genes into their mice as insurance to get the H U M A N EVOLUTION

mice through fetal development.

That move was a bit more successful in
Rvan's mice than in Pisztv's: Rvan's mice Y Chromosome Shows That
make human fetal hemoglobin until after
birth. whereas Pisztv's mice turn off the hu-
man fetal gene before birth, causing many of
Adam Was an African
them to suffer severe sickling just hours af-
ter they are born, and die. But the surviving I n the beginning, there was mitochondrial California, Berkeley, announced that they had
mice from both labs show a fuller comple- Eve-a woman who lived in Africa between found our mitochondrial ancestor. They had
ment of sickle-cell symptoms than earlier 100,000and 200,000 years ago and was ances- compared mitochondrial DNA variants found
mice. They have much more severe anemia tral to all living humans. Geneticists traced around the world and traced a common ances-
and also much more infarction, tissue death her identity by analyzing DNA passed exclu- tor by sorting out the variants on an ancestral
resulting from clogged blood vessels. "In Dr. sively from mother to daughter in the mito- phylogenetic tree. But Eve ignited fierce de-
Piszty's model, we are actually seeing infarcts chondria, energy-producingorganelles in the bate, as some scientists challenged the methods
much more frequently than in other mod- cell. To test this view of human origins, scien- and assumptions used to place her in Africa
els," says Elizabeth Manci, a pathologist at tists have been searching ever since for Eve's from 100,000 to 200,000 years ago (Science,
the University of South Alabama Medical genetic consort: "Adam," the man whose Y 14 August 1992, p. 873). Even if the Wilson
Center in Mobile who has studied human chromosome (the male sex chromosome) was team was right-and intense debate contin-
sickle-cell disease and the mouse models for passed on to every living man and boy. u e d ' t h e mitochondrialDNA is just one gene
many years. Now, after almost a decade of study, two lineage," says University of Michigan, Ann
Researchers can use the mice to study the international teams have found the genetic Arbor, paleoanthropologist Milford Wolpoff.
changes in the red-cell membranes that trail leading to Adam, and it points to the same Different genes might trace back to different
make them stick to blood vessel walls, says time and place where mitchondrial Eve lived. ancestors on a different continent.
Bunn, and perhaps devise new strategies for ~escribedthis month at a The only way to test
blocking the process. What's more, unlike symposium on human evo- the storv of mitochon-
earlier mouse models that used supersickling lution at Cold Spring Har- drial Eve was to trace the
P-globin, the new mice have exactly the bor Laboratory in New ancestry of other genetic
same mutant P-globin (known as p)as the York, the genetic trail is so lineages in the nucleus of
. , of humans with the disease.
vast maioritv clear that it allows research- the cell to see if seuarate
notes University of California, San Fran- ers to compare the migra- lines of evidence also led
cisco, biologist Y. W. Kan, a pioneer of re- tion patterns of men and back to African ances-
search on hemoglobin diseases. That, he women tens of thousands of tors. And the obvious
says, makes them ideal subjects in the search years ago (see sidebar). It place to start was the Y
for drugs that may inhibit the hemoglobin even pinpoints the living chromosome, which is
clumping that causes red blood cells to sickle. men whose Y chromosomes passed from fathers to
Bunn notes that one of the most ~romis- most resemble Adam's: a sons and therefore pro-
ing ways to block sickling is to keep the nor- few Ethiopians, Sudanese, vides an independent
mal fetal globin genes switched on after birth, and Khoisan people living test of the mitochon-
to provide a source of normal, antisickling in southem Africa, includ- drial Eve hypothesis.
hemoglobin. One drug, hydroxyurea, has al- ing groups once known as The bulk of the Y chro-
ready proven effective at keeping the genes Hottentots and Bushmen. mosome remains un-
active, but researchers hope to find better The findings, by teams Son of Adam. Y chromosome links changed through genera-
ones. "The fact that this current mouse based at Stanford Univer- some Ethiopians to a genetic "Adam." tions, except for rare mu-
model expresses fetal hemoglobin during sity and the University of tations hidden in regions
fetal development, with a switch to adult Arizona, are the latest in a series of genetic that don't code for proteins. By comparing
fP-globin," Bunn says, "opens up the oppor- studies that point to Afnca as the recent birth- variation at the same site in different indi-
tunity to expose these animals to various place of modem humans-people who then viduals' DNA (known as polymorphisms),
agents, to ask which ones may [prolong fetal] spread around the world and replaced other geneticists can sort out which populations are
globin expression." human populations. "It's very comforting to see most closely related and then build a phyloge-
The Berkeley Lab and Alabama teams the Y is giving us the same picture as mitochon- netic tree that traces the descent of men, just
haven't compared their mice side by side yet, drial Eve.". savs
, molecular anthromloeist
A " Mark as the mtDNA traces the descent of women.
but it is already clear that the disease progresses Stoneking of Pennsylvania State University in And by using average mutation rates for
somewhat differentlv in each one. That., too., University Park, who was part of the team that nuclear DNA, they can estimate how long ago
could be an asset; each may have particular identified "Eve" as an African. "There's no particular mutations appeared, and thus how
strengths and weaknesses for testing therapies. doubt that there's some clear event of modem long ago each limb of the tree branched off.
"Having more than one model is a tremendous humans coming out of Africa." Now the ques- SkGching the branches of a Y chromo-
advantage" for double-checking the effec- tion is whether the wave of modem humans some tree has been painstakingly slow, how-
tiveness of any experimental treatment, says from out of Africa completely replaced the ever, because few polymorphisms in the Y
Marie Trudel of the Institut de Recherches people on other continents, or whether there chromosomehad been found (Science, 26 May
Cliniaues in Montreal. who created some of was some interbreeding. 1995, p. 1183). But new tools to speed the
the earlier mouse models. Perhaps this multi- In science, unlike the Old Testament, Eve detection of variation in DNA sequences
ulicitv
* , of models will usher in a better arrav of came before Adam--specifically, in 1987, have recently given a boost to research on the
treatments for sickle cell patients. when Stoneking and other researchers in the Y. One big break has come at Stanford Uni-
-Marcia Barinaga lab of the late Allan Wilson at the University of versity, where biochemist Peter Oefner and
SCIENCE VOL. 278 31 OCTOBER 1997 www.sciencemag.org
molecular biologist Peter Underhill have outside of Africa, as well as most African men, was replaced by this," says Hammer. Underhill
developed an automated system for rapidly carry the T," says Underhill. agrees: "I think this speaks persuasively for an
detecting subtle differences in DNA se- Meanwhile, another team headed by ge- Out of Africa origin for modem humans."
quences. Now they have hamessed this sys- neticist Michael Hammer at the University of But Hammer's group,whose findings are in
tem to find genetic markers for evolutionary Arizona, Tucson, surveyed another non- press in thejournal Moknrlm Biology a n d E d -
studies. The method involves mixing and coding region of the Y chromosome in 1544 tion, has added a twist to the scenario. These
heating amplified copies of Y chromosomes men worldwide and found the same pattern. researchers also see evidence that some of
from two men to unzip their double-stranded The DNA sequences varied among indi- Adam's descendants who emigrated to Asia
DNA. Then the single strands from the two viduals, but Hammer found that the vari- later returned to Africa, with a new mutation
Ys are reannealed. If their sequences match, ants cluster into 10 major groups, known as on the Y that arose in Asia. In addition,
they emit a single peak of ultraviolet light. If haplotypes,which oc- ,Hammer says that
they differ by as little as one nucleotide, they cur in different fre- 1 Europe Africa Asia If! African males could
emit two or more peaks. quencies in different have interbred with
Present'
The Stanford researchers got the system populations. Asian females. and
working full-time this year. So far, they have Haplotype 1A, de- traces of those wo-
found 93 new polymorphisms in the Y chromo- fined by an A at a 150-200 men's genes may still
somes of men from around the world. "It's a particular site, ap- (thousands of be in our nuclear ge-
major breakthrough-unquestionably," ex- pears to be ancestral years ago) nome. Indeed. other
ults geneticist Luca Cavalli-Sforza, head of because the A is researchers have al-
the lab where Underhill has done this re- found in chimpan- ready reported signs
search. And when the team started sorting zees, and Hammer's of an ancient Asian
these polymorphismsinto a phylogenetic tree, team found that in origin for a P-globin
1 million
they found one particularly ancient marker, humans. it occurs years ago gene (Science, 25
called M42. In its most ancient form, shared only in some Afri- April, p. 535).
by other primates, this marker is an A, or cans. "It's at the high- Range expans,o,'--u-) So. Hammer fa-
adenine. Today, it is found only in Africa, in est frequency in the 4 w~threplacement vors a model that
just a few of the 900 males they scanned- ~ h ~ ~ h~i & says--
, " +Range withoutexpanshon
replacement H E x ~ s t ~Yn gIbneages Shows a wave of mod-
15% of the Khoisan, and 5% to 10% of the the same population 4 c e n eflow em people coming
Ethiopians and Sudanese. These men must
have inherited this ancient form from a com-
fingered by-under- of n*n. The if
ancestor out ofAfrica, replac-
hill's team. Although all men's Y chromosome was inherited from an mg of the genes
mon ancestor. "We think we have tagged the ancient form of African, whose descendants spread worldwide. of ancient people, but
Adam," says Underhill, who reported the work 1A persisted in some interbreeding enough
at this week's annual meeting of the American .groups in Africa, it also underwent a change to add some ancient non-African genes to our
Society of Human Genetics in Baltimore. to a G (guanine) 150,000 to 200,000 years genome. Paleoanthropologist Fred Smith of
The data further show that sometime in ago in one descendant of Adam's. Like the T Northern Illinois University in De Kalb, who
the past 100,000 to 200,000 years, this M42 in Underhill's site. this form was carried out ~romsedone such intermediate model. ure-
site underwent a mutation-a change from A of Africa when men moved away and re- hick that like so much of human histo;,*the
to T (thymine)in one of Adam's descendants.
While men with the A stayed in Africa, some
- laced other males around the globe. real stow "won't be black or white. Genes and
Both sets of results bolster &e so-called fossils &e showing that population dynamics
of the Africans with the T left the continent Out of Africa model of human origins. "We are a lot more complex than we thought."
and spread around the globe. Today, "all men thlnk that anything existing in Asian males -Ann Gibbons
:ncemag.org SCIENCE VOL. 278 31 OCTOBER 1997