If
humans are 99.9 percent genetically identical, as President Bill
Clinton is fond of asserting when he extols the Human Genome Project,
that 10th-of-a-percent difference has a lot of explaining to do.
How does genetic variation determine a person's unique physical
traits? Can it predict someone's susceptibility to a disease?
Such questions, pertaining to the present or future, are what occupy
most human geneticists. A small group, however, studies genetic
variation as a clue to the past. Sometimes called molecular anthropologists,
these researchers use DNA polymorphisms, or markers, to hypothesize
about human evolution and population migrations. An estimated 20
labs worldwide are intensively engaged in this work, and a growing
number are peripherally involved.
Two developments lately have boosted their endeavors. Scientists
have discovered enough useful DNA markers over the past 20 years
to form a critical mass. And techniques and equipment, some
of which are spillover from genome sequencing projects, have become
increasingly efficient.
Freighted
with scientific jargon and numbers, papers in molecular anthropology
nevertheless afford fascinating glimpses into history1--"National
Geographic magazine kind of stuff," as one researcher puts it. Some
findings are also of biomedical use, helping target the genetic
causes of diseases. This justifies limited public funding in a field
that often depends on private grants.
The interests of molecular anthropologists range widely, from small
tribes to humankind, from the emergence of Homo sapiens to population
dislocations in recent centuries. The work of Luigi Luca Cavalli-Sforza,
a professor emeritus of genetics at Stanford University School of
Medicine, typifies the ambitions of the field. For the past two
decades, he has been examining genetic variation to deduce migrations
into Europe. Among his most striking conclusions is that a vast
influx of farmers from the Middle East occurred during the Neolithic
period.2
For Cavalli-Sforza, a founder of molecular anthropology in the 1950s
when protein (rather than DNA) polymorphisms were the object of
attention, says his work is far from complete: "We have really just
scratched the surface. We need more markers. We need to study more
individuals than we have done. We need to have better collections
[of samples]." Charting variation in many genes is also crucial,
according to Aravinda Chakravarti, a genetics professor at Case
Western Reserve University School of Medicine. "In a process of
evolutionary events, not every gene behaves in exactly the same
way," he observes.
Genome Diversity Projects
In 1991, Cavalli-Sforza cofounded the Human Genome Diversity Project
(HGDP) to coordinate the gathering and analysis of DNA samples from
ethnic groups around the world. But HGDP soon became embroiled in
ethical and political controversies, and a National Research Council
report in 1997, while largely favorable to the project,3 didn't
give it a needed boost. Large-scale government funding for a worldwide
HGDP hasn't come through.
"The present trend is for countries to take their own initiatives,"
says Cavalli-Sforza. He describes North America, Europe, Japan,
Russia, and most African nations as open to such research. He singles
out HGDP programs in China, Israel, and Pakistan as excellent. But
he adds, "A number of indigenous groups, including many American
Indians, have declared their unwillingness to collaborate." And
India, the world's second most populous nation, won't allow its
citizens' DNA to be sent abroad.
Cavalli-Sforza is enthusiastic about a new project by the Paris-based
Centre d'Etude du Polymorphisme Humain (CEPH). "My idea was for
all the labs which, like mine, have generated cell lines in various
parts of the world to donate these cell lines to CEPH," he says.
"And CEPH can grow them, make DNA, and distribute it to research
workers." Distribution is slated to begin this fall after CEPH has
collected 1,000 cell lines representing about 50 populations. The
DNA will be available at modest prices that are expected to finance
this nonprofit project. Researchers will be asked to enter the results
of their studies of the DNA into CEPH's database.
Y Chromosome
Cavalli-Sforza's research has concentrated on the Y chromosome in
the past decade. Because only 1 percent of the chromosome, at its
tip, recombines with the X chromosome during meiosis, Y polymorphisms
are an ideal source of information on men's paternal ancestry. Until
several years ago, few Y markers were known. The problem was twofold:
Mutations may be rarer on the Y chromosome than on autosomes, and
detection of markers via nonautomated DNA sequencing and some gel-based
techniques was slow and laborious. "We couldn't live on finding
one marker a year," recalls Peter A. Underhill, now a senior research
scientist in Cavalli-Sforza's lab. "It was so hard to motivate people
to come in every day, do experiments, and--nothing, nothing, nothing."
Cavalli-Sforza's research has concentrated on the Y chromosome in
the past decade. Because only 1 percent of the chromosome, at its
tip, recombines with the X chromosome during meiosis, Y polymorphisms
are an ideal source of information on men's paternal ancestry. Until
several years ago, few Y markers were known. The problem was twofold:
Mutations may be rarer on the Y chromosome than on autosomes, and
detection of markers via nonautomated DNA sequencing and some gel-based
techniques was slow and laborious. "We couldn't live on finding
one marker a year," recalls Peter A. Underhill, now a senior research
scientist in Cavalli-Sforza's lab. "It was so hard to motivate people
to come in every day, do experiments, and--nothing, nothing, nothing."
The situation brightened considerably in 1995 when Underhill and
Stanford biochemist Peter J. Oefner developed denaturing high-performance
liquid chromatography (DHPLC). This method detects polymorphism-containing
DNA heteroduplexes when they bind differently to columns than homoduplexes
do. Screening samples with DHPLC, Underhill and Oefner have discovered
many Y markers,4 which they're using to reexamine Cavalli-Sforza's
theories about migrations into Europe. Less than half a percent
of the 59-megabase Y chromosome has been scanned, but 200 single
nucleotide polymorphisms (SNPs), 40 microsatellites, and two minisatellites
have already been detected, according to Michael F. Hammer, an associate
professor of anthropology at the University of Arizona in Tucson.
(Satellites are tandemly repeated DNA sequences that may display
great person-to-person variability in the number of repeats.)
Though Y-marker analysis is new, the New York Times recently trumpeted
that scientists could trace human lineages back to "10 sons of a
genetic Adam."5 Hammer is more cautious, noting that the idea that
all men descend from 10 individuals, as if no other men lived at
that time, "is a statistical artifact of the way the data are analyzed."
Indeed, molecular anthropologists readily acknowledge how speculative
their hypotheses are. Models may rest on shaky assumptions about
DNA mutation rates and past human reproductive behavior.
Mitochondrial DNA
Tracing maternal ancestry through mitochondrial DNA (mtDNA) dates
back to the 1970s, a decade before Y-marker analysis began in earnest.
Human eggs hold 100,000 mitochondria, each with a circular mtDNA
of 16,569 nucleotides. This DNA is passed exclusively from mother
to offspring. How does a mutation in one mtDNA of one individual
replace all the nonmutant mtDNA in a population's mitochondria?
In a process called replicative segregation, dividing cells bequeath
more mutant mtDNAs to some daughter cells. Countless mitoses magnify
this effect until the nonmutant DNA is eliminated.
Thousands of mtDNA polymorphisms have been found, many in the organelle's
hypervariable control region, according to Douglas C. Wallace, director
of the center for Molecular Medicine at Emory University School
of Medicine. The Center maintains a searchable database
that listed about 1,400 mtDNA markers as of the end of June.
Analysis of such polymorphisms led to the 1987 proposal by Allan
C. Wilson at the University of California, Berkeley, that an "Eve"--a
source of all people's mtDNA--lived 200,000 years ago.6 Since that
proposal, Wallace and his colleagues have grouped humans into 27
lineages based on mtDNA markers.7
The chronology of the branching of these lineages is still a point
of contention between some paleontologists and molecular anthropologists.
But the debate isn't totally polarized. "There are excellent physical
anthropologists who feel that the fossil data are quite consistent
with the molecular data," Wallace notes.
Two years ago, his team generated a buzz when it found that
some American Indians display a pattern of mtDNA markers consistent
with a European origin. That result has been replicated, he says,
and assiduous attempts to detect the same pattern of markers in
Asia--the presumed origin of native Americans--have been unsuccessful.
Wallace's team is now on the cusp of finishing a 13-year project
to completely sequence about 50 mtDNAs from all the major human
lineages. "That's allowing us to look at very detailed questions,
like the radiation of individual small populations, and very close
time-frame questions," he says. He hopes to submit the results of
the project for publication this summer.
"People are
just too hung up on mitochondrial DNA and Y chromosomes," complains
Kenneth K. Kidd, a genetics professor at Yale University School
of Medicine. "Everybody thinks recombination is a problem, diploidy
is a problem. And they're not. They're easily overcome. They just
require more sophisticated analysis."
Kidd confesses to having mixed feelings about what he perceives
as this neglect of autosomes. It means less competition for his
work on autosomal genes in humans and chimps. Yet more autosomal
studies are crucial for advancing the field of molecular anthropology:
The 22 autosomes, after all, harbor the lion's share of polymorphisms.
"Genes on the mitochondrial genome or the Y chromosome don't unambiguously
allow you to infer population history," notes Andrew G. Clark, a
biology professor at Pennsylvania State University. "That's because
there's a lot of stochasticity, a lot of chance, that goes on in
sampling of those genomes from generation to generation. What the
autosomal genes get us is many more realizations of genes passing
through history. If we look at enough of them, we'll be able to
get a good call on the true population history." Especially ripe
for examination, Clark adds, are autosomal regions with low rates
of recombination, which are just now being identified.
Kidd's lab maintains a rapidly growing database containing gene
frequency data on more than 175 markers and 60 populations. The
database, named ALFRED, can be accessed at the Web site info.med.yale.edu/genetics/kkid
Unlike ALFRED, the SNP Consortium's database of more than 100,000
mapped markers at snp.cshl.org
is not broken down by ethnic group and hence is less useful
for molecular anthropologists. Last month, however, the consortium
began comparing the frequencies of 120,000 SNPs in Africans, Asians,
Caucasians, and pre-Columbians, according to chairman Arthur Holden.
In a series of studies building on a seminal 1996 paper,8 Kidd and
his colleagues discovered that chromosomes in African populations
show more variation and randomness than chromosomes in non-African
groups. Kidd explains this finding as follows: In Africa, genes
have had time to be scrambled by recombination. here, the genetic
patterns inherited from the few founders of a population haven't
had time to be scrambled. Thus, humans must have originated in Africa,
where populations are oldest. Small migrating groups then populated
the rest of the world. Kidd, who investigates alcoholism and psychiatric
disorders, also argues for the medical value of characterizing populations,
as molecular anthropologists do in the course of their work. In
seeking the genetic origins of diseases, "you can hardly interpret
the data in a mixed population," he warns. He regrets that studies
routinely use such populations.9
Biomedical researchers must also know more about population than
its degree of homogeneity. In associational gene cloning, Kidd notes,
"If you're studying an African population, you have to have five
or six times more markers than if you're studying a European population."
The reason is that African chromosomes have been more scrambled
by recombination. As a result, genetic markers are likely to be
associated with (i.e., found in a population disproportionately
together with) a putative disease-promoting polymorphism only if
they're very close to that polymorphism. A high density of markers
is needed to ensure such proximity.
Molecular anthropology oscillates between investigations of "macro"
topics, such as evolution and continental migration, and "micro"
topics, such as whether two populations are genetically related.
For the near future, Cavalli-Sforza foresees a shift toward regional
work "because you can do a better job. But eventually you have to
be able to connect all the regions." Molecular anthropology, meanwhile,
is a "very, very hot" research area, according to Wallace, who notes
that it has prompted three Cold Spring Harbor symposia in the last
five years and many international meetings. The public is also starting
to become aware of the field. "I get a lot of E-mail from regular
folks out there, nonscientists, who are interested in this kind
of work," Hammer says. "I think people have a growing interest in
genealogy, a growing interest in who they are genetically and whom
they're related to."
Satisfying that curiosity could stir up ethnocentrism and bigotry,
but the scientists interviewed for this article recalled few such
cases. "The genetics is telling a story that does not support racist
attitudes," contends Hammer.
Nevertheless, Underhill remembers occasionally receiving hate mail
when a study is publicized in the press. Tell some people they're
"related to Africans, and then you get the neo-Nazi kooks," he observes.
Though he doesn't set out to threaten people's "origin stories,"
Underhill maintains, "As a scientist, I follow the data." S
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- K.
Owens, M.-C. King, "Genomic views of human history," Science,
286:451-3, 1999.
- L.L. Cavalli-Sforza,
Genes, Peoples, and Languages (New York, North Point Press, 2000).
For an approach to this topic using mitochondrial DNA, see L.
Simoni et al., "Geographic patterns of mtDNA diversity in Europe,"
American Journal of Human Genetics, 66:262-78, 2000.
- D. Steinberg,
"NIH jumps into genetic variation studies," The Scientist, 12[2]:1,
Jan. 19, 1998
- See, e.g.,
P.A. Underhill et al., "Detection of numerous Y chromosome biallelic
polymorphisms by denaturing high-performance liquid chromatography,"
Genome Research, 7:996-1005, 1997.
- N. Wade,
"The human family tree: 10 Adams and 18 Eves," New York Times,
May 2, 2000, p. F1. 6. R.L. Cann et al., "Mitochondrial DNA and
human evolution," Nature, 325:31-6, 1987.
- D.C. Wallace,
"Mitochondrial DNA variation in human evolution and disease,"
Gene, 238:211-30, 1999.
- S.A. Tishkoff
et al., "Global patterns of linkage disequilibrium at the CD4
locus and modern human origins," Science, 271:1380-7, 1996.
- See, e.g.,
A.M. Kang et al., "Global variation of a 40-bp VNTR in the 3'
untranslated region of the dopamine transporter gene (SLC6A3),"
Biological Psychiatry, 46:151-60, 1999.
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