Biomedical subjects

Dan Geiger

Publications and source records attributed to Dan Geiger.

9 recordsLinked to original sources

PubMed2005

A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma.

Neurocutaneous syndromes represent a vast, largely heterogeneous group of disorders characterized by neurological and dermatological manifestations, reflecting the common embryonic origin of epidermal and neural tissues. In the present report, we describe a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK syndrome). Using homozygosity mapping in two large families, we localized the disease gene to 22q11.2 and identified, in all patients, a 1-bp deletion in SNAP29, which codes for a SNARE protein involved in vesicle fusion. SNAP29 expression was decreased in the skin of the patients, resulting in abnormal maturation of lamellar granules and, as a consequence, in mislocation of epidermal lipids and proteases. These data underscore the importance of vesicle trafficking regulatory mechanisms for proper neuroectodermal differentiation.

Antigens, Polyomavirus Transforming↗

PubMed2005

Finding approximate tandem repeats in genomic sequences.

An efficient algorithm is presented for detecting approximate tandem repeats in genomic sequences. The algorithm is based on a flexible statistical model which allows a wide range of definitions of approximate tandem repeats. The ideas and methods underlying the algorithm are described and its effectiveness on genomic data is demonstrated.

Algorithms↗

PubMed2005

Identification of a novel locus associated with congenital recessive ichthyosis on 12p11.2-q13.

Congenital recessive ichthyoses represent a vast and markedly heterogeneous group of diseases that have been mapped to at least seven distinct chromosomal loci. In this study, we ascertained two consanguineous families presenting with congenital ichthyosis. Using homozygosity mapping, we identified a 6.5 cM homozygous region on 12p11.2-q13 shared by all affected individuals. Multipoint logarithm of odds ratio (LOD) score analysis placed the new locus between markers D12S345 and D12S390 with a maximum LOD score of 4.79 at marker CH12SSR13. This region harbors PPHLN1, encoding periphilin 1, a protein involved in the cornification process. No deleterious mutations were identified within the coding region of this gene, suggesting the existence of another gene associated with epidermal differentiation on 12p11.2-q13.

Antigens, Neoplasm↗

PubMed2005

Polyadenylation and degradation of human mitochondrial RNA: the prokaryotic past leaves its mark.

RNA polyadenylation serves a purpose in bacteria and organelles opposite from the role it plays in nuclear systems. The majority of nucleus-encoded transcripts are characterized by stable poly(A) tails at their mature 3' ends, which are essential for stabilization and translation initiation. In contrast, in bacteria, chloroplasts, and plant mitochondria, polyadenylation is a transient feature which promotes RNA degradation. Surprisingly, in spite of their prokaryotic origin, human mitochondrial transcripts possess stable 3'-end poly(A) tails, akin to nucleus-encoded mRNAs. Here we asked whether human mitochondria retain truncated and transiently polyadenylated transcripts in addition to stable 3'-end poly(A) tails, which would be consistent with the preservation of the largely ubiquitous polyadenylation-dependent RNA degradation mechanisms of bacteria and organelles. To this end, using both molecular and bioinformatic methods, we sought and revealed numerous examples of such molecules, dispersed throughout the mitochondrial genome. The broad distribution but low abundance of these polyadenylated truncated transcripts strongly suggests that polyadenylation-dependent RNA degradation occurs in human mitochondria. The coexistence of this system with stable 3'-end polyadenylation, despite their seemingly opposite effects, is so far unprecedented in bacteria and other organelles.

3' Untranslated Regions↗

PubMed2005

Maximum likelihood haplotyping for general pedigrees.

Haplotype data is valuable in mapping disease-susceptibility genes in the study of Mendelian and complex diseases. We present algorithms for inferring a most likely haplotype configuration for general pedigrees, implemented in the newest version of the genetic linkage analysis system SUPERLINK. In SUPERLINK, genetic linkage analysis problems are represented internally using Bayesian networks. The use of Bayesian networks enables efficient maximum likelihood haplotyping for more complex pedigrees than was previously possible. Furthermore, to support efficient haplotyping for larger pedigrees, we have also incorporated a novel algorithm for determining a better elimination order for the variables of the Bayesian network. The presented optimization algorithm also improves likelihood computations. We present experimental results for the new algorithms on a variety of real and semiartificial data sets, and use our software to evaluate MCMC approximations for haplotyping.

Algorithms↗

PubMed2004

Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13.

We have recently described a novel autosomal recessive disorder, lethal congenital contractural syndrome type 2 (LCCS2) (OMIM 607598), in a large Israeli Bedouin kindred. The phenotype, which is lethal in the neonatal period, is distinguished by the presence of a markedly distended urinary bladder. Association of LCCS2 to the known loci associated with arthogryposis was excluded. In the present study, we set out to determine the genetic locus harboring the gene defective in this disease. We performed genome-wide linkage analysis, demonstrating linkage to a approximately 6 cM (corresponding to approximately 7.2 Mb) homozygosity region on chromosome 12q13 between markers D12S1604 and D12S83. Based on recombination events, the interval harboring the disease-associated locus was further narrowed to a region spanning approximately 6 cM ( approximately 6.4 Mb) between D12S325 and D12S1072. Linkage of LCCS2 to that locus was established, with two significant maximum peaks at markers D12S1604 (Z(max) = 10.56 at theta = 0.01) and D12S1700 (Z(max) = 9.23 at theta = 0.00).

Chromosome Mapping↗

PubMed2004

Efficient approximations for learning phylogenetic HMM models from data.

MOTIVATION: We consider models useful for learning an evolutionary or phylogenetic tree from data consisting of DNA sequences corresponding to the leaves of the tree. In particular, we consider a general probabilistic model described in Siepel and Haussler that we call the phylogenetic-HMM model which generalizes the classical probabilistic models of Neyman and Felsenstein. Unfortunately, computing the likelihood of phylogenetic-HMM models is intractable. We consider several approximations for computing the likelihood of such models including an approximation introduced in Siepel and Haussler, loopy belief propagation and several variational methods. RESULTS: We demonstrate that, unlike the other approximations, variational methods are accurate and are guaranteed to lower bound the likelihood. In addition, we identify a particular variational approximation to be best-one in which the posterior distribution is variationally approximated using the classic Neyman-Felsenstein model. The application of our best approximation to data from the cystic fibrosis transmembrane conductance regulator gene region across nine eutherian mammals reveals a CpG effect.

Algorithms↗

PubMed2004

Model-based inference of haplotype block variation.

The haplotype block structure of SNP variation in human DNA has been demonstrated by several recent studies. The presence of haplotype blocks can be used to dramatically increase the statistical power of genetic mapping. Several criteria have already been proposed for identifying these blocks, all of which require haplotypes as input. We propose a comprehensive statistical model of haplotype block variation and show how the parameters of this model can be learned from haplotypes and/or unphased genotype data. Using real-world SNP data, we demonstrate that our approach can be used to resolve genotypes into their constituent haplotypes with greater accuracy than previously known methods.

Algorithms↗

PubMed2004

Optimizing exact genetic linkage computations.

Genetic linkage analysis is a challenging application which requires Bayesian networks consisting of thousands of vertices. Consequently, computing the probability of data, which is needed for learning linkage parameters, using exact computation procedures calls for an extremely efficient implementation that carefully optimizes the order of conditioning and summation operations. In this paper, we present the use of stochastic greedy algorithms for optimizing this order. Our algorithm has been incorporated into the newest version of SUPERLINK, which is a fast genetic linkage program for exact likelihood computations in general pedigrees. We demonstrate an order of magnitude improvement in run times of likelihood computations using our new optimization algorithm and hence enlarge the class of problems that can be handled effectively by exact computations.

Algorithms↗