Classification using functional data analysis for temporal gene expression data

MOTIVATION: Temporal gene expression profiles provide an important characterization of gene function, as biological systems are predominantly developmental and dynamic. We propose a method of classifying collections of temporal gene expression curves in which individual expression profiles are modeled as independent realizations of a stochastic process. The method uses a recently developed functional logistic regression tool based on functional principal components, aimed at classifying gene expression curves into known gene groups. The number of eigenfunctions in the classifier can be chosen by leave-one-out cross-validation with the aim of minimizing the classification error. RESULTS: We demonstrate that this methodology provides low-error-rate classification for both yeast cell-cycle gene expression profiles and Dictyostelium cell-type specific gene expression patterns. It also works well in simulations. We compare our functional principal components approach with a B-spline implementation of functional discriminant analysis for the yeast cell-cycle data and simulations. This indicates comparative advantages of our approach which uses fewer eigenfunctions/base functions. The proposed methodology is promising for the analysis of temporal gene expression data and beyond. AVAILABILITY: MATLAB programs are available upon request.     

A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism that can cause significant morbidity and mortality. Since the implementation, in many states and countries, of newborn screening (NBS) by tandem mass spectrometry, IVA can now be diagnosed presymptomatically. Molecular genetic analysis of the IVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C-->T (A282V), in 47% of mutant alleles. Surprisingly, family studies identified six healthy older siblings with identical genotype and biochemical evidence of IVA. Our findings indicate the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA. This has significant consequences for patient management and counseling.     

Structural organization of authentic,mature HIV-1 virions and cores

Mature, infectious HIV-1 particles contain a characteristic cone-shaped core that encases the viral RNA and replication proteins. The architectures of mature virions and isolated cores were studied using cryo-electron microscopy. The average size ( approximately 145 nm) of the virion was unchanged during maturation. Most virions contained a single core but roughly one-third contained two or more cores. Consideration of the capsid protein concentration during core assembly indicated that core formation in vivo is template-mediated rather than concentration-driven. Although most cores were conical, 7% were tubular. These displayed a stacked-disc arrangement with 7-, 8-, 9- or 10-fold axial symmetry. Layer line filtration of these images showed that the capsid subunit arrangement is consistent with a 9.6 nm hexamer resembling that previously seen in the helical tubes assembled from purified capsid protein. A common reflection (1/3.2 nm) shared between the tubular and conical cores suggested they share a similar organization. The extraordinary flexibility observed in the assembly of the mature core appears to be well suited to accommodating variation and hence there may be no single structure for the infectious virion.     

The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo

In the mouse embryo, significant numbers of primordial germ cells (PGCs) fail to migrate correctly to the genital ridges early in organogenesis. These usually die in ectopic locations. In humans, 50% of pediatric germ line tumors arise outside the gonads, and these are thought to arise from PGCs that fail to die in ectopic locations. We show that the pro-apoptotic gene Bax, previously shown to be required for germ cell death during later stages of their differentiation in the gonads, is also expressed during germ cell migration, and is required for the normal death of germ cells left in ectopic locations during and after germ cell migration. In addition, we show that Bax is downstream of the known cell survival signaling interaction mediated by the Steel factor/Kit ligand/receptor interaction. Together, these observations identify the major mechanism that removes ectopic germ cells from the embryo at early stages.     

High sexual signalling rates of young individuals predict extended life span in male Mediterranean fruit flies

In a laboratory study, we monitored the lifetime sexual signalling (advertisement) of wild male Mediterranean fruit flies, and we tested the hypothesis that high lifetime intensity of sexual signalling indicates high survival probabilities. Almost all males exhibited signalling and individual signalling rates were highly variable from the beginning of the adults maturity and throughout their life span (average life span 62.3 days). Sexual signalling rates after day 10 (peak maturity) were consistently high until about 1 week before death. There was a positive relationship between daily signalling rates and life span, and an increase in signalling level by one unit over all times was associated with an approximately 50% decrease in mortality rate. Signalling rates early in adult life (day 6–20) were higher in the longest-lived than in the shortest-lived flies. These results support the hypothesis that intense sexual signalling indicates longer life span. We discuss the importance of age-specific behavioural studies for understanding the evolution of male life histories.     

Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5

AIMS: New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, and hypercholesterolemia that resembles the human metabolic syndrome. This study was performed in order to locate genes responsible for elevated serum cholesterol and to compare their effects under a standard and high fat diet.METHODS: A backcross population of NZO with SJL mice (NZO x F1(SJL x NZO)) was generated. Mice were raised on a normal or high fat diet and were monitored for 22 weeks (body weight, serum cholesterol, and blood glucose). A genome-wide scan was performed by genotyping of approximately 200 polymorphic microsatellite markers by PCR and linkage analysis was performed with the MAPMAKER program.RESULTS: In the genome-wide scan, a single susceptibility locus for hypercholesterolemia (Chol1/NZO, maximum LOD score 14.5 in a combined population of 523 backcross mice) was identified on chromosome 5. Cholesterol levels were significantly elevated in both male and female homozygous carriers of the Chol1/NZO allele. The locus maps 40cM distal of the previously described obesity locus Nob1 in the vicinity of the marker D5Mit244 and in the vicinity of hypercholesterolemia QTL previously identified in the NZB, CAST, and C57BL/6J strains. Chol1/NZO was not associated with elevated body weight, serum insulin, or hyperglycemia. The high fat diet significantly increased serum cholesterol levels, but the fat content of the diet did not alter the absolute effect of Chol1/NZO.Conclusions: Chol1/NZO is a major susceptibility locus on the distal mouse chromosome 5, which produces gender-independent hypercholesterolemia in NZO mice. The effect of Chol1/NZO was independent of the dietary fat content and was not associated with the other traits of the metabolic syndrome. Thus, it is suggested that the responsible gene might be involved in cholesterol metabolism.     

Ligand crowding at a nascent signal sequence

We have systematically analyzed the molecular environment of the signal sequence of a growing secretory protein from Escherichia coli using a stage- and site-specific cross-linking approach. Immediately after emerging from the ribosome, the signal sequence of pOmpA is accessible to Ffh, the protein component of the bacterial signal recognition particle, and to SecA, but it remains attached to the surface of the ribosome via protein L23. These contacts are lost upon further growth of the nascent chain, which brings the signal sequence into sole proximity to the chaperone Trigger factor (TF). In its absence, nascent pOmpA shows extended contacts with L23, and even long chains interact in these conditions proficiently with Ffh. Our results suggest that upon emergence from the ribosome, the signal sequence of an E. coli secretory protein gradually becomes sequestered by TF. Although TF thereby might control the accessibility of pOmpA's signal sequence to Ffh and SecA, it does not influence interaction of pOmpA with SecB.