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the presence or absence of alleles is reported. showed no significant deviation from Hardy- HapMap project12, needs to cover segmental
For a duplicon variant, this leads to confound- Weinberg equilibrium in more than 1,500 duplications. Although this may require spe-
ing of one of the homozygous classes with the individuals. This leaves their recommended cial attention to duplicon variation and geno-
heterozygous class (Table 1). MSVs will be procedure: incorporating CHM samples sys- typing, Fredman et al. reach the conclusion
scored as heterozygous if there is variation in tematically as controls in the genotyping that 50% of the markers in the public data-
the sample at any interrogated site. Such geno- experiments. base for these regions are probably true SNPs,
type misassignment has the potential to create Although MSVs may be avoided as markers a density similar to that found elsewhere in
uncertainties in mapping studies. when possible, there are instances where it is the genome. The concentration of genes in
The quantification required to genotype desirable to interrogate a single site in the duplicated segments that they and others3
these polymorphisms correctly is tedious, and presence of complex polymorphism. report shows that it will be important to have
2004 Nature Publishing Group http://www.nature.com/naturegenetics
not possible with all genotyping methodolo- Examples might include the TCR/ and these SNPs deployed for disease-mapping.
gies13. In any case, multisite polymorphisms IGH loci on chromosome 14, which have
1. Fredman, D. et al. Nat. Genet. 36, 861866 (2004).
are difficult to interpret. Thus, other complicated repeat structures and potential 2. Bailey, J.A. et al. Science 297, 10031007 (2002).
approaches to identify duplicon markers in disease relevance. Other examples occur in 3. Cheung, J. et al. Genome Biol. 4, R25 (2003).
an initial screen are attractive. Segregation plants: Brassica napus (rapeseed) is an 4. Emanuel, B.S. & Shaikh, T.H. Nat. Rev. Genet. 2,
791800 (2001).
may be inconsistent with expectations of an amphidiploid, composed of copies of B. oler- 5. Shaw, C.J. & Lupski, J.R. Hum. Mol. Genet. 13 Spec
ordinary SNP. If insufficient family samples acea (cauliflower) and B. rapa (turnip) No 1, R57R64 (2004).
are available to detect this, an alternative is to genomes. Four copies of the same gene may 6. Samonte, R.V. & Eichler, E.E. Nat. Rev. Genet. 3,
6572 (2002).
examine deviations from Hardy-Weinberg be present, two originating from each of the 7. Estivill, X. et al. Hum. Mol. Genet. 11, 19871995
equilibrium. But Fredman et al. show ancestral species. To be sure of obtaining spe- (2002).
8. Hurles, M. Science 298, 1509 (2002).
instances with little or no deviation from cific SNP genotyping, a PCR step can be 9. Prince, J.A. et al. Genome Res. 11, 152162 (2001).
Hardy-Weinberg when allele presence or designed to amplify a single gene followed by 10. Schouten, J.P. et al. Nucleic Acids Res. 30, e57
absence is scored. Only 50% of the MSVs that allele-specific detection. Fredman et al. spec- (2002).
11. Sherry, S.T. et al. Nucleic Acids Res. 29, 308311
they identified showed significant deviation ulate that MSVs might in some instances have (2001).
(P < 0.01) when tested in 32 diploid DNA direct relevance to disease and, therefore, be 12. The International HapMap Consortium. Nature 426,
samples. To counter the argument that 32 important to characterize. 789796 (2003).
13. Gut, I.G. in Molecular Analysis and Genome Discovery
may be too small for sufficient power, they A complete linkage disequilibrium map of (eds. Rapley, R. & Harborn, S.) 4369 (Wiley,
provide the example of two MSVs that the human genome, such as proposed in the Chichester, UK, 2004).
Marfan syndrome is a dominantly inherited Takeshi Mizuguchi and colleagues3 report regulators and can also induce differentia-
disorder of fibrous connective tissue affect- that inactivating mutations in TGFBR2 at tion, apoptosis, cell migration, adhesion
ing the skeletal, cardiovascular and ocular 3p24.2p25 cause Marfan syndrome type 2 and extracellular matrix deposition5. In a
systems, with an incidence of 1 in 10,000. (MFS2). This finding may fuel further Franco-Japanese collaboration, Mizuguchi
Some have suggested that Abraham Lincoln debate as to the molecular etiology of this et al.3 investigated 11 sporadic and 10 famil-
and Paganini had Marfan syndrome. disease, as it has been suggested that fib- ial cases of Marfan syndrome not associated
Approximately 80% of Marfan cases are due rillin functions by limiting activation of with mutations in FBN1. They found a com-
to inactivating mutations in FBN1, encod- TGF in vivo4. plex cytogenetic disruption of TGFBR2 in
ing the extracellular microfibrillar protein one individual with Marfan syndrome, as
fibrillin. Controversy surrounds the issue of TGFs and cancer well as four independent missense muta-
clinical and genetic heterogeneity in the The TGFs are multifunctional growth fac- tions, two of which segregated with the dis-
remaining 20% of individuals with Marfan tors that signal through a well-characterized ease in family studies, and one of which
syndrome, specifically with respect to a sec- pathway of transmembrane serine-threo- occurred in both a French family and an
ond locus on chromosome 3p24.2p25 nine kinase receptors and intracellular sig- independent Japanese individual. All the
(refs. 1,2). On page 855 of this issue, naling molecules of the SMAD family5. missense mutations occur at conservative
Their biological effects are context-depen- amino-acid residues in the serine-threonine
Rosemary J. Akhurst is at the Mt. Zion Cancer dent, varying with tissue type and the activ- kinase domain of the receptor, inactivating
Research Institute, University of California, San ity of other intracellular signaling pathways the receptor, as assayed by TGF reporter
Francisco, USA. e-mail: rakhurst@cc.ucsf.edu in the cell. They are potent negative growth assays in vitro.
It may come as a surprise to cancer biolo- Table 1 Germline mutations in components of the TGF superfamily signaling pathways
gists that individuals with MFS2 do not
have a higher rate of cancer. TGFBR2 has Gene OMIM OMIM
been reported to be a tumor-suppressor number Syndrome number
gene, particularly for cancers of the gas- ENG 131195 HHT1 187300
trointestinal tract5. Downregulation of ACVRL1 601284 HHT2 600376
TGF1 or TRII (the TGF type II recep- SMAD4 600993 JPS 174900
tor) in transgenic mice has been shown to JPS and HHT syndrome 175050
enhance epithelial tumor development5, BMPR1A 601299 JPS 174900
and genetic ablation of Tgfbr2 in mouse BMPR2 60079 Familial primary pulmonary hypertension 1 178600
2004 Nature Publishing Group http://www.nature.com/naturegenetics
Experiencing VEGF
2004 Nature Publishing Group http://www.nature.com/naturegenetics
In late eighteenth-century London, the VEGF and the ventricle of memory expression increased in both of these settings,
Scottish anatomist and surgeon John Hunter On page 827 of this issue, Matthew During but not after physical exercise alone.
interrupted the arterial supply to a stags and colleagues provide evidence linking Intracerebral injection of an adeno-associated
antler and found that blood flow was reestab- VEGF to a form of neurogenesis that occurs virus vector expressing human VEGF
lished through newly formed vessels. Such as a result of experience and may be involved increased hippocampal VEGF expression and
vascular sprouting, or angiogenesis, is crucial in memory and learning (Fig. 1). enhanced performance in tests of associative
to the survival of developing tissues and neo- Environmental enrichment, maze training (passive avoidance) and spatial (Morris water
plasms as they outgrow their blood supply, and physical exercise are known to stimulate maze) learning, both of which depend on
and measures to stimulate or inhibit angio- hippocampal neurogenesis, but the underly- hippocampal function. Placental growth fac-
genesis are prospective treatments for ing mechanisms are unclear. To explore this tor (PGF), a VEGF family member that inter-
ischemia and cancer. Angiogenesis is com- connection, the authors probed rat hip- acts with VEGFR1 but not VEGFR2, had no
plex, but its most celebrated mediator is vas- pocampus for mRNAs induced by environ- such effect, despite the fact that, like VEGF, it
cular endothelial growth factor, or VEGF, a mental enrichment and by training in a stimulated angiogenesis. Therefore, neither
hypoxia-inducible protein that promotes the Morris water maze. They found that VEGF VEGFR1 activation nor angiogenesis can
proliferation and survival of vascular
endothelial cells. VEGF and its tyrosine
kinase receptors, VEGFR1 (also called Flt1) a b
and VEGFR2 (also called KDR or Flk1), are
also expressed by nonvascular cells including Morris
neurons, suggesting that they have a broader water maze
physiological role.
Studies on the neuronal effects of VEGF
establish at least three types of action. First,
VEGF exerts neurotrophic effects manifested
by increased axonal outgrowth and improved Dentate
cell survival in neuronal cultures1,2. Second, gyrus
VEGF protects neurons from insults such as
hypoxia3 and glutamate toxicity4, which may
explain its ability to reduce injury and improve VEGF
outcome after experimental stroke57; con-
Michael Pace
On page 791, in the second column, the second full sentence should begin, Camurati-Engelmann syndrome, a bone overgrowth defect due to
TGFB1 missense mutations....
On page 837, in the right column, the first full sentence should begin, The G variant of this SNP had a higher frequency in affected individuals
from the US (62.7%) than in matched controls (52.4%; P = 0.0008)...
In Figure 2, the arrow indicating the direction of transcription of SUMO4 should be pointing to the right.
The version of Supplementary Table 1 that initially appeared online was incorrect and has been replaced with the correct version.
In Figure 2c, 805delCCCTG should read 806delCCCTG. In Figure 3, the y axis in panel a should read Absorbance 325 nm and the y axis in
panel c should read AT-ral peak area (A368nm).