Volume 41 Issue 9, September 2009

Although genome-wide analyses have identified somatic alterations contributing to the pathogenesis of pediatric acute lymphoblastic leukemia (ALL), few studies have identified germline variants conferring risk of this disease. Two reports now provide the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis.

Making causative connections between genotypic and phenotypic variation is a major challenge for geneticists engaged in the study of human disease. A study drawing this connection for a type 1 diabetes risk locus now demonstrates the importance of focusing on specific quantitative traits and studying them in normal subjects.

The discovery that a cocktail of transcription factors can reprogram somatic cells into induced pluripotent stem (iPS) cells keeps revealing new secrets of cell fate specification. A new study with hematopoietic cells shows that progenitor cells are far more susceptible than differentiated cells to reprogramming.

David Craig and colleagues recently reported methods allowing detection of individual genotypes from summary data of high-density SNP arrays. Eran Halperin and colleagues now report analyses of the statistical power of these methods, employing likelihood ratio statistics to provide an upper-bound to the limits of detection.

Konrad Hochedlinger and colleagues show that hematopoietic stem and progenitor cells give rise to induced pluripotent stem cells 300 times more efficiently than terminally differentiated B and T lymphocytes, yielding reprogramming efficiencies of up to 27%. These findings identify adult hematopoietic progenitors as an attractive cell type for applications of iPS technology in research and therapy.

Benjamin Cheyette and colleagues show that mouse Dact1 mutants have posterior malformations arising from impaired morphogenesis of the primitive streak. Their findings suggest a critical role for Dact1 in regulating cell adhesion at the primitive streak by altering levels or distribution of Vangl2 protein at the plasma membrane.

Stephen Chanock and colleagues report a genome-wide association study of pancreatic cancer. They identify common variants at the ABO blood group locus associated with susceptibility to pancreatic cancer, consistent with previous epidemiological evidence suggesting that individuals with A or B blood types have greater risk of this cancer than individuals with blood type O.

Xifeng Wu and colleagues show that a common variant in the prostate stem cell antigen (PSCA) gene on 8q24 is associated with susceptibility to urinary bladder cancer. The risk allele truncates the amino terminus of the PSCA gene product and reduces PSCA promoter activity in bladder cancer cell lines.

Paul Pharoah and colleagues report results of the first genome-wide association study for epithelial ovarian cancer. They identify a susceptibility locus on chromosome 9p22.

Mary Relling and colleagues report results of a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) and its subtypes, identifying a specific association between common variants in ARID5B and B-hyperdiploid ALL.

Richard Houlston and colleagues report results of a genome-wide association study of childhood acute lymphoblastic leukemia. Identified risk loci include IKZF1 on 7p12.2 and ARID5B on 10q21.2, which encode transcription factors involved in the differentiation of B-cell progenitors.

Linda Wicker and colleagues examine the effect of SNPs in the IL2RA region, previously associated to type 1 diabetes, on CD25 protein expression on the cell surface of primary immune cells from donors within the Cambridge BioResource. They demonstrate the value of using fresh primary cells from a large bioresource of genotype-selectable healthy volunteers.

Stefan Mundlos and colleagues report the identification of mutations in PYCR1 that cause autosomal recessive cutis laxa. PYCR1 encodes an enzyme involved in proline metabolism and localizes to mitochondria.

Marco Tartaglia and colleagues report the identification of mutations of SHOC2 in individuals with Noonan-like syndrome with loose anagen hair. The mutations cause aberrantly acquired N-myristoylation of SHOC2 resulting in aberrant targeting of SHOC2 to the plasma membrane. SHOC2 is believed to function as a scaffold linking RAS to downstream signal transducers.

Stephane Schurmans and colleagues show that mice lacking the enzyme inositol polyphosphate-5-phosphatase E (Inpp5e) develop a multiorgan disorder with defects in primary cilia. They also report a mutation in human INPP5E in a family with MORM syndrome, a condition similar to Bardet-Biedl syndrome.

Joseph Gleeson and colleagues show that mutations in INPP5E, encoding the enzyme inositol polyphosphate-5- phosphatase E, cause Joubert syndrome. Functional studies suggest that the mutations promote premature destabilization of cilia in response to stimulation.

Kathleen Millen and colleagues report that mutations in FOXC1 lead to cerebellar defects and contribute to Dandy-Walker malformation in humans.