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8

Mitochondria, Second Edition, by Immo E. Schefﬂ er

MITOCHONDRIAL DNA

SEQUENCING AND

ANTHROPOLOGY

Summary

A large number of base changes in mtDNA are neutral, either because they do not

cause amino acid substitutions in proteins, or because amino acid substitutions are

conservative, or because they occur in noncoding regions of the mitochondrial

genome such as the so - called control region (with the exception of some speciﬁ c

promoter or origin sequences). They can be detected as restriction fragment length

polymorphisms (RFLPs) or by explicit sequencing.

A large database of such polymorphisms has accumulated over the past decade.

These polymorphisms have served in a variety of interesting studies and investiga-

tions. All human ethnic groups have highly distinguishing haplotypes. The evolution

of these haplotypes and their dispersion over the globe have have given invaluable

support to hypotheses about human evolution and the migratory patterns of human

populations starting with a subpopulation in Africa which is increasingly acknowl-

edged to constitute the origin of modern humans.

Even within a narrowly deﬁ ned ethnic group, there are polymorphisms that

connect pedigrees and can also serve in forensic investigations. Its small size, com-

plete sequence, and the presence of perhaps thousands of copies per cell make

mtDNA a unique target and frequently the only nucleic acid preserved in sufﬁ cient

quantities to permit PCR ampliﬁ cations for analysis.

418 MITOCHONDRIAL DNA SEQUENCING AND ANTHROPOLOGY

8.1 INTRODUCTION

In 1987 Cann, Stoneking and Wilson (1) published a paper on the analysis by

restriction mapping of mtDNAs from 147 people, drawn from ﬁ ve widely

spaced geographic populations (34 Asians, 21 Australian aboriginals, 26 aborig-

inal New Guineans, 46 Caucasians, and 20 Africans). The scientiﬁ c impact of

this paper was enormous. The application of methods from molecular genetics

to the study of primate and human evolution, with a focus on mitochondrial

DNA, had been suggested by Brown (2) , and several publications by Brown,

Wilson, and colleagues had preceded the landmark 1987 paper (3 – 5) . However,

the large number and diversity of people represented in this paper provided

convincing evidence for the potential strength of this approach in addressing

questions about the relatively recent human evolution, about the origins of

modern humans, and about the migratory patterns of our ancestors. The short

abstract of the paper contained the following eye - catching and provocative

statement: “ All these mitochondrial DNAs stem from one woman who is pos-

tulated to have lived about 200,000 years ago, probably in Africa. ” Unfortu-

nately, the popular press took this statement literally, and the misconception

arose that she was the single ancestor of us all. The catchy headlines derived

from this study certainly promoted interest in this ﬁ eld and popularized human

evolution among the molecular biologists who can relate more easily to a

DNA sequence than to a jaw bone.

In the past two decades, not only have the analyses been vastly reﬁ ned by

the use of many more restriction enzymes, the application of the powerful

polymerase chain reaction, and actual sequencing of deﬁ ned regions, but also

human mtDNAs from the remotest areas of the globe have been analyzed,

and one can only imagine what it would be like to explain to a Chukchi from

north easternmost Siberia or a Yanomama from South America why their

mtDNA is of such interest, and how it proves that ultimately they all had

descended from a mother in Africa.

The biological and molecular basis for the value and fruitfulness of mito-

chondrial DNA sequence variations is derived from three facts. There is a

strictly maternal mode of inheritance, hence no scrambling of information by

recombination during sexual reproduction. The rate of evolution of mtDNA

is estimated to be an order of magnitude greater than that of nuclear DNA,

thus providing resolution on a time scale that is appropriate for human evolu-

tion: A few thousand years are a sufﬁ ciently long time to generate informative

variants. Finally, mtDNA represents a distinct molecule that has been com-

pletely sequenced. It is abundant in cells (high copy number) and is therefore

experimentally easily accessible.

The maternal mode of inheritance is an important consideration. There is

universal agreement that >> 99% of mtDNA in an individual is derived from

the mother ’ s egg, and no complications are expected in the analysis of a pedi-

gree of three or more generations. However, phylogeny on an evolutionary

time scale could well be inﬂ uenced by the rare transmission of mtDNA from

HUMAN EVOLUTION 419

the paternal side, and a challenge of the current dogma was issued from a

broad consideration of fertilization and the fate of the sperm mitochondria

(6) , and also from some very well - controlled studies with interspecies hybrid

mice (7) . Since there was evidence for biparental inheritance in interspecies

hybrids, it became urgent to prove that this was the exception rather than the

rule, and some such proof has been provided recently (8) . There is no argument

over the observation that sperm mitochondria are found in the zygote shortly

after fertilization. The most recent studies suggest, however, that paternal

mtDNA is speciﬁ cally eliminated in intraspecies crosses by a ubiquitination -

dependent mechanism (9) – (11) . In interspecies crosses, in contrast, the mecha-

nism apparently fails to recognize the parental mitochondria, and therefore

they escape destruction and elimination. A rare case of paternal inheritance

of mtDNA in humans has been reported (12) . The question of biparental

inheritance and the possibility of recombination in humans (mammals) con-

tinues to be raised periodically, and a recent expert evaluation of the available

evidence can be found in the review by Elson and Lightowlers (13) . The

authors correctly emphasize the importance of the paradigm of mtDNA

clonality, and they ﬁ nd none of the published evidence in favor of mtDNA

recombination in human lineages to be compelling.

The accumulation of base changes in mtDNA occurs on a time scale sufﬁ -

ciently short to generate polymorphisms within populations of the same broad

ethnic category (e.g., Caucasians); there are polymorphisms/haplotypes distin-

guishing the various human population groups; and there are polymorphisms

within a single individual, generated by somatic mutations, or when inherited

as heteroplasmy. Heteroplasmy in relation to mitochondrial diseases has been

discussed in Chapter 8. In an apparent paradox, most individuals are homo-

plasmic. Homoplasmy is either (a) the result of a severe “ bottleneck ” in oocyte

development (see Chapter 8) or (b) more apparent than real, depending on

the sensitivity with which the analysis or search for heteroplasmy is carried

out (14) .

8.2 HUMAN EVOLUTION

While sequencing the mtDNAs of large numbers of diverse humans provides

hard and undisputed data, the interpretation of the data has created a great

deal of controversy. At ﬁ rst it looks deceptively simple. In their original eye -

opening paper, Wilson and his students simply compared the number of muta-

tions in various peoples (1) . A population that has been in existence and in

place for a long time should, upon sampling, reveal a large diversity of mito-

chondrial genomes, assuming that the molecular clock (nucleotide changes per

unit time or per generation) was ticking away steadily. A population estab-

lished only recently by a small number of founders would be expected to be

relatively homogeneous with respect to mtDNA sequences. This was indeed

found: Africans had by far the greatest diversity, a ﬁ nding that was interpreted

420 MITOCHONDRIAL DNA SEQUENCING AND ANTHROPOLOGY

in terms of a mitochondrial Eve out - of - Africa. A second aspect of the same

study was to use estimated rates of the molecular clock to deduce that the

total number of mutations observed in the African population would require

somewhere between 140,000 and 280,000 years. Criticisms soon appeared,

related to several methodological details of the study. Restriction analysis is a

crude way of sampling a sequence; and with a small sample size, valuable

information could be missed or misinterpreted. African Americans had been

used to represent Africans, with a possibility of bias. Finally, the formal

methodology to build the phylogenetic tree was questioned.

With time, many of the criticisms were refuted. The sample size and the

number of representatives from each geographic region could be increased

signiﬁ cantly, including contributions from other groups of researchers. The

sequence analysis could be improved by the inclusion of more restriction

enzymes and even complete sequences. The mtDNA segment favored in these

studies was the control region, a noncoding region containing promoter ele-

ments and origins of DNA replication (see Chapter 4 ) which evolves particu-

larly quickly. The massive amounts of data were analyzed with a newly

developed computer program called PAUP, or Phylogenetic Analysis Using

Parsimony. Such a program is designed to generate the most parsimonious

phylogenetic trees, and this is where the controversy starts. When Wilson and

his colleagues followed their original 1987 paper with another much more

detailed analysis in 1991 (15) , they concluded that our common mtDNA ances-

tor indeed lived in Africa about 200,000 years ago. Lost in the detail, but dis-

covered by a subsequent critic, was the untenable splitting of the 25!Kung

bushmen of Africa on the deepest branches of the tree, in the face of their

seemingly obvious relatedness. Recalculations showed that the computer

program had not succeeded in ﬁ nding the most parsimonious tree and that

there is no absolutely unique and most parsimonious solution (at least with a

limited computation time). Even with the best solutions, the tree has no

obvious roots, or roots pointing unambiguously to Africa.

A recent reexamination of the mtDNA data of Cann et al. (1) and of

Vigilant et al. (15) was attempted by Wills (16) . This highly technical paper

introduces a method referred to as “ topiary pruning, ” a term that describes

the attempt to reveal the true shape of an ornamental topiary tree by removing

the obscuring “ new growth. ” It is argued that a phylogenetic tree may have

similar new growth that can obscure signiﬁ cant branches. The “ new growth ”

on a phylogeentic tree may be the result of recent, repeated mutations in dif-

ferent lineages at hypermutable sites. The pruning produces data sets with a

reduced number of taxa, and this simpliﬁ cation in turn makes the data sets

more amenable to analysis by a variety of statistical methods. A combination

of such methods (pruning, weighting, bootstrapping) is expected to yield a tree

that is closer to the “ true ” tree. While Wills is careful to state that the African

origin of the human mitochondrial tree is not proved by this approach, the

interpretation of the pruned tree adds strength to the argument in favor of an

African origin.

Scheffler Immo E. Mitochondria

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