also show that the Nadene were derived from a different founding population that developed much more recently than the Amerinds. The overall age of
three of the four Amerind mtDNA lineages is 21,000 to 42,000 years, an estimate
that is consistent with the ages of the oldest archeological sites. However, it is
currently unclear whether the founder effect that isolated these mtDNA lineages
occurred as Asians migrated across the Bering land bridge or as they migrated into
the Siberian steppes. Hence, to complete the story of American Indian origins, we
must analyze the mtDNA variation of Siberians, their closest related Asian population (Posukh et al. 1990).
Received 3 July 1991; revision received 8 November 1991.

Figure 2. Phylogenetic tree of Native American mtDNA haplotypes. A, B, C, and D indicate the
four haplotype lineages, with the key below the dendrogram indicating the characteristic
mutation of each one. The numbers at the end of each branch refer to distinct mtDNA
haplotypes (Tables 1 and 2), with solid circles indicating those present in Amerinds, open
circles indicating those present in Nadene, and shaded circles indicating those present in
both groups. hypanc is the hypothetical ancestor [from Cann et al. (1987)]. Individual
branch lengths are proportional to the number of mutational steps between haplotypes.
Haplotypes 28 and 29 lack characteristic Native American mutations and do not cluster in
any of the four lineages. Because they have mutations observed in whites, they were probably introduced by European admixture. This dendogram was inferred using parsimony
analysis (PAUP, version 3.0m; Swofford 1989), is 77 mutational steps in length with a
consistency index of 0.844, and is the consensus of 100 trees generated by the tree bisection and reconnection (TBR) method. Intragroup sequence divergences of each lineage
were calculated according to the method of Nei and Tajima (1983). Modified from Torroni
et al. (1992).

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