RESEARCH

HIGHLIGHTS

HIGHLIGHT ADVISORS

SEAN B. CARROLL

UNIVERSITY OF WISCONSIN,USA

NANCY J. COX

UNIVERSITY OF CHICAGO, USA

RALPH J. GREENSPAN

THE NEUROSCIENCESINSTITUTE, CALIFORNIA, USA

YOSHIHIDE HAYASHIZAKI

RIKEN GENOMIC SCIENCESCENTER, JAPAN

PETER KOOPMAN

UNIVERSITY OF QUEENSLAND,AUSTRALIA

LEONID KRUGLYAK

FRED HUTCHINSON CANCERRESEARCH CENTER, USA

BARBARA MEYER

UNIVERSITY OF CALIFORNIA,BERKELEY, USA

JOHN QUAKENBUSH

THE INSTITUTE FOR GENOMICRESEARCH, USA

NADIA ROSENTHAL

EMBL MONTEROTONDO, ITALY

MARC VIDAL

DANA-FARBER CANCERINSTITUTE, BOSTON, USA

VIRGINIA WALBOT

STANFORD UNIVERSITY, USA

DETLEF WEIGEL

MAX PLANCK INSTITUTE FORDEVELOPMENTAL BIOLOGY,GERMANY

PHIL ZAMORE

UNIVERSITY OFMASSACHUSETTS, USA

LEONARD I. ZON

CHILDREN’S HOSPITAL,BOSTON, USA

250 | APRIL 2005 | VOLUME 6 www.nature.com/reviews/genetics

The DNA sequence of the human X chromosome — the fourteenthhuman chromosome to have itsgenetic line-up deciphered — has nowbeen published. The sequence revealsthe many unique features of thischromosome and could provide use-ful insights into X-chromosome inac-tivation and the origin and evolutionof mammalian sex chromosomes.

The sequencing effort, which wascarried out using shotgun and bothBAC- and PAC-based sequencing,shows that this ~155-Mb chromo-some is surprisingly gene poor. Withonly 1,098 annotated genes its genedensity is among the lowest of all thehuman chromosomes that have beenannotated. Consistent with its lowgene density, the frequency of pre-dicted CpG islands is exactly halfthe estimated genome average. The X chromosome is also highly enrichedin interspersed repeats, particularlythose of the LINE1 class. The distrib-ution of these repeats on the chromo-some is consistent with a proposedrole in X-chromosome inactivation.

The origin of the mammalian X chromosome is fascinating for sev-eral reasons, including its uniquedosage-compensation mechanismand its relationship to the human Y chromosome. The authors con-firm that, indeed, the X chromo-some has by far the most conservedgene arrangement in placental mam-mals. Sequence alignments betweenthe human X chromosome and thechicken genome corroborates theautosomal origin of the mammalian

sex chromosomes before they wererecruited into a chromosomal systemfor sex determination. Further analy-sis provides valuable information onthe timing and location of a series ofrearrangements that have takenplace on this chromosome over thelast 300 million years, and on the pro-gressive loss of recombination betweenthe sex chromosomes that allowedthe X and Y chromosomes to evolveindependently.

The X chromosome holds aunique place in the history of medicalgenetics. X-linked diseases are rela-tively easy to recognize owing to theirmode of inheritance, and the phe-notypic consequences of recessive,X-linked mutations are revealed inmales. Therefore, despite its gene-poor

An X ordinary sequence

G E N O M I C S content, almost 10% of diseaseswith a Mendelian pattern of inheri-tance have been assigned to the X chromosome.

The annotation of the X chromo-some will accelerate the process of dis-covering new genes that are involvedin rare genetic disorders. Moreover,the study of the sequence could helpus to understand the mysteries thatunderlie X-chromosome inactivation,genomic imprinting and sex-chromo-some evolution. Taking advantage offurther genome sequences, compar-isons could be made to unravel the dif-ferent evolutionary forces that shapesex chromosomes in mammalian andnon-mammalian systems.

Ekat Kritikou

References and linksORIGINAL RESEARCH PAPER Ross, M. T. et al.The DNA sequence of the human X chromosome.Nature 17 March 2005 (doi:10.1038/nature 03440)WEB SITESHuman X Chromosome Project:http://www.sanger.ac.uk/HGP/ChrXVEGA database:http://vega.sanger.ac.uk/Homo_sapiens

© 2005 Nature Publishing Group