Just Below a
"Steady-State" Top Ten, a Trio
Awaits
by Jeremy Cherfas
Biology Top Ten
Papers
Rank
Papers
Cites Jan-Feb
09
Rank
Nov-Dec 08
1
Intl. HapMap Consortium
(K.A. Frazer, et
al.), "A second
generation human haplotype
map of over 3.1 million
SNPs," Nature,
449(7164): 854-61, 18
October 2007. [72
institutions worldwide]
*221LY
83
3
2
K. Takahashi, et
al., "Induction of
pluripotent stem cells from
adult human fibroblasts by
defined factors,"
Cell, 131(5):
861-72, 30 November 2007.
[Kyoto U., Japan; CREST,
Kawaguchi, Japan; Gladstone
Inst. Cardio. Dis., San
Francisco, CA] *243MG
76
†
3
A. Barski, et al.,
"High-resolution profiling
of histone methylations in
the human genome,"
Cell, 129(4):
823-37, 18 May 2007.
[NHLBI, NIH, Bethesda, MD;
U. Calif., Los Angeles]
*172FA
54
4
4
D.F. Easton, et
al., "Genome-wide
association study
identifies novel
breast
cancer
susceptibility loci,"
Nature,
447(7148): 1087-93, 28
June 2007. [87
institutions worldwide]
*183HT
54
†
5
V. Cherezov, et
al., "High-resolution
crystal structure of an
engineered human
ß2-adrenergic
G protein-coupled
receptor,"
Science,
318(5854): 1258-65, 23
November 2007. [Scripps
Res. Inst., La Jolla, CA;
Stanford U., CA] *233JG
44
5
6
M. Wernig, et al.,
"In vitro
reprogramming of
fibroblasts into a
pluripotent ES-cell-like
state," Nature,
448(7151): 318-24, 19 July
2007. [5 U.S. institutions]
*191GC
41
6
7
T.S. Mikkelsen, et
al., "Genome-wide maps
of chromatin state in
pluripotent and
lineage-committed cells,"
Nature, 448(7153):
553-60, 2 August 2007. [6
U.S. institutions] *195XV
40
8
8
T. Korn, et al.,
"IL-21 initiates an
alternative pathway to
induce proinflammatory
TH17 cells,"
Nature, 448(7152):
484-7, 26 July 2007.
[Harvard Med. Sch., Boston,
MA] *193VG
39
†
9
K. Okita, T. Ichisaka, S.
Yamanaka, "Generation of
germline-competent induced
pluripotent stem cells,"
Nature, 448(7151):
313-7, 19 July 2007. [Kyoto
U., Japan; Japan Sci. Tech.
Agency, Kawaguchi] *191GC
38
7
10
Landgraf, et al.,
"A mammalian microRNA
expression atlas based on
small RNA library
sequencing," Cell,
129(7): 1401-14, 29 June
2007. [27 institutions
worldwide] *188HQ
Can biology really have reached some sort of steady
state? A glance across at the current What’s Hot
suggests maybe it has; not a single new entry in the lists.
A couple are reappearing, having dropped out, but every
paper has been here before. Things are not, however,
standing still. Outside the Top Ten is a trio of papers
that depends on the very papers which, because they remain
so highly cited, are blocking access to the Top Ten.
Autism, type 1
diabetes,
and
breast cancer are just three of the
diseases whose prevalence and complexity have by turns
attracted and baffled researchers, and there they all
are, revealing hitherto unimaginable details of their
genetic links thanks to the new tools of molecular
biology.
At #14, Jonathan Sebat and
Michael Wigler, of the
Cold Spring Harbor Laboratory, lead
a team that has uncovered, for the first time, a genetic
basis for autism (J. Sebat, et al.,
Science, 316[5823]: 445-9, 20 April 2007; 34
citations this period, 110 overall).
A genetic component has long been suspected; if one of
a pair of identical twins is affected, there is a 70%
chance the other will be too, almost 10 times the risk
factor for non-identical twins and full siblings. And
yet the actual mutations—or even links to
specific genetic regions—have been very hard to
pin down. Previous studies have implicated parts of 20
different chromosomes. The new paper indicates why.
Rather than being associated with particular genes,
autism seems to be linked with copy number variations
that are not present in the patient's parents.
The study depended on performing whole-genome scans on
parents and their children, affected and unaffected, from
264 families, an unthinkable effort just a few years ago.
With complex procedures for ensuring that observed
mutations were indeed novel and not present in either
parent, mutations, generally quite large deletions, were
found to be present in 10% of patients with no affected
relatives, certainly an underestimate. They were also
widely spread across the genome, sometimes involving a
single gene and sometimes several genes.
While these results are a far cry from understanding the
genetic basis of autism or the mechanisms leading to the
many variants of the condition, they do indicate that
damage at several different sites can contribute to the
syndrome. And they suggest differences between sporadic, or
simplex, autism, in which no other family members are
involved, and which is associated with de novo
copy number variations, and multiplex autism, where more
than one sibling is affected and which show much lower
frequency of new mutations.
The power of genomic analysis is further revealed in the
paper at #15 (J. Todd, et al., Nature
Genetics, 39[7]: 857-64, July 2007; 33 citations this
period, 162 overall), in which a team led by John Todd,
director of the Juvenile Diabetes Research Foundation of
the Wellcome Trust in Cambridge, England, has identified
four chromosome regions associated with type 1 diabetes
(T1D). This paper is in a sense the pin-up for a series of
studies that emerged from the Wellcome Trust Case Control
Consortium's publication of "A genome wide association
study of 14,000 cases of seven common diseases and 3,000
shared controls," (Nature, 447[7145]: 661-78,
2007). The genome wide association study (GWAS) used the
HapMap to identify links with common diseases. Todd's group
went further, to screen the links and ensure that they
truly are associated with T1D.
The big problem is statistical. If you are looking at
500,000 different potential sites that could be linked to
the disease in question, five are going to be statistically
highly associated just by chance. Todd's group used a range
of techniques to narrow the field from twelve potential
links to just four, adding a fifth from another GWAS. As
the authors note, "[t]his study increases the number of T1D
loci from six to at least ten." More than that, it rules
out eight loci that might well have been a waste of time.
The final paper, at #16, conducts a GWAS for sporadic
postmenopausal breast cancer (D.J. Hunter, et al.,
Nature Genetics, 39[7]: 870-4, July 2007; 33
citations this period, 161 overall). This is the late-onset
version of breast cancer, which usually affects women with
no family history of the disease. Not surprisingly, it has
been much harder to identify genetic factors. David Hunter,
of Harvard Medical School, and his team identified four
mutations, all affecting a "tumor-supressor" receptor gene
that is often overexpressed in breast cancer. As with the
diabetes study, the results are important also because they
rule out four mutations that were false positives.
Three diseases, three papers, all taking advantage of the
phenomenal power of modern molecular biology and
statistical techniques to offer improved targets for
therapeutic research. If this is the steady state, long may
it continue.
Dr. Jeremy Cherfas is Science Writer at Bioversity
International in Rome, Italy.
KEYWORDS: AUTISM, BREAST CANCER, TYPE 1 DIABETES, GENOME
WIDE ASSOCIATION STUDY, GWAS, JONATHAN SEBAT, MICHAEL
WIGLER, JOHN TODD, DAVID HUNTER.