NEWS AND VIEWS 142 VOLUME 39 | NUMBER 2 | FEBRUARY 2007 | NATURE GENETICS carboxypeptidase A inhibitor, but how this is relevant to stem cell numbers is unclear. Lxn expression is highest in the most primitive cells, but at the same time it reduces their numbers. Stem cells in congenic animals carrying the DBA/2 Lxn allele cycled faster and appeared to be resistant against apoptosis, but these parameters were not assessed after retroviral overexpression of Lxn. As a complement to the overexpression experiments, it would have been informative if the authors had attempted to repress endogenous latexin levels by RNA interference to assess whether this would lead to an increase in stem cell numbers, a clinically relevant issue. Recently, Lxn knockout animals have been created that show reduced pain sen- sing 8 . It will be interesting to quantify hemato- poietic stem cell numbers in these mice. The genetics of complex traits Although it is evident that latexin can affect hematopoietic stem cell numbers, no func- tional quantitative trait SNP has been iden- tified, and it remains formally possible that latexin is not the only stem cell QTL on chro- mosome 3. From a biological perspective, however, this uncertainty is not very relevant. The main objective of this study was to iden- tify new genes that regulate hematopoietic stem cells, and the authors have accomplished exactly that. Together with recently published data that identified the Polycomb group gene Ezh2 as another stem cell regulator 9 , this study clearly proves the validity of an approach that was initiated more than 25 years ago. This study documents the strength of using a genetic reference panel of inbred mice to iden- tify quantitative trait genes. The recombinant inbred strains of mice have been phenotyped for hundreds of classical phenotypes and tens of thousands of gene expression phenotypes measured in multiple organs (including hema- topoietic stem cells, various neuronal tissues, eye and liver), all stored in a user-friendly online database (http://www.genenetwork.org) 10 . The power of integrating all these genetic and genomic data has now been well documented, offering a glimpse of what the future of com- plex trait genetics will look like. Model systems that are genetically more complex, including extensive eight-strain crosses 11,12 and haplotype association studies using large panels of regular inbred strains of mice, and even humans, are on the horizon. These resources will prove to be very powerful and will aid in dissecting clinically relevant complex phenotypes into their individ- ual components, thus allowing the identification of causative genes. 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Fanconi anemia and breast cancer susceptibility Ketan J Patel Two new studies show that the Fanconi anemia complementation group N results from biallelic mutations in PALB2, which encodes a recently identified interaction partner of the breast cancer susceptibility protein BRCA2. A third study shows that monoallelic PALB2 mutations are associated with breast cancer susceptibility, providing yet more links between Fanconi anemia, homologous recombination repair and cancer predisposition. Ketan J. Patel is at the Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, UK. e-mail: kjp@mrc-lmb.cam.ac.uk Almost 50 years have passed since the Swiss pediatrician Guido Fanconi described a genetic condition characterized by developmental abnormalities, bone marrow failure and can- cer susceptibility 1 . This curious disease, called Fanconi anemia, has spawned an international research effort because of its intriguing pheno- type and its remarkable genetic heterogeneity. Indeed, the disease has thus far been associated with mutations in any of 13 genes, suggesting that their gene products function in a common pathway (Fig. 1). Most of the Fanconi anemia gene products form a multiprotein E3 ubiqui- tin ligase known as the Fanconi anemia nuclear core complex, and three others seem to func- tion downstream of this complex: FANCD2 (the core complex’s known ubiquitination sub- strate), BRIP1 (a DNA helicase, also known as FANCJ) and BRCA2 (also known as FANCD1). The nuclear core complex and the downstream proteins probably function to resolve DNA rep- lication blocks, an impediment potentiated by agents that crosslink DNA 2 . However, despite the identification of so many of the underlying Fanconi anemia gene products, a coherent pic- ture of how this pathway functions to preserve genome integrity remains elusive. Moreover, little is known about how these molecular com- ponents relate to the phenotypic features of Fanconi anemia such as progressive bone mar- row stem cell loss, abnormal development and cancer risk. Therefore, considerable emphasis has been placed on identifying new Fanconi anemia genes that may help fill the crucial gaps in our knowledge of this pathway. On pages 155 and 158 of this issue, Xia et al. 3 and Reid et al. 4 report the discovery that the Fanconi anemia complementation group FA-N results from biallelic mutations in PALB2 (‘part- ner and localizer of BRCA2’), encoding a protein recently identified as a binding partner of the breast cancer tumor suppressor protein BRCA2 (ref. 5). In a third study on page 161 of this issue, Rahman et al. 6 report that monoallelic PALB2 mutations are associated with increased suscepti- bility to familial breast cancer. Collectively, these studies add to the mounting body of evidence linking components of the Fanconi anemia path- way with breast cancer risk. Guilt by association To appreciate the background behind these dis- coveries, it is helpful to recount a short history of BRCA2 and its association with Fanconi ane- mia. Mouse cells with truncating mutations in Brca2 were initially shown to accumulate aber- rant chromosomes, sharing strong similarities with human Fanconi anemia cells 7 . However, © 2007 Nature Publishing Group http://www.nature.com/naturegenetics