午夜福利1000集合

IT鈥橲 a guy thing. When the genetic pack was shuffled and the cards dealt
there were no Y chromosomes for the female players. Y is strictly for men only.
Wags will tell you it鈥檚 the site of the genes for incessantly clicking the TV
remote control and for the excruciating embarrassment that accompanies asking a
stranger for directions. But a small band of pioneering researchers is now
finding that the Y chromosome is an unmatched repository of human evolutionary
and behavioural information. You鈥檝e heard of mitochondrial Eve, now meet nuclear
Adam.

For fifteen years, population geneticists have been scrutinising the genes
inside mitochondria, our cells鈥� powerhouses. Because no mitochondria from sperm
enter the egg at fertilisation, we get all our mitochondria from our mothers.
This means that they carry information about when and where our most recent
common female ancestor lived. But tracking mitochondrial Eve has many pitfalls.
Controversy over the findings has persuaded researchers to clamber down the
other side of the evolutionary tree in an attempt to identify Adam.

However, until now the Y chromosome has not been forthcoming with its
secrets. 鈥淚t was recognised over a decade ago that the Y would be ideal to
decipher human evolutionary patterns,鈥� says Peter Underhill of the department of
genetics at Stanford University. 鈥淏ut putting the concept into practice has been
unsuccessful鈥攗ntil now.鈥� The key to Underhill鈥檚 success is a technological
breakthrough. He and Peter Oefner, also at Stanford, have devised a way of
rapidly identifying genetic differences between individuals which has huge
implications for the study of the human genome and could convert the cottage
industry of Y chromosome research into big business.

To understand the promise and the difficulties inherent in Y chromosome
analysis, first consider how molecular anthropologists read history in the
genetic code. When you listen to music at a hoedown in the North Carolina hills,
you are struck by the similarity of the style to Irish reels and jigs. This is
no accident, of course: those American hills were peopled by farming families of
Celtic origin. And along with their fiddles and bows, they brought their genes.
The themes and patterns in their genetic information reflect their mother
country as much as their music does. In addition, genetic variation
distinguishes them from people of other origins, in the same way that any jig
differs from any Japanese folk tune.

Such differences are music to the ears of population geneticists. Just as
folk melodies are based on a similar five-tone musical scale, so genes are made
from a four-letter alphabet of chemicals called bases which in various
combinations generate different proteins. Random mutations can change the
identity of a single base in a gene. As long as this mutation does not affect
the individual鈥檚 ability to reproduce, it may be preserved and handed down to
offspring, becoming widespread in the population. Such mutations, which
characterise populations and also groups within them, are called
鈥减辞濒测尘辞谤辫丑颈蝉尘蝉鈥�.

Anthropologists, however, are not primarily interested in genes, but in times
and places. They construct 鈥渇amily trees鈥� based on the polymorphisms in the
human populations they study and then work out when and where the various
branches originated. Mutations occur rarely, but at a fairly constant rate over
evolutionary time, providing researchers with a 鈥渕olecular clock鈥�. The clock is
calibrated by comparing the genes of chimps and humans to see how many bases
have mutated in the 6 million years since we parted ways. Armed with this
mutation rate, researchers can estimate the age of particular polymorphisms. A
mutation can arrive in a particular part of the world in one of two
ways鈥攅ither it arises there or people with that mutation migrate there
from elsewhere. So with mathematical modelling and educated guesswork
researchers can trace the wanderings of generations by looking for genetic
variation in people living today.

Any genetic mutation can provide this sort of information, whether it be in
the mitochondria, on the sex chromosomes or any of the other 22 pairs of
chromosomes in the nucleus. But the Y is special. One of its big advantages is
that most of the chromosome does not undergo recombination鈥攖he shuffling
of the genetic pack during egg and sperm production that creates new
combinations of genes. Recombination occurs when chromosomes pair up with their
opposite numbers and exchange small chunks of similar but not identical genetic
material. All the chromosome pairs have matching genetic sequences except the Y,
which shares little sequence with its partner X. Females have two copies of X,
so recombination goes ahead as normal. But in males exchange is not an option
between X and 95 per cent of the Y. As a result, any Y chromosome contains all
the mutations that ever occurred in its long lineage.

Mitochondrial genes also never undergo recombination, a fact that spurred the
hunt for mitochondrial Eve. But mutation rates in mitochondria are high, so that
a single site may have changed several times over the generations, blurring
ancestral lines. The Y, in contrast, has a very low mutation rate, even compared
with the other nuclear chromosomes. Michael Hammer of the University of Arizona
in Tucson describes the chromosome as 鈥渁 sea of monomorphism鈥�, where genetic
differences between individuals are few and far between. Because mutations are
so rare, he adds, the assumption of 鈥渙ne polymorphism, one mutation event鈥� is
reasonable.

Underhill鈥檚 group at Stanford has used the Y chromosome鈥檚 unique properties
to find what he claims is the first unequivocal genetic evidence that modern
humans are descended from a single migration of archaic Homo sapiens
out of Africa. The analysis of 718 men worldwide revealed that a particular
section of the Y chromosome exists in three forms or haplotypes. 鈥淎ll men in the
world can trace their ancestry back to a small subset of original haplotypes in
Africa,鈥� says Underhill.

Out of Africa

The researchers identified the ancestral haplotype鈥攏uclear
Adam鈥攂y looking at the corresponding section of Y in chimpanzees, gorillas
and orang-utans. Our closest animal relatives all have the same genetic sequence
in this section and it matches the one Underhill found in small human
populations in northern and southern Africa. The other African and all European
populations share a single mutation in the lineage leading away from the common
African-European ancestor, and a haplotype derived from this is found more
globally. Underhill concludes that the first mutation must have arisen in Africa
because it occurs widely there today and in populations closely related to the
groups that have the ancestral version of the DNA. He has found the same pattern
in two other stretches of the Y chromosome, which convinces him that these
variations could only have found their way into European populations by human
migration out of Africa. 鈥淭his is the pattern everyone was looking for鈥攚e
found it first,鈥� says Underhill.

Chris Tyler-Smith of the biochemistry department at the University of Oxford
and his team have also caught the scent of a Y chromosome trail. Their findings
resurrect an old theory about the colonisation of Europe. The Finnish language
is unique in northern Europe in tracing its ancestry to the Uralic, rather than
Indo-European language family. This suggests that some of the Finnish genome
originated in northern Asia with Uralic. But when genetic analysis seemed to
show that Finnish populations are closely related to the rest of Europe,
researchers concluded that the spread of language, not genes, accounts best for
the uniqueness of Finnish. Now Tyler-Smith鈥檚 group has discovered that Y
polymorphisms present in abundance in Asia are also widespread in Finnish
populations. This genetic smoking gun is evidence of a migration out of Asia
that is hard to refute.

The potential of Y chromosome analysis is huge. Underhill has described it as
鈥渁 playground to study human history鈥�. But its very advantages鈥攖he rarity
of polymorphism and absence of recombination鈥攈ave also been its Achilles
heel. Looking for variation on the Y chromosome with conventional techniques of
DNA sequencing is like searching for a needle in a haystack. Underhill recalls
using 鈥渂rute-force sequencing鈥� to identify one of the first out-of-Africa
polymorphisms. 鈥淚t brought home the brutal reality of the effort required to
find just one marker,鈥� he says. In a part of the genome that is virtually the
same among individuals, sequencing provides mostly redundant data. So four years
ago Underhill started looking for a technique that would quickly sift through
the identical sites, revealing only genes that exhibit the rare and valuable
polymorphisms.

The solution to Underhill鈥檚 problem was on his doorstep. Down the corridor in
the biochemistry department, Oefner was perfecting a technique for separating
fragments of DNA that differed in length by only a few bases, using a method
known as high-performance liquid chromatography, or HPLC. Working together,
Underhill and Oefner came up with a variation on the technique called denaturing
HPLC which can detect differences of a single base in fragments of DNA that are
the same length (see 鈥淩ecipe for success鈥�). They have now used DHPLC to scan an
astonishing 93 000 bases in samples from 718 men. The effort has unearthed 150
polymorphisms, the mother lode of the Y chromosome business.

According to Oefner, the new technique takes just a few minutes and is nearly
as accurate as full DNA sequencing, but costs much less and can be fully
automated. Tyler-Smith predicts that DHPLC will allow researchers to complete a
global survey of genetic variability of the Y chromosome within five years. But
despite this, Underhill and his collaborators remain the only people using
DHPLC. Most labs do not have the funds or human resources to change to a new
system. Having invested in expensive technology, many believe it is time to
consolidate their current approaches rather than change tack. So for the time
being, these teams have set about doing more with less.

Into America

Hammer, for example, and his colleague Stephen Zegura from the anthropology
department at Arizona are using a new analytical technique developed by
geneticist Alan Templeton at Washington University in Saint Louis, Missouri.
Nested cladistic analysis identifies statistically significant associations
between genetic polymorphisms and geographical locations. Its big advantage is
that researchers can now distinguish between genetic variations caused by human
migrations and those caused by interbreeding between established populations.
This makes molecular anthropology 鈥渁 whole new ball game鈥�, says Zegura.

As one of the authors of the controversial 鈥渢hree-wave鈥� hypothesis of the
peopling of the Americas, Zegura has been particularly interested in using the Y
chromosome to detect and count migrations into America across the Bering land
bridge. Mitochondrial studies support any number of waves, from one to six.
Initial data from Y chromosome analysis of native Americans suggested that there
was only one. But with a greater number of Y polymorphisms and nested cladistic
analysis Zegura and Hammer now have statistical evidence of at least two broad
migrations. A single lineage originating in Asia accounts for half of all Y
chromosomes sampled from Alaska down to South America. The rest are from another
group, probably also of Asian origin.

In another study, Hammer and Zegura have not only found the out-of-Africa
signature in Y chromosomes, but also a previously undetected migration from
Eurasia back into Africa. They calculate that the latter migration occurred
around 31 000 years ago, 10 000 years before the height of the last ice age in
Europe.

The team has also tried to distinguish between male and female dispersions by
comparing their Y chromosome data with Templeton鈥檚 studies of mitochondrial DNA.
Their findings suggest that men have tended to make longer, intercontinental
migrations. Women, by contrast, are more mobile regionally. This fits with an
idea first proposed by Luca Cavalli-Sforza, an eminent human population
geneticist from Stanford University. He suggested that mitochondrial DNA is
surprisingly well travelled because historically women may often have moved in
with their husbands鈥� families after marriage, just as they do in many
contemporary aboriginal societies.

Michael Bamshad, his colleague Lynn Jorde, and their collaborators at the
University of Utah in Salt Lake City have also been comparing mitochondrial and
Y chromosome data in their study of the genetic effect of the caste system upon
Indian populations. 鈥淭he caste structure is still extraordinarily rigid,
especially in rural areas, despite the fact that the government abolished the
system many years ago,鈥� says Bamshad.

A passage in India

Even so, there has always been some 鈥渙vert and covert gene flow鈥� between
adjacent castes. High-caste males, for example, may have had a wife from their
caste and a mistress from the caste below. This was frowned upon, but probably
had little effect on the man鈥檚 public standing. Offspring of the high-low union
would generally take the caste of the father, leading to upward mobility of the
mother鈥檚 genes, if not the mother herself. By contrast, women from high castes
virtually never engaged in lower-caste unions. In fact, in some rural areas,
such a union was an outrage punishable by death.

Official records of these behaviours are rare. But the genetic data do tell
the story. Mitochondrial DNA analysis reveals blurred genetic lines between
castes, with a tendency for variations characteristic of lower castes to be
present in higher ones, but not the reverse. This confirms the upward mobility
of daughters who were the product of high-low unions. On the other hand, Y
polymorphisms鈥攁nd the men who transmitted them鈥攖ended to stay within
caste boundaries. This means that sons of lower-caste mothers have taken their
father鈥檚 caste. People have looked for this using classical genetic indicators
such as blood types, says Bamshad, but they have never found such convincing
evidence. His team now plans to extend this work using the fast-mutating
mitochondrial genes to throw light on evolution at the subcaste level, and the
slowly changing Y to examine the genetics of the subcontinent鈥檚 pre-caste
colonisers.

Bringing nuclear Adam face to face with mitochondrial Eve is proving a
fascinating venture, but the problems of blurred ancestry that have dogged
mitochondrial analysis will remain. Underhill is confident DHPLC will allow
researchers to exploit the greater accuracy of Y chromosome analysis to the
full. Once enough Y polymorphisms have been identified, researchers will be able
to trace lines of descent with great accuracy. They should also be able to
assess what Hammer sardonically refers to as 鈥渢estosterone-driven behaviours鈥�.
Warmongering and polygamy have both played their part in determining human
genetic inheritance. Only Y chromosome analysis will reveal the evolutionary
significance of history鈥檚 Genghis Kahns and Casanovas.

TAKE two men. Remove tiny fragments from the same gene on each of their Y
chromosomes and replicate these. Mix the DNA in a test tube and heat to near
boiling. Each DNA fragment will melt, splitting into its two component strands.
As the mixture cools, these strands find a partner again. If the two men鈥檚 DNA
fragments are identical, any rejoined strands will form a perfect match, whether
they find their own partner or team up with the complementary stretch of DNA
from the other individual. But if the original DNA differs by just a single
building block, or base, when strands from the two men come together there will
be a mismatch at this point in the sequence. This 鈥渂ubble鈥� at the polymorphic
site is central to a new technique for charting the evolution of humans.

Known as denaturing high performance liquid chromatography (DHPLC), it is
based on an old method for separating mixtures into their component parts
according to their relative abilities to stick to a solid matrix, or column.
Peter Oefner, formerly at the University of Innsbruck in Austria and now at
Stanford University, has adapted the method to detect single base changes in
genes. His success has been in finding a medium for which DNA has a particular
liking, but which binds more strongly to Y chromosome fragments without bubbles
than those with bubbles. When treated DNA from two men travels along the
chromatographic column, it will arrive at the end in a single wave if the men鈥檚
DNA is identical. If the DNA is mismatched, however, it will arrive in two
peaks. By making many comparisons like this, the Stanford researchers are able
to trace Y chromosome mutations over space and time.

鈥淚t has revolutionised the way we do science,鈥� says Peter Underhill, Oefner鈥檚
colleague and a key player in Y chromosome research. He foresees that DHPLC will
find roles way beyond the study of human evolution and behaviour. It will come
into its own once the human genome has been sequenced. Having a single version
of the human genome sequence is not enough, he says. Resequencing to discover
the variability of genes is the next big step. Such information can be used to
improve the human genetic map and to gauge the contributions of different genes
to common diseases such as cancer and heart disease. DHPLC is already being used
at Stanford to examine polymorphisms in the recently discovered breast cancer
genes. 鈥淓soteric studies of human evolution鈥� have contributed to the most
pragmatic of genetic research, says Underhill.