[BiO BB] To whomever can help
derek at biotechrecruiter.org
Wed Nov 6 20:57:01 EST 2002
Rebecca L. Cann*, Mark Stoneking & Allan C. Wilson
"Mitochondrial DNA and Human Evolution," Nature, 325 (1987), 31-6.
Department of Biochemistry, University of California, Berkeley,
California 94720, USA
Mitochondrial DNAs from 147 people, drawn from five geographic
populations have been analysed by restriction mapping. All these
mitochondrial DNAs stem from one woman who is postulated to have lived
about 200,000 years ago, probably in Africa. All the populations
examined except the African population have multiple origins, implying
that each area was colonised repeatedly.
MOLECULAR biology is now a major source of quantitative and objective
information about the evolutionary history of the human species. It has
provided new insights into our genetic divergence from apes1-8 and into
the way in which humans are related to one another genetically 9-14. Our
picture of genetic evolution within the human species is clouded,
however, because it is based mainly on comparisons of genes in the
nucleus. Mutations accumulate slowly in nuclear genes. In addition,
nuclear genes are inherited from both parents and mix in every
generation. This mixing obscures the history of individuals and allows
recombination to occur. Recombination makes it hard to trace the history
of particular segments of DNA unless tightly linked sites within them
Our world-wide survey of mitochondrial DNA (mtDNA) adds to knowledge of
the history of the human gene pool in three ways. First, mtDNA gives a
magnified view of the diversity present in the human gene pool, because
mutations accumulate in this DNA several times faster than in the
nucleus15. Second, because mtDNA is inherited maternally and does not
recombine16, it is a tool for relating individuals to one another.
Third, there are about 1016 mtDNA molecules within a typical human and
they are usually identical to one another 17-19. Typical mam-
malian females consequently behave as haploids, owing to a bottleneck in
the genetically effective size of the population of mtDNA molecules
within each oocyte20. This maternal and haploid inheritance means that
mtDNA is more sensitive than nuclear DNA to severe reductions in the
number of individuals in a population of organisms". A pair of breeding
individuals can transmit only one type of mtDNA but carry four haploid
sets of nuclear genes, all of which are transmissible to offspring. The
fast evolution and peculiar mode of inheritance of mtDNA provide new
perspectives on how, where and when the human gene pool arose and grew.
MtDNA was highly purified from 145 placentas and two cell lines, HeLa
and GM 3043, derived from a Black American and an aboriginal South
African (!Kung), respectively. Most placentas (98) were obtained from US
hospitals, the remainder coming from Australia and New Guinea. In the
sample, there were representatives of 5 geographic regions: 20 Africans
(representing the sub- Saharan region), 34 Asians (originating from
China, Vietnam, Laos, the Philippines, Indonesia and Tonga), 46
Caucasians (originating from Europe, North Africa, and the Middle East),
21 aboriginal Australians, and 26 aboriginal New Guineans. Only two of
the 20 Africans in our sample, those bearing mtDNA types I and 81 (see
below) were born in sub-Saharan Africa. The other 18 people in this
sample are Black Americans, who bear many non-African nuclear genes
probably contributed mainly by Caucasian mates. Those males would not be
expected to have introduced any mtDNA to the Black American population.
Consistent with our view that most of
these 18 people are a reliable source of African mtDNA, we found that 12
of them bear restriction site markers known21 to occur exclusively or
predominantly in native sub-Saharan Africans (but not in Europeans,
Asians or American Indians nor, indeed, in all such Africans). The mtDNA
types in these 12 people are 2-7, 37-41 and 82 (see below). Methods used
to purify mtDNA and more detailed ethnographic information on the first
four groups are as described 17,22; the New Guineans are mainly from the
Eastern Highlands of Papua New Guinea
Each purified mtDNA was subjected to high resolution map Ping 22-24 with
12 restriction enzymes (Hpal, Avall, FnuDII, Hhal, Hpall, Mbol, TaqI,
Rsal, Hinfl, Haelll, Alul and DdeI). Restriction sites were mapped by
comparing observed fragment patterns to those expected from the known
human mtDNA sequence25. In this way, we identified 467 independent
sites, of which 195 were polymorphic (that is, absent in at least one
individual). An average of 370 restriction sites per individual were
surveyed, representing about 9% of the 16,569 base-pair human mtDNA
The 147 mtDNAs mapped were divisible into 133 distinct types. Seven of
these types were found in more than one individual; no individual
contained more than one type. None of the seven shared types occurred in
more than one of the five geographic regions. One type, for example, was
found in two Australians. Among Caucasians, another type occurred three
times and two more types occured twice. In New Guinea, two additional
types were found three times and the seventh case involved a type found
in six individuals.
A histogram showing the number of restriction site differences between
pairs of individuals is given in Fig. 1; the average number of
differences observed between any two humans is 9.5. The distribution is
approximately normal, with an excess of pairwise comparisons involving
large numbers of differences. From the number of restriction site
differences, we estimated the extent of nucleotide sequence divergence
26 for each pair of individuals. These estimates ranged from zero to 1.3
substitutions per 100 base pairs, with an average sequence divergence of
0.32%, which agrees with that of Brown17, who examined only 21 humans.
Table I gives three measures of sequence divergence within and between
each of the five populations examined. These measures are related to one
another by equation (1):
where is the mean pairwise divergence (in percent) between individuals
within a single population (X), is the corresponding value for another
population (Y), is the mean pairwise divergence between individuals
belonging to two different populations (X and Y), and is a measure of
the interpopulation divergence corrected for intrapopulation divergence.
Africans as a group are more variable ( = 0.47) than other groups.
Indeed, the variation within the African population is as great as that
between Africans and any other group ( = 0.40- 0.45). The within-group
variation of Asians ( = 0.35) is also comparable to that which exists
between groups. For Australians, Caucasians, and New Guineans, who show
nearly identical amounts of within-group variation ( = 0.23-0.25), the
variation between groups slightly exceeds that within groups.
When the interpopulational distances () are corrected for
intrapopulation variation (Table 1), they become very small ( =
0.01-0.06). The mean value of the corrected distance among populations (
= 0.04) is less than one-seventh of the mean distance between
individuals within a population (0.30). Most of the mtDNA variation in
the human species is therefore shared between populations. A more
detailed analysis supports this vie27.
Figure 2 shows the sequence divergence () calculated for each population
across seven functionally distinct regions of the 14,11,11 mtDNA genome.
As has been found before , the most variable region is the displacement
loop (k = 1.3), the major noncoding portion of the mtDNA molecule, and
the least variable region is the 16S ribosomal, RNA gene (5x = 0.2). In
general, Africans are the most diverse and Asians the next most, across
all functional regions.
A tree relating the 133 types of human mtDNA and the reference sequence
(Fig. 3) was built by the parsimony method. To interpret this tree, we
make two assumptions, both of which have extensive empirical support:
(1) a strictly maternal mode of mtDNA transmission (so that any variant
appearing in a group of lineages must be due to a mutation occurring in
the ancestral lineage and not recombination between maternal and
paternal genomes) and (2) each individual is homogeneous for its
multiple mtDNA genomes. We can therefore view the tree as a genealogy
linking maternal lineages in modern human populations to a common
ancestral female (bearing mtDNA type a).
Many trees of minimal or near-minimal length can be made from the data;
all trees that we have have examined share the following features with
Fig. 3. (1) two primary branches, one composed entirely of Africans, the
other including all 5 of the populations studied; and (2) each
population stems from multiple lineages connected to the tree at widely
dispersed positions. Since submission of this manuscript, Horai et al.29
built a tree for our samples of African and Caucasian populations and
their sample of a Japanese population by another method; their tree
shares these two features.
Among the trees investigated was one consisting of five primary branches
with each branch leading exclusively to one of the five populations.
This tree, which we call the population-specific tree, requires 51 more
point mutations than does the tree of minimum length in Fig. 3. The
minimum-length tree requires fewer changes at 22 of the 93
phylogenetically-informative restriction sites than does the
population-specific tree, while the latter tree required fewer changes
at four sites; both trees require the same number of changes at the
remaining 67 sites. The minimum-length tree is thus favoured by a score
of 22 to 4. The hypothesis that the two trees are equally compatible
with the data is statistically rejected, since 22:4 is significantly
different from the expected 13:13. The minimum-length tree is thus
significantly more parsimonious than the population-specific tree.
We infer from the tree of minimum length (Fig. 3) that Africa is a
likely source of the human mitochondrial gene pool. This inference comes
from the observation that one of the two primary branches leads
exclusively to African mtDNAs (types 1-7, Fig. 3) while the second
primary branch also leads to African mtDNAs (types 37-41, 45, 46, 70,
72, 81, 82, 111 and 113). By postulating that the common ancestral mtDNA
(type a in Fig. 3) was African, we minimize the number of
intercontinental migrations needed to account for the geographic
distribution of mtDNA types. It follows that b is a likely common
ancestor of all non-African and many African mtDNAs (types 8-134 in Fig.
Multiple lineages per race
The second implication of the tree (Fig. 3)-that each non-African
population has multiple origins-can be illustrated most simply with the
New Guineans. Take, as an example, mtDNA type 49, a lineage whose
nearest relative is not in New Guinea, but in Asia (type 50). Asian
lineage 50 is closer genealogically to this New Guinea lineage than to
other Asian mtDNA lineages. Six other lineages lead exclusively to New
Guinean mtDNAs, each originating at a different place in the tree (types
12, 13, 26-29, 65, 95 and 127-134 in Fig. 3). This small region of New
Guinea (mainly the Eastern Highlands Province) thus seems to have been
colonised by at least seven maternal lineages (Tables 2 and 3).
In the same way, we calculate the minimum numbers of female lineages
that colonised Australia, Asia and Europe (Tables 2 and 3). Each
estimate is based on the number of region-specific clusters in the tree
(Fig. 3, Tables 2 and 3). These numbers, ranging from 15 to 36 (Tables 2
and 3), will probably rise as more types of human mtDNA are discovered.
Tentative time scale
A time scale can be affixed to the tree in Fig. 3 by assuming that mtDNA
sequence divergence accumulates at a constant rate in humans. One way of
estimating this rate is to consider the extent of differentiation within
clusters specific to New Guinea (Table 2; see also refs 23 and 30),
Australia30 and the New World31. People colonised these regions
relatively recently: a minimum of 30,000 years ago for New Guinea32,
40,000 years ago for Australia33, and 12,000 years ago for the New
World34. These times enable us to calculate that the mean rate of mtDNA
divergence within humans lies between two and four percent per million
years; a detailed account of this calculation appears
elsewhere30. This rate is similar to previous estimates from animals as
disparate as apes, monkeys, horses, rhinoceroses, mice, rats, birds and
fishes". We therefore consider the above estimate of 2%-4% to be
reasonable for humans, although additional comparative work is needed to
obtain a more exact calibration.
As Fig. 3 shows, the common ancestral mtDNA (type a) links mtDNA types
that have diverged by an average of nearly 0.57%. Assuming a rate of
2%-4% per million years, this implies that the common ancestor of all
surviving mtDNA types existed 140,000-290,000 years ago. Similarly,
ancestral types b-j may have existed 62,000-225,000 years ago (Table 3).
When did the migrations from Africa take place? The oldest of the
clusters of mtDNA types to contain no African members stems from
ancestor c and included types 11-29 (Fig. 3). The apparent age of this
cluster (calculated in Table 3) is 90,000-180,000 years. Its founders
may have left Africa at about that time. However, it is equally possible
that the exodus occurred as recently as 23-105 thousand years ago (Table
2). The mtDNA results cannot tell us exactly when these migrations took
Other mtDNA studies
Two previous studies of human mtDNA have included African
individua21,28, both support an African origin for the human mtDNA gene
pool. Johnson et al 21 surveyed 40 restriction sites in each of 200
mtDNAs from Africa, Asia, Europe and the New World, and found 35 mtDNA
types. This much smaller number of mtDNA types probably reflects the
inability of their methods to distinguish between mtDNAs that differ by
less than 0.3% and may account for the greater clustering of mtDNA
types by geographic origin that they observed. (By contrast, our methods
distinguish between mtDNAs that differ by 0.03%.) Although Johnson et al
favoured an Asian origin, they too found that Africans possess the
greatest amount of mtDNA variability and that a midpoint rooting of
their tree leads to an African origin.
Greenberg et al28 sequenced the large noncoding region, which includes
the displacement loop (D loop), from four Caucasians and three Black
Americans. A parsimony tree for these seven D loop sequences, rooted by
the midpoint method, appears in Fig. 4. This tree indicates (1) a high
evolutionary rate for the D loop (at least five times faster than other
other mtDNA regions), (2) a greater diversity among Black American D
loop sequences, and (3) that the common ancestor was African.
Nuclear DNA studies
Estimates of genetic distance based on comparative studies of nuclear
genes and their products differ in kind from mtDNA estimates. The latter
are based on the actual number of mutational differences. between mtDNA
genomes, while the former rely on differences in the frequencies of
molecular variants measured between and within populations. Gene
frequencies can be influenced by recombination, genetic drift,
selection, and migration, so the direct relationship found between time
and mutational distance for mtDNA would not be expected for genetic
distances based on nuclear DNA. But studies based on polymorphic blood
groups, red cell enzymes, and serum proteins show that (1) differences
between racial groups are smaller than those within, such groups and (2)
the largest gene frequency differences are between Africans and other
populations, suggesting an African origin for the human nuclear gene
pool11,12,35. More recent studies of restriction site polymorphisms in
nuclear DNA 14,36-42 support these conclusions.
Relation to fossil record
Our tentative interpretation of the tree (Fig. 3) and the associated
time scale (Table 3) fits with one view of the fossil record: that the
transformation of archaic to anatomically modern forms of Homo sapiens
occurred first in Africa 43-45, about 100,000-140,000 years ago, and
that all present-day humans are descendants of that African population.
Archaeologists have observed that blades were in common use in Africa
80-90 thousand years ago, long before they replaced flake tools in Asia
But the agreement between our molecular view and the evidence from
palaeoanthropology and archaeology should be treated cautiously for two
reasons. First, there is much uncertainty about the ages of these
remains. Second, our placement of the common ancestor of all human mtDNA
diversity in Africa 140,000-280,000 years ago need not imply that the
transformation to anatomically modern Homo sapiens occurred in Africa at
this time. The mtDNA data tell us nothing of the contributions to this
transformation by the genetic and cultural traits of males and females
whose mtDNA became extinct.
An alternative view of human evolution rests on evidence that Homo has
been present in Asia as well as in Africa for at least one million
years48 and holds that the transformation of archaic to anatomically
modern humans occurred in parallel in different parts of the Old
World33,49. This hypothesis leads us to expect genetic differences of
great antiquity within widely separated parts of the modern pool of
mtDNAs. It is hard to reconcile the mtDNA results with this hypothesis.
The greatest divergences within clusters specific to non-African parts
of the World correspond to times of only 90,000-180,000 years. This
might imply that the early Asian Homo (such as Java man and Peking man)
contributed no surviving mtDNA lineages to the gene pool of our species.
Consistent with this implication are features, found recently in the
skeletons of the ancient Asian forms, that make it unlikely that Asian
erectus was ancestral to Homo sapiens50-52. Perhaps the non-African
erectus population was replaced by sapiens migrants from Africa;
incomplete fossils indicating the possible presence of early modern
humans in western Asia at Zuttiyeh (75,000-150,000 years ago) and Qafzeh
(50,000-70,000 years ago) might reflect these first migrations45,53.
If there was hybridization between the resident archaic forms in Asia
and anatomically modem forms emerging from Africa, we should expect to
find extremely divergent types of mtDNA in present-day Asians, more
divergent than any mtDNA found in Africa. There is no evidence for these
types of mtDNA among the Asians studied 21,54-16 . Although such archaic
types of mtDNA could have been lost from the hybridizing population, the
probability of mtDNA lineages becoming extinct in an expanding
population is low57. Thus we propose that Homo
erectus in Asia was replaced without much mixing with the invading Homo
sapiens from Africa.
Conclusions and prospects
Studies of mtDNA suggest a view of how, where and when modern humans
arose that fits with one interpretation of evidence from ancient human
bones and tools. More extensive molecular comparisons are needed to
improve our rooting of the mtDNA tree and the calibration of the rate of
mtDNA divergence within the human species. This may provide a more
reliable time scale for the spread of human populations and better
estimates of the number of maternal lineages involved in founding the
It is also important to obtain more quantitative estimates of the
overall extent of nuclear DNA diversity in both human and African ape
populations. By comparing the nuclear and mitochondrial DNA diversities,
it may be possible to find out whether a transient or prolonged
bottleneck in population size accompanied the origin of our species15.
Then a fuller interaction between palaeoanthropology, archaeology and
molecular biology will allow a deeper analysis of how our species arose.
We thank the Foundation for Research into the Origin of Man, the
National Science Foundation and the NIH for support. We also thank P.
Andrews, K. Bhatia, F. C. Howell, W. W. Howells, R. L. Kirk, E. Mayr, E.
M. Prager, V. M. Sarich, C. Stringer and T. White for discussion and
help in obtaining placentas.
From: bio_bulletin_board-admin at bioinformatics.org
[mailto:bio_bulletin_board-admin at bioinformatics.org] On Behalf Of Brett
Sent: Tuesday, November 05, 2002 8:01 PM
To: bio_bulletin_board at bioinformatics.org
Subject: [BiO BB] To whomever can help
To whomever can help me,
My name is Brett Safford, I am a junior at University of Connecticut,
majoring in computer science and minoring in Bio-Informatics.
I am searching for an article called "Mitochondrial DNA and human
by Rebecca Cann, Mark Stoneking and Allan Wilson. It was published in
magazine, Nature, January 1, 1987.
I realize that this is an old article, but I really would like to get a
of it and read it.
If anyone can help me out, I would greatly appreciate it.
BiO_Bulletin_Board maillist - BiO_Bulletin_Board at bioinformatics.org
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