Finding genes that underlie complex traits

Phenotypic variation among organisms is central to evolutionary adaptations underlying natural and artificial selection, and also determines individual susceptibility to common diseases. These types of complex traits pose special challenges for genetic analysis because of gene-gene and gene-environment interactions, genetic heterogeneity, low penetrance, and limited statistical power. Emerging genome resources and technologies are enabling systematic identification of genes underlying these complex traits. We propose standards for proof of gene discovery in complex traits and evaluate the nature of the genes identified to date. These proof-of-concept studies demonstrate the insights that can be expected from the accelerating pace of gene discovery in this field.     

The class of 2005. Germany: deciphering cellular processes

Biochemist Anne Spang will soon take up her first tenured faculty position--a professorship--at the Biozentrum in Basel, Switzerland. Her research career has taken her to four countries, where she has investigated fundamental cell biological questions.     

Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling

The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.     

Comment on "Mixed-layer deepening during Heinrich events: a multi-planktonic foraminiferal delta18O approach"

Rashid and Boyle (Reports, 19 October 2007, p. 439) analyzed oxygen isotopes in planktonic foraminera from marine sediments and concluded that Heinrich events (massive iceberg discharges into the North Atlantic Ocean) caused upper water masses to deepen. We question the robustness of this interpretation and argue that a strongly stratified mixed layer characterized by dense sea-ice cover and production of oxygen-18-depleted brines likely prevailed during such events.     

Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number

Most organisms rely on interhomolog crossovers (COs) to ensure proper meiotic chromosome segregation but make few COs per chromosome pair. By monitoring repair events at a defined double-strand break (DSB) site during Caenorhabditis elegans meiosis, we reveal mechanisms that ensure formation of the obligate CO while limiting CO number. We find that CO is the preferred DSB repair outcome in the absence of inhibitory effects of other (nascent) recombination events. Thus, a single DSB per chromosome pair is largely sufficient to ensure CO formation. Further, we show that access to the homolog as a repair template is regulated, shutting down simultaneously for both CO and noncrossover (NCO) pathways. We propose that regulation of interhomolog access limits CO number and contributes to CO interference.     

Formation of Maillard reaction products during heat treatment of carrots

As indicators of the early stage of the Maillard reaction in carrots, N-(furoylmethyl) amino acids (FMAAs) formed during acid hydrolysis of the corresponding Amadori products were analyzed using RP-HPLC with UV detection. N(ε)-FM-Lys (furosine), FM-Gly, FM-Ala, FM-Val, FM-Ile, FM-Leu, and FM-GABA were identified using synthesized standard material by means of mass spectrometry. Furthermore, N(ε)-carboxymethyllysine (CML) and pyrraline were analyzed as indicators for advanced stages of glycation. For commercial samples with high water content, the formation of Amadori compounds predominates, whereas the advanced stage of Maillard reaction plays only a minor part. Carrot juices, baby food, and tinned carrots showed quite low rates of amino acid modification up to 5%. For dehydrated carrots, significantly higher values for Amadori products were measured, corresponding to a lysine derivatization of up to 58% and nearly 100% derivatization of GABA. Drying experiments revealed great differences in reactivity between the amino acids studied. Whereas furosine reached constant values quite quickly, some FMAAs showed a continuous increase with heating time, indicating that selected FMAAs can be used as a hallmark for the early Maillard reaction to control processing conditions.