Nature Systems Biology

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2001 was a landmark year in genomics

in February,the draft sequence ofthe human genome was published.

Although the word draftwas dropped

by many, the International Human

Genome Sequencing Consortium

(IHGSC) did not forget that there was

work left to do.In a follow-up paper inNature, they now report the results of

the effort to finish what they had left

undone in 2001.

The 2001 draft sequence omit-

ted 10% of the euchromatin and

was interrupted by ~150,000 gaps;

moreover, many local segments

remained unordered and the corre-

sponding clones were not oriented.

The finishing process involved pro-

ducing finished maps contin-

uous and accurate paths of overlap-

ping large-insert clones spanning

the euchromatic region of each

chromosome arm and

finished clones continuous

and accurate nucleotide sequenceacross each large-insert clone. The

finishedproduct (known as Build 35)

now contains 2.85 billion nucleotides

interrupted by only 341 gaps. The

euchromatic human genome is now

~99% complete,with an error rate of

only 1 in 105 bases.

Among the many interesting facts

about the genome that the report con-

siders are the gaps that remain in the

current sequence. Thirty three of

them fall within heterochromatin,

which was not targeted by the human

genome project owing to its repetitive

nature. A further 35 gaps are at the

boundaries between euchromatin and

heterochromatin,but the remaining

273 gaps lie within euchromatin and

are mostly associated with segmen-

tal duplications. The IHGSC intend

to close all of these euchromatic

gaps, but rather than persevere with

the existing strategies, which

have so far failed in these cases,

they propose to develop focused

strategies, such as using DNA from a

single haploid source and new kindsof large insert libraries.

As the quality of the sequence

went up, the estimate of the total

number of protein coding genes went

down.The 2001 prediction was in the

region of 30,000; now, the IHGSC is

talking about 20,00025,000; the fig-

ures are derived from a combination

of high quality sequence and gene

annotation, which has now been

manually augmented, taking into

consideration gene structure, ESTs

and transcript evidence.As the mem-

bers of the IHGSC point out, this

number refers to protein-coding

genes only and point out that almost

nothing is known about the non-cod-

ing transcripts, despite the recent

flood of reports about them.

So here we are, the euchromatic

sequence of the human genome has

essentially been completed. But what

of its heterochromatic portion? Will

that be sequenced? The IHGSC says

that to overcome the cloning and

sequencing problems,new technolo-

gies would have to be developed. Butwill knowing the sequence of hete-

rochromatic regions actually be that

helpful in understanding this portion

of the genome?Magdalena Skipper

References and links

ORIGINAL RESEARCH PAPER International

Human Genome Sequencing Consortium.

Finishing the euchromatic sequence of the

human genome. Nature 21 October 2004

(doi: 10.1038/nature03001)

FURTHER READING Eichler, E. E. et al.An

assessment of the sequence gaps: unfinished

business in a finished human genome. Nature Rev.

Genet. 5, 345354 (2004)

RESEARCH

HIGHLIGHTS

HIGHLIGHT ADVISORS

SEAN B. CARROLL

UNIVERSITY OF WISCONSIN,

USA

NANCY J. COX

UNIVERSITY OF CHICAGO, USA

RALPH J. GREENSPAN

THE NEUROSCIENCES

INSTITUTE, CALIFORNIA, USA

YOSHIHIDE HAYASHIZAKI

RIKEN GENOMIC SCIENCES

CENTER, JAPAN

PETER KOOPMAN

UNIVERSITY OF QUEENSLAND,

AUSTRALIA

LEONID KRUGLYAK

FRED HUTCHINSON CANCER

RESEARCH CENTER, USA

STANLEY MALOY

SAN DIEGO STATE UNIVERSITY,

USA

BARBARA MEYER

UNIVERSITY OF CALIFORNIA,

BERKELEY, USA

JOHN QUAKENBUSH

THE INSTITUTE FOR GENOMIC

RESEARCH, USA

NADIA ROSENTHAL

EMBL MONTEROTONDO, ITALY

NORIYUKI SATOH

KYOTO UNIVERSITY, JAPAN

MARC VIDAL

DANA-FARBER CANCER

INSTITUTE, BOSTON, USA

VIRGINIA WALBOT

STANFORD UNIVERSITY, USA

DETLEF WEIGEL

MAX PLANCK INSTITUTE FOR

DEVELOPMENTAL BIOLOGY,

GERMANY

PHIL ZAMORE

UNIVERSITY OF

MASSACHUSETTS, USA

LEONARD I. ZON

CHILDRENS HOSPITAL,

BOSTON, USA

Enjoy the complete coverage

H U M A N G E N O M I C S

80 4 | NOVEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics2004 NaturePublishingGroup


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NATURE REVIEWS | GENETICS VOLUME 5 | NOVEMBER 2004 | 80 5

IN THE NEWS

A new study that reveals Hoxgenes

scattered throughout the genome of

the tunicate Oikopleura dioicahas

put to rest the perceived wisdom that

the genes in this family need to be

clustered.

Hoxgenes are crucial for specifying

differential development along the

anteroposterior axis in bilaterally sym-

metrical animals. These genes have

always been found in a genomic clus-

ter,usually ordered in a way that corre-

sponds to the sequential expression of

the genes along the anteroposterior

axis during development.

Seo and colleagues studied the Hox

genes ofO.dioica, a representative of a

chordate lineage that diverged at an

early stage from the lineage that gave

rise to vertebrates. We already knew

that the Hoxgenes of tunicates might

be slightly unusual after the sequenc-

ing ofCiona intestinalisrevealed a

Hoxcluster with a number of strange

features. However,even considering

these previous findings, Seo and co-workersresults were unexpected, to

say the least.

The authors identified, cloned and

phylogenetically classified full-length

cDNAs for all O. dioicas nine Hox

genes. Using in situ hybridization,

they studied the expression patterns

of these genes during early develop-

ment.As for other chordates,expres-

sion patterns varied among tissues

distributed along the anteroposte-

rior axis, with a subset of the Hox

gene complement being expressed

in each tissue; but in this case, the

Hoxgene expression domains were

mostly non-overlapping. However,

the order of expression of these

genes along the axis was generally

correlated with the position in the

Hoxgene cluster of the paralogous

genes in other chordates.

So far,so good: the differences that

the authors identified between the Hox

gene complement and expression pat-

terns in O.dioicacompared with other

chordates, although interesting and

notable, were not particularly unusual

considering the overall variation

between bilateral lineages. The unex-

pected result came when the authors

took the next obvious step and looked

at the genomic organization of the

O.dioicaHoxgenes.

Seo and colleagues screened an

O. dioicagenomic BAC library with

their nine Hox cDNA probes, no

doubt expecting to be able to quickly

locate the clone that contained thestandard Hoxcluster. Instead, they

found nine separate BAC clones that

contained individual Hox genes.

Follow-up sequencing of the clones

confirmed that none of the initial set

of nine genes was located anywhere

near the others, and indeed many

unrelated genes surround each of

these at the high density that is

expected in this compact genome.

The disintegration of the Hox

cluster in this tunicate might be most

surprising to vertebrate developmen-

tal biologists, as the integrity of this

cluster has been clearly demonstrated

to be essential for temporal coordina-

tion ofHoxgene expression in the

mouse. By contrast, partially frag-

mented Hox clusters have already

been found in the fly, worm andC. intestinalis. The authors raise the

intriguing possibility that in the tuni-

cates C. intestinalisand O. dioica, it is

the transition to determinative devel-

opment, since divergence from their

common ancestor with vertebrates,

that has allowed the Hoxgene family

to be split apart: a hypothesis that is

also consistent with worm data. In

determinative development, the des-

tiny of most cell lineages is engaged

during the first division of the egg,so

the authors postulate that the usual

function ofHoxgenes after axis for-

mation might have become superflu-

ous, and with it the genomic cluster-

ing of these genes. Regardless of the

underlying cause,these striking newresults deal the most important blow

so far to the pervasive and persistent

idea that the Hoxcluster is ultimately

required to build a complex animal.

Nick Campbell,Nature Publishing Group


ORIGINAL RESEARCH PAPER Seo, H.-C. et al.

Hoxcluster disintegration with persistent

anteroposterior order of expression in Oikopleura

dioica. Nature 431, 6771 (2004)

WEB SITE

Daniel Chourrouts laboratory:

http://www.sars.no

Breaking up the family

E V O - D E V O

A barcode for life?

According to two recentstudies, a DNA barcode

could revolutionize

taxonomy, potentially savinghours of peering down

microscopes or poring over

lists of morphologicalfeatures to identify species.The barcode in question

is a 648-bp stretch ofthe mitochondrial gene

cytochrome c oxidase-I.

As mitochondrial genesmutate at a high rate, enough

changes should have takenplace in this gene to provide a

unique sequence for eachspecies, allowing taxonomists

to quickly and accuratelyidentify specimens.

A group led by Paul Hebert

at the University of Guelphtested the technique in a

study of 260 bird species.The barcoding approach

proved an accurate way ofdistinguishing between

species, and even identifiedfour potential new species

that might have been missed

previously. [Birds are] big,theyre coloured differently,

and they sing different songs yet even in that easy to

identify group, there arehidden species, commented

Hebert (CBC News Online).

In a second study, the sametechnique revealed that the

skipper butterfly,Astrapesfulgerator, is actually made

up of at least ten species thatlook similar as adults, but have

different characteristics ascaterpillars. Taxonomist Felix

Sperling, who wasnt involvedin the study, is enthusiastic,

describing this work as an

excellent demonstration of thepower of DNA barcoding to

make sense of a confusingwelter of ecological and color

pattern variation (The

Scientist Online).But the method is less

popular among some

taxonomists, and even those

who are in favour are far fromsuggesting that barcoding is

the solution to all taxonomicproblems. Theres strong

debate about whether onesize fits all, stresses ecologist

Craig Moritz, We have to bea little bit cynical about where

it works and where it doesnt

([email protected]).

Louisa Flintoft

R E S E A R C H H I G H L I G H T S

2004 NaturePublishingGroup


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IN THE NEWS

80 6 | NOVEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics

A new study adds fuel to the contro-

versy over whether yeast cells

undergo programmed cell death by

suggesting that it occurs for the good

of the species.

Death spares no one, not even

yeast cells. But the how and why of

death in Saccharomyces cerevisiaeis

dividing the community. In a recent

paper,Paola Fabrizio and colleagues

propose that the death of older yeast

cells occurs to allow younger cells to

thrive in essence, therefore, they

suggest that apoptosis occurs in yeast

as an adaptive process that benefits

other members of the group. Thisconclusion is controversial for two

reasons first, because it presup-

poses that death is actually pro-

grammed in yeast and that it occurs

by apoptosis, and second, because it

invokes the maligned theory ofgroup

selection, which runs counter to the

well-established idea that selection

occurs at the level of the individual.

Fabrizio and colleagues first

addressed how cell death occurs.

The ageing yeast cells

they studied showed

many features of mam-

malian apoptosis,

including chromatin

condensation and acidi-

fication of the cytosol.

Also consistent with

programmed ageing in

yeast was the cellular

pathway used to bring

about death: the authors

found that ageing and

dying yeast cells downregu-

late an inhibitor of super-

oxide (SOD2, a superoxidedismutase) and become

sensitive to superoxide, both

of which mediate cell death

in higher eukaryotes. Indeed,

mutant yeast colonies in

which SODgenes are upregu-

lated live longer.

To see whether this pro-

grammed death had an adap-

tive purpose, the authors

assayed the ability of various

Yeast: a death foretold?

A G E I N G

An important question about

silencing by small RNAs concerns

why some target genes are

regulated at the level of

transcription,whereas others are

regulated post-transcriptionally.

Phillip Zamore and colleaguessuggest that the simple system

that operates in the yeast

Schizosaccharomyces pombecould

help to find the answer.

Argonaute (Ago) proteins

are crucial for the execution

of gene silencing by small

RNAs. Many species express

multiple Ago proteins, and

some of these induce silencing

at the transcriptional level

(transcriptional gene silencing

(TGS)), whereas others

specifically mediate post-

transcriptional gene silencing

(PTGS).Yeasts are poor relations

in this respect; for example,

S. pombeencodes a single Ago

protein, Ago1, which functions inTGS. However, despite lacking

other members of the Ago family,

previous studies have hinted that

PTGS also occurs in this species.

To confirm this, the authors

replaced the S.pombe adh1 gene

with an adh1:GFP fusion. They

then used a GFP hairpin RNA to

induce silencing of the transgene.

An intron was included in the

hairpin construct,a strategy that

had been shown to increase the

efficiency of PTGS

in other studies.

Expression of the

hairpin decreased GFP

fluorescence,indicating successful

silencing of the fusion gene. To test

whether this was mediated by TGS

or PTGS,the authors measured

both the total levels ofadh1:GFP

mRNA and the levels of its

transcription.Overall, adh1:GFP

mRNA levels decreased in cells

expressing the hairpin, but the rateof transcription remained the

same, indicating that silencing was

post-transcriptional.

As Ago1 is the only S. pombeAgo

protein, is it responsible for PTGS

as well as TGS? Silencing of

adh1:GFP was abolished in Ago

mutants,confirming that this is the

case. Interestingly, the authors

went on to show that proteins that

interact with Ago1 to mediate TGS

are not required for PTGS,

Simple, but effective

R N A S I L E N C I N G

Dung DNA set to foil

ivory poachers

Elephant dung could be more

valuable than ivory to the

elephants at least. A test thatcompares DNA from illegal

ivory with maps of genetic

variation based on dungsamples might hold the keyto tracking down poachers.

The ban on ivory tradinghas driven poachers into

forests, where their activitiesare more difficult to detect.

Tom Milliken of TRAFFIC, anorganization that monitors

trade in ivory, thinks thedung-based maps could

help to pinpoint poachinghotspots: the largest

uncertainty in our chain iswhere it is coming from, and

this method will help withthat ([email protected]).

The group that constructedthe map, from the University

of Washington in Seattle,took skin and dung samples

from 16 African countries.the most important

breakthrough is the ability toget it (DNA) from feces

because we can samplemany countries very quickly

now, said Samuel Wasser,

who led the study(Reuters.com). Because

forest elephants live in

isolated communities,genetic variation is sufficientto distinguish between

animals from different areas.We have incredible precision

at telling one forest locationfrom another, Wasser

explained (newscientist.com).But there is room for

improvement, as the map isntas good at distinguishing

man-made boundaries: Rightnow, its probably not precise

enough because it mightnot tell us if a consignment

comes from one side of a

national border or another,commented Julian Blanc ofthe World Conservation

Union (The Guardian, UK,28 September, 2004).

However, increased accuracyshould make the map a

valuable tool in the future.But this requires more dung,

and Wasser has a plea forthose who patrol the areas

affected: please, just askthem to pick up the poop,

([email protected]).

Louisa Flintoft



4/7

mutations, its presence favours the

selection and growth of mutants

that are better adapted to the envi-

ronment.

The results were not peculiar to

laboratory strains, as the same phe-

nomena occurred in three strains

newly collected from the wild.

Computational simulations tell a

similar story that a population

that undergoes premature death

and has a high mutation frequency

is more likely to adapt to a changing

environment.

So in yeast, at least, apoptosis is

an altruistic act, as not dying dam-

ages the chances of survival of the

whole group. If the theory stands

up to scrutiny then what conse-

quences does it have for humans?

Should we thwart any attempt toextend our lives for the sake of our

species? Whatever the eventual

answer, this is a debate that isnt

being laid to rest.Tanita Casci


ORIGINAL RESEARCH PAPER Fabrizio, P. et al.

Superoxide is a mediator of an altruistic aging

program in Saccharomyces cerevisiae.J. Cell Biol.

166, 10551067 (2004)

WEB SITE

Longos laboratory: http://www.usc.edu/

programs/pibbs/site/faculty/longo_v.htm

yeast strains of varying

longevity to repopulate a

yeast colony after a substantial

proportion of the colony had died.

This phenomenon, called adaptive

regrowth, occurs normally in wild

type strains however, the longer-

lived strains, which overexpress

SOD enzymes, could not repopu-

late the colony in the long term, and

eventually died out. So, although

longevity might confer an immedi-

ate advantage, it is detrimental to

the species as a whole. Short-livedstrains that lack the superoxide

inhibitors were even better than the

wild type at adaptive regrowth;

the authors show that the ability of

superoxide to promote adaptive

regrowth depends on its ability to

release nutrients from dying cells

into the growth media, which in

turn would allow younger cells to

thrive and reproduce. In addition,

because superoxide induces DNA


IN BRIEF


suggesting that Ago1 functions as

part of distinct complexes to

mediate the two types of silencing.

The fact that both TGS and PTGS

are mediated by Ago1 in S. pombe

indicates that it is not simply the

availability of specialized Ago

proteins that determines which

pathway is used to silence specific

genes. Gene-specific characteristics

are also likely to be important,such

as the chromosomal context of the

gene or its rate of transcription.Thesimple system provided by silencing

in S. pombeshould be a useful tool

for dissecting these requirements.

Louisa Flintoft


ORIGINAL RESEARCH PAPER Sigova, A.,

Rhind, N. & Zamore, P. D. A single Argonaute

protein mediates both transcriptional and

post-transcriptional silencing in

Schizosaccharomyces pombe. Genes Dev. 18,

23592367 (2004)

WEB SITE

http://www.umassmed.edu/bmp/faculty/

zamore.cfm?start=0&

The PLETHORA genes mediate patterning of theArabidopsis root stem cell niche.

Aida, M. et al. Cell119, 109120 (2004)

In Arabidopsis thaliana, root stem-cells are maintained by a small

set of organizing cells, known as the quiescent centre (QC), the

location of which depends on auxin accumulation. By using a

promoter-trap screen, the authors identified two putative

transcription factors, PLETHORA 1 (PLT1) and PLT2, which are

required for QC specification and for maintaining root stem-cells

during embryonic pattern formation; in addition,evidence

indicates that their expression in the QC responds to auxin.

Foxa2 is required for transition to air breathing at birth.

Wan, H. et al. Proc. Natl Acad. Sci. USA 101, 1444914454 (2004)

A fundamental adaptation faced by a newborn mammal is the

ability to breathe in air through its lungs.Now, by knocking out

gene function in the epithelial cells of the developing mouse lung,

Wan and colleagues show that Foxa2, which encodes a forkhead

transcription factor, is a master gene required for lung

maturation at birth. This finding could inform treatments for

premature babies and for individuals with lung disease or injury.

Hmx2 and Hmx3 homeobox genes direct developmentof the murine inner ear and hypothalamus and can be

functionally replaced by Drosophila Hmx.Wang, W. et al. Dev. Cell7, 439453 (2004)

The authors show that the roles of mouse homeobox genes Hmx2

and Hmx3 in the development of the vestibular system are

overlapping and distinct, but that their roles in the central nervous

system (CNS) are interchangeable. Moreover, the single flyHmx

can rescue the CNS and inner-ear phenotype in double-knockout

mice, despite differences in morphology.The authors propose that

evolution of complex organs such as the vertebrate inner ear might

involve cooption of primitive genetic programmes to new locations,

not just from acquisition and modification of protein domains.

Genome-wide mRNA surveillance is coupled tomRNA export.

Hieronymus, H. et al. Genes Dev., 1 November 2004 (doi:10.1101/gad.1241204)

The authors found evidence to suggest that there are links

between DNA and RNA surveillance and mRNA export. A screen

of annotated, non-essential Saccharomyces cerevisiaegenes

identified new factors required for mRNA export, including Rrp6,

an mRNA surveillance factor, and Lrp1, a DNA-repair protein.

The authors found that Lrp1 can mediate mRNA degradation and

requires Rrp6 for nuclear localization to the genes that encode

their target mRNAs.

G E N E E X P R E S S I O N

D E V E L O PM E N T A L B I O L O GY

D E V E L O PM E N T A L B I O L O G Y

P L A N T D E V E LO P M EN T



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Although systems biology helps to make

sense of the complex interactions betweengenes, proteins and other biologically

relevant molecules,most studies have

provided only snapshots of how these

networks operate in specific conditions. A

recent paper in Naturedescribes the first

genome-scale study of how biological

networks are rewired according to the needs

of the cell, revealing some important insights

into network dynamics.

Luscombe and colleagues first defined a

network of known interactions between 142

transcription factors and 3,420 genes in the

yeast Saccharomyces cerevisieae. They then

incorporated data from previous studies thathad examined patterns of gene expression

during the cell cycle, sporulation, diauxic

shift (the switch from anaerobic to aerobic

respiration),DNA damage and the stress

response, and used an algorithm to identify

sub-networks of interactions that are active

in these different conditions.

To characterize these sub-networks, the

authors devised a statistical method

SANDY (statistical analysis of network

dynamics) for the analysis of interactions

both within and between conditions.Overall

comparisons grouped the five sub-networks

into two categories.The exogenous diauxicshift, DNA-damage and stress-response sub-

networks were characterized by the

regulation of several genes by each

transcription factor, and by shorter pathways

leading from transcription factors to their

target genes. This fits in with their ability to

produce large and rapid responses to changes

in the environment. By contrast, the

endogenouscell-cycle and sporulation sub-

networks allow more precise,multi-stage

control,with longer pathways to activation

and more inter-regulation between

transcription factors.

Although these results might not seemsurprising, given the biological functions of

the sub-networks,more unexpected patterns

emerged when other characteristics were

investigated. Static gene-regulatory networks

are characterized by the existence of hubs

individual transcription factors that

regulate a disproportionately large number

of genes.The importance of these hubs

suggests that they are likely to function

across a range of conditions,as they regulate

key pathways,and this is supported by

theoretical simulations. However, the

authors found the reverse to be true: most

hubs (78%) were important in only a single

set of conditions and were therefore dubbed

transient hubs.Another surprising result

was seen when the interactions made by

those hubs that do function across several

conditions,known as permanent hubs,were

examined. Rather than using a similar set ofinteractions in each condition, these hubs

redefined their interactions just as

frequently as transient hubs further

evidence that networks are more dynamic

than was previously thought.

As Luscombe and colleagues point out,

their study was limited to results that were

available from previous experiments,

although the robustness of the features they

describe in response to random noise

suggests that similar patterns are likely to

emerge from direct studies ofS. cereviseae

network dynamics.The increasing

availability of genome-wide data onregulatory interactions in cell types should

allow future studies to determine whether

these features apply on a wider scale.

Louisa Flintoft


ORIGINAL RESEARCH PAPER Luscombe, N. M. et al.

Genomic analysis of regulatory network dynamics reveals large

topological changes. Nature 431, 308312 (2004)

FURTHER READING Barabsi, A. L. & Oltvai, Z. N. Network

biology: understanding the cells functional organization.

Nature Rev. Genet. 5, 101113 (2004)

WEB SITE

Web supplement to original research paper:

http://SANDY.TopNet.GersteinLab.org

Rewiring the network

S Y S T E M S B I O L O G Y

Developmental signalling pathways

defy simple job descriptions; partly

because nature has effectively recy-

cled them in many capacities, but

largely because we are ignorant of

just how varied their jobs are.This is

illustrated in a recent paper by Joseph

Bateman and Helen McNeill. By

analysing mutations in the fly eye, they

show that the insulin receptor (InR)

and Tor pathways which have a

well-conserved function in controlling

cell and organ size have an unex-

pected role in determining when cells

differentiate.

This conclusion was derivedfrom work on a gene, tsc1 (tuberous

sclerosis complex 1), which the

authors recovered in a genetic

screen for fly mutants with defective

planar polarity in the eye.As expected

from the mutant phenotype of the

vertebrate homologue oftsc1,which

encodes a tumour suppressor,homo-

zygous mutant photoreceptor cells are

larger than normal, but otherwise

differentiate normally. What was

peculiar, however, was that several

types of mutant photoreceptor cells

which are studied precisely

because their differentiation is so

stereotypical differentiated more

precociously than their genetically

wild-type neighbours. This speeded-

up development did not lead to anabnormal eye unit or to ectopic cell

fates, but simply to an acceleration of

the normal differentiation program.

How does wild-type tsc1 control

the rate of differentiation? Mutations

that activate the InR pathway cause

precocious differentiation in the

eye, as with mutations in tsc1. The

converse experiment, in which the

InR and Tor pathways were inacti-

vated, led to delays in neuronal dif-

ferentiation. This work further sup-

ports the involvement oftsc1 in InR

and Tor pathways and, importantly,

implicates these pathways in the

control of developmental timing.

The cells that make up each eye unit

in the fly are recruited to their fate

by reiterative signalling through the

Ras/MAPK pathway; however, lack

oftsc1 does not seem to affect this

signalling,indicating that tsc1 acts

downstream of known components

of this pathway or in parallel to

them.Uncoupling the execution of cell-

fate decisions from the time at which

the decisions are made might allow

Keeping an eye on the tempo

D E V E L O P M E N TA L B I O L O G Y



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Mendell and co-workers have uncovered the physio-

logical function of the nonsense mediated decay

(NMD) pathway in higher eukaryotes it is a cru-

cial mechanism for post-transcriptional regulation,

which is interlinked with essential homeostatic

mechanisms.

Whose line is it anyway a successful comedy-

cum-game show has entertained audiences on

both sides of the Atlantic. The contestants actors,

actresses and other celebrities are asked to per-

form a series of tasks. In one, they are presented

with an object and asked to indicate through acting

as many uses for it as possible. The intended use of

the object is not always clear, but in the game, this is

beside the point. The real purpose or function ofbiological phenomena can be frustratingly elusive;

this is often because the experimental conditions

that are used are artificial. But unlike in the example

above, uncovering the natural function is essential

in biology.

As its name suggests, NMD is a mechanism that

removes mRNAs that carry nonsense mutations. But

as Dietz and colleagues point out, this role alone

could not account for the evolutionary conservation

of the pathway it must, therefore, have another

function.

To uncover it, the authors knocked down the

pathway in HeLa cells and,using microarray analysis,

they compared transcription profiles of these cell-

swith those in which the pathway was intact. The

results revealed that almost 5% of genes were upreg-

ulated the transcripts of these genes are normally

eliminated by the NMD pathway.Among them are

transcripts that harbour upstream open reading

frames that lie in 5UTRs, transcripts in which non-

sense codons or frameshift mutations have been

introduced by alternative splicing, those that contain

introns in their 3 UTRs and transcripts that are

derived from ancient transposons and endogenous

retroviruses. A common feature of most of these

transcripts is the presence of a spliced intron located

at least 50 nucleotides downstream of the termina-tion codon a feature that is sufficient to activate

the NMD response.

The authors noted that many of the NMD-

pathway substrates are involved in amino-acid

metabolism and the cellular response to amino-

acid starvation. This observation revealed an inter-

esting homeostatic feedback mechanism.Amino-acid

starvation inhibits translation,so as the authors say:

Since NMD requires ongoing translation, it is likely

that regulation of these transcripts by nonsense sur-

veillance couples their expression level to translational

efficiency. Thus, under conditions of amino-acid

starvation,inhibition of translation and NMD would

increase expression of transcripts that promote

restoration of amino-acid homeostasis. This

mechanism of preserving amino-acid homeostasis

is evolutionarily conserved as revealed by the

authors analysis of previously published data on

NMD-regulated gene expression in yeast.

The work of Mendell et al. has put the role of the

NMD pathway in an interesting perspective. Its pre-dominant physiological function seems to involve

the regulation of many transcripts,whereas its role in

human disease caused by nonsense mutation,

although medically important, seems evolutionarily

insignificant.

Magdalena Skipper


ORIGINAL RESEARCH PAPER Mendell, J. T.et al.

Nonsense surveillance regulates expression of diverse classes of

mammalian transcripts and mutes genomic noise. Nature Genet.

36, 10731078 (2004)

FURTHER READING He, F. et al. Genome-wide analysis of mRNAs

regulated by the nonsense-mediated and 5 to 3mRNA decay

pathways in yeast. Mol. Cell12, 14391452 (2003)

The true purpose

G E N E E X P R E S S I O Nbetter control over the execution of

the developmental program. For

example, in the case oftsc1 the tem-

poral control is linked to nutrient

conditions through its connection

with the insulin pathway when

nutrients are scarce the organism

could then coordinate a slow down in

its development, in line with its

reduced growth. The authors also

showed that the temporal control

function of InR/Tor pathways holds

true for neuronal cell types outside

the fly eye, but just how broadly it

applies in flies and beyond,and pre-

cisely how the control is effected, is

not yet known.

Tanita Casci


ORIGINAL RESEARCH PAPER Bateman, J. M.

& McNeill, H. Temporal control of differentiation by

the Insulin receptor/Tor pathway in Drosophila. Cell

119, 8796 (2004)WEB SITE

Helen McNeills laboratory:

http://science.cancerresearchuk.org/research/loc/

london/lifch/mcneillh/



7/7



IN BRIEF

Genes feel the heat

C O N S E R V A T I O N G E N E T I C S

Birth and adaptive evolution of a hominoid gene thatsupports high neurotransmitter flux.

Burki, F. & Kaessmann, H. Nature Genet. 36, 10611063 (2004)

There are two glutamate dehydrogenase genes in humans: GLUD1

a housekeeping gene and GLUD2, which is expressed

specifically in neural tissue and testis. The authors show that

GLUD2originated by retrotransposition from GLUD1 in our

ancestor,23 Mya.The changes that giveGLUD2its tissue specific

properties are a result of positive selection, following a

duplication event. GLUD2probably contributed to enhanced

brain function in humans and apes, and has also been implicated

in late memory formation.

Global patterns of human mitochondrial DNA andY-chromosome structure are not influenced byhigher migration rates of females versus males.

Wilder, J. A. et al. Nature Genet. 36, 11221125 (2004)

Genetic evidence supports demic diffusion of Hanculture.

Wen, B. et al. Nature431, 302305 (2004)

These studies analyse the effects of historical migration on

human population structure.Wen et al. examined patterns of

Y-chromosome and mitochondrial DNA (mtDNA) variation

to study the spread of the Han Chinese culture. Their results

indicate that this spread followed migration of the Han people,

rather than diffusion of the culture through social interchangewithout genetic mixing, and show that males had a greater role

than females in this expansion. Wilder et al. tested the theory

that population structures have been more strongly influenced

by female migration than that of males due to patrilocality,

which occurs when females move to the locality of their

spouses following marriage. Analysis of genetic variation

between ten populations from different global regions showed

that this is not the case, at least at the continental and global

level, as similar levels of variation for Y-chromosomes and

mtDNA indicate roughly equal contributions of male and

female migration.

Regulatory evolution across the protein interactionnetwork.

Lemos, B. et al. Nature Genet. 36, 10591060 (2004)

These authors showed that, for a specific gene, the number of

interactions that its protein product participates in is negatively

correlated with the level of variation in gene expression,both

within and between species. Furthermore, for pairs of interacting

genes, levels of variation in gene expression were more similar

than for randomly assigned pairs. These results indicate that

proteinprotein interactions might have an important role in

constraining evolutionary changes in gene regulation.

E V O L U T I O N A R Y G E N E T I C S

P O P U L AT I O N G E N E T I C S

E V O L UT I O N A R Y G E N E T I C S

A recent study suggests that climate change affects wildlife at the genetic

level, with implications for protecting biodiversity in the face of changing

weather patterns.

Hadly and colleagues studied historical changes in genetic variation in

northern pocket gophers and montane voles.The two species thrive in wet

climates,so population numbers of both are expected to decrease during

periods of dry weather.But there are also differences between the two

species: whereas pocket gophers are home-loving animals and tend not to

venture far from the sub-populations they live in, montane voles are more

adventurous,with more migration between groups. What impact might

these ecological differences have on genetic variation in these species

during periods of climate change?

Over the past 2,500 years,two periods of climate change occurred

the Medieval Warm Period (1,150650 years ago) and the Little Ice Age

(65050 years ago).To investigate the effects of these periods on gopher

and vole genetic diversity,the authors took advantage of the abundance of

fossils for the two species that have been found in Yellowstone NationalPark, in the United States. They used mitochondrial DNA from these fossils

to estimate effective population sizes and levels of genetic variation at

different times over the past 2,500 years.

In keeping with their preference for damper climes,both species

underwent population decreases during the Medieval Warm Period.

However,this similarity didnt hold up for genetic variation: whereas the

gophers showed reduced genetic diversity during this period, the reverse

was true for the voles.This fits in well with the ecological strategies of the

two species.The high level of migration between vole sub-populations is

expected to contribute to genetic diversity in this species,and a recent

study has shown that migration increases at times of low population

density. By contrast,as gophers live in closed populations, this means

of maintaining variation would not have applied to them.Another

explanation is that genetic variation increased in the voles due to

stronger selective pressure, a possibility that needs further investigation.

Whatever the case, this study indicates that climate change affects

genetic variation,with varying effects on different species.As levels

of genetic variation can contribute to the likelihood of extinction,

further studies could provide important pointers as to which species

are likely to be hit hardest by climate change.

Louisa Flintoft


ORIGINAL RESEARCH PAPER Hadly, E. A. et al. Genetic response to climatic change: insights from

ancient DNA and phylochronology. PloS Biol. 2, e290 (2004)

WEB SITE Hadlys laboratory: http://www.stanford.edu/group/hadlylab/index.html


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