Doron Lancet

Protocells at life’s origin are often conceived as bilayer-enclosed precursors of life, whose self-reproduction rests on the early advent of replicating catalytic biopolymers. This Perspective describes an alternative scenario, wherein reproducing nanoscopic lipid micelles with catalytic capabilities were forerunners of biopolymer-containing protoc...

“The Lipid World” was published in 2001, stemming from a highly effective collaboration with David Deamer during a sabbatical year 20 years ago at the Weizmann Institute of Science in Israel. The present review paper highlights the benefits of this scientific interaction and assesses the impact of the lipid world paper on the present understanding...

Life is that which replicates and evolves, but there is no consensus on how life emerged. We advocate a systems protobiology view, whereby the first replicators were assemblies of spontaneously accreting, heterogeneous and mostly non-canonical amphiphiles. This view is substantiated by rigorous chemical kinetics simulations of the graded autocataly...

We studied the simulated replication and growth of prebiotic vesicles composed of 140 phospholipids and cholesterol using our R-GARD (Real Graded Autocatalysis Replication Domain) formalism that utilizes currently extant lipids that have known rate constants of lipid-vesicle interactions from published experimental data. R-GARD normally modifies ki...

We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare seg...

Background A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant-harboring genes are associated with a patient’s disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include Gene...

A major challenge in understanding gene regulation is the unequivocal identification of enhancer elements and uncovering their connections to genes. We present GeneHancer, a novel database of human enhancers and their inferred target genes, in the framework of GeneCards. First, we integrated a total of 434 000 reported enhancers from four different...

The MalaCards human disease database (http://www.malacards.org/) is an integrated compendium of annotated diseases mined from 68 data sources. MalaCards has a web card for each of ∼20 000 disease entries, in six global categories. It portrays a broad array of annotation topics in 15 sections, including Summaries, Symptoms, Anatomical Context, Drugs...

The study of human diseases is at the core of present-day biological research. It is an interdisciplinary effort encompassing genomics, bioinformatics, systems biology, and systems medicine. Currently, many efforts are being made to elucidate the genetic underpinnings of human diseases. A consequence thereof is that many different sources use diffe...

We present here an exploration of the evolution of three well-established, web-based resources dedicated to the dissemination of information related to olfactory receptors (ORs) and their functional ligands, odorants. These resources are: the Olfactory Receptor Database (ORDB), the Human Olfactory Data Explorer (HORDE) and ODORactor. ORDB is a repo...

Background Olfaction is a versatile sensory mechanism for detecting thousands of volatile odorants. Although molecular basis of odorant signaling is relatively well understood considerable gaps remain in the complete charting of all relevant gene products. To address this challenge, we applied RNAseq to four well-characterized human olfactory epith...

Background Next generation sequencing (NGS) provides a key technology for deciphering the genetic underpinnings of human diseases. Typical NGS analyses of a patient depict tens of thousands non-reference coding variants, but only one or very few are expected to be significant for the relevant disorder. In a filtering stage, one employs family segre...

GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experienc...

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part...

rs17315309 genotyping. 1 Risk allele G. 2 Patients of Jewish extraction. 3 Chi-squared test. (DOCX)

CNBD2 does not promote PV serum-induced cell-cell disadhesion. NHEKs were transfected with a ST18 expression vector (ST18), with a control vector (EV) or with a CNBD2 expression vector (CNBD2) and were grown to confluency in the presence of PV serum or control serum. Epidermal sheets were released from the tissue plates and subjected to mechanical...

Correlation between anti-Dsg3 ELISA status of and ST18 genotype. EUROIMMUN anti-Desmoglein 3 ELISA (IgG) test kit was used to determine Dsg3 antibody titers in PV patient serum (n = 43). A cut-off of 20 RU/ml was used to demarcate patients with high or low Dsg3 reactivity. No correlation was found between Dsg3 reactivity and rs17315309 genotype (Ch...

Linkage disequilibrium plot at the ST18 locus. Linkage disequilibrium (LD) values were generated using the Haploview software. LD levels between the various single-nucleotide polymorphisms across this region are represented by variations in the color of the squares, increasing from white (minimal LD) to bright red (maximal LD). Using deep sequencin...

Efficiency of TP53 or TP63 knock down and ST18 overexpression. (a,b) TP53, TP63 expression in keratinocytes transfected with either TP53 siRNA (si-p53), TP63 siRNA (si-p63) or control siRNA (si-Cont) was measured using qRT-PCR. (c) ST18 expression in keratinocytes transfected with either ST18 expression vector (ST18) or empty control vector (vector...

GeneCards is a one-stop shop for searchable human gene annotations (http://www.genecards.org/). Data are automatically mined from ∼120 sources and presented in an integrated web card for every human gene. We report the application of recent advances in proteomics to enhance gene annotation and classification in GeneCards. First, we constructed the...

Postgenomics data are produced in large volumes by life sciences and clinical applications of novel omics diagnostics and therapeutics for precision medicine. To move from "data-to-knowledge-to-innovation," a crucial missing step in the current era is, however, our limited understanding of biological and clinical contexts associated with data. Prom...

Congenital general anosmia (CGA) is a neurological disorder entailing a complete innate inability to sense odors. While the mechanisms underlying vertebrate olfaction have been studied in detail, there are still gaps in our understanding of the molecular genetic basis of innate olfactory disorders. Applying whole-exome sequencing to a family multip...

Background: TECPR2 was first described as a disease causing gene when the c.3416delT frameshift mutation was found in five Jewish Bukharian patients with similar features. It was suggested to constitute a new subtype of complex hereditary spastic paraparesis (SPG49). Results: We report here 3 additional patients from unrelated non-Bukharian fami...

Diabetic nephropathy, as the most prevalent chronic disease of the kidney, has also become the primary cause of end-stage renal disease with the incidence of kidney disease in type 2 diabetics continuously rising. As with most chronic diseases, the pathophysiology is multifactorial with a number of deregulated molecular processes contributing to di...

The study of biological pathways is key to a large number of systems analyses. However, many relevant tools consider a limited number of pathway sources, missing out on many genes and gene-to-gene connections. Simply pooling several pathways sources would result in redundancy and the lack of systematic pathway interrelations. To address this, we ex...

Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identifica...

Background The quasispecies model refers to information carriers that undergo self-replication with errors. A quasispecies is a steady-state population of biopolymer sequence variants generated by mutations from a master sequence. A quasispecies error threshold is a minimal replication accuracy below which the population structure breaks down. Theo...

Systems medicine provides insights into mechanisms of human diseases, and expedites the development of better diagnostics and drugs. To facilitate such strategies, we initiated MalaCards, a compendium of human diseases and their annotations, integrating and often remodeling information from 64 data sources. MalaCards employs, among others, the prov...

Present life portrays a two-tier phenomenology: molecules compose supramolecular structures, such as cells or organisms, which in turn portray population behaviors, including selection, evolution and ecological dynamics. Prebiotic models have often focused on evolution in populations of self-replicating molecules, without explicitly invoking the in...

Abstract Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies...

The Model Organism Protein Expression Database (MOPED, http://moped.proteinspire.org ) is an expanding proteomics resource to enable biological and biomedical discoveries. MOPED aggregates simple, standardized and consistently processed summaries of protein expression and metadata from proteomics (mass spectrometry) experiments from human and model...

Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies can only...

We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein ab...

Background / Purpose: MalaCards is a compendium of human maladies (1). MalaCards merges a variety of sources to produce a comprehensive web card for each disease. Main conclusion: MalaCards is a proficient research tool.

Olfactory receptors (ORs) constitute the largest gene family in the mammalian genome. The existence of these proteins underlies the nature of, and variability in, odorant perception. The Human Olfactory Receptor Data Explorer (HORDE, http://genome.weizmann.ac.il/horde/ ) is a free online resource, which presents a complete compendium of all OR gene...

A network of biological databases is reviewed, supplying a framework for studies of human genes and the association of their genomic variations with human phenotypes. The network is composed of GeneCards, the human gene compendium, which provides comprehensive information on all known and predicted human genes, along with its suite members GeneDeck...

Autophagy dysfunction has been implicated in a group of progressive neurodegenerative diseases, and has been reported to play a major role in the pathogenesis of these disorders. We have recently reported a recessive mutation in TECPR2, an autophagy-implicated WD repeat-containing protein, in five individuals with a novel form of monogenic heredita...

Comprehensive disease classification, integration and annotation are crucial for biomedical discovery. At present, disease compilation is incomplete, heterogeneous and often lacking systematic inquiry mechanisms. We introduce MalaCards, an integrated database of human maladies and their annotations, modeled on the architecture and strategy of the G...

Genetic variations in olfactory receptors likely contribute to the diversity of odorant-specific sensitivity phenotypes. Our working hypothesis is that genetic variations in auxiliary olfactory genes, including those mediating transduction and sensory neuronal development, may constitute the genetic basis for general olfactory sensitivity (GOS) and...

We propose an automaton, a theoretical framework that demonstrates how to improve the yield of the synthesis of branched chemical polymer reactions. This is achieved by separating substeps of the path of synthesis into compartments. We use chemical containers (chemtainers) to carry the substances through a sequence of fixed successive compartments....

We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified o...

Motivation: Non-coding RNA (ncRNA) genes are increasingly acknowledged for their importance in the human genome. However, there is no comprehensive non-redundant database for all such human genes. Results: We leveraged the effective platform of GeneCards, the human gene compendium, together with the power of fRNAdb and additional primary sources...

In this paper we explore the question of whether there is an optimal set up for a putative prebiotic system leading to open-ended evolution (OEE) of the events unfolding within this system. We do so by proposing two key innovations. First, we introduce a new index that measures OEE as a function of the likelihood of events unfolding within a univer...

Information on nucleotide diversity along completely sequenced human genomes has increased tremendously over the last few years. This makes it possible to reassess the diversity status of distinct receptor proteins in different human individuals. To this end, we focused on the complete inventory of human olfactory receptor coding regions as a model...

Figures S1-S9, Table S1, Table S2, Table S3.

A List of duplications and inversions in the OR genes.

OR protein haplotypes. Haplotypes are represented by their segregating positions (fourth column) where 0 is reference-genome allele and 1 is non-reference allele. Segregating position names are composed from the chromosome name, genomic coordinate, reference amino-acid, protein position and non-reference amino-acid.

A list of nonfunctional variations in the OR genes.

OR intact loci for with bi-allelic deletion allele.

Considerable evidence supports the idea that odorant recognition depends on specific sequence variations in olfactory receptor (OR) proteins. Much of this emerges from in vitro screens in heterogenous expression systems. However, the ultimate proof should arise from measurements of odorant thresholds in human individuals harboring different OR gene...

It is widely accepted that autocatalysis constitutes a crucial facet of effective replication and evolution (e.g., in Eigen's hypercycle model). Other models for early evolution (e.g., by Dyson, Gánti, Varela, and Kauffman) invoke catalytic networks, where cross-catalysis is more apparent. A key question is how the balance between auto- (self-) and...

Paenibacillus dendritiformis is a Gram-positive, soil-dwelling, spore-forming social microorganism. An intriguing collective faculty of this strain is manifested by its ability to switch between different morphotypes, such as the branching (T) and the chiral (C) morphotypes. Here we report the 6.3-Mb draft genome sequence of the P. dendritiformis C...

Many reports in different populations have demonstrated linkage of the 10q24-q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24-q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple...

Detailed description of clinical sample and diagnostic methods. (DOC)

The top results for association with schizophrenia (p<1×10−3) in the 10q24-26 region, by using the dominant model. P-values, allelic frequencies and Hardy Weinberg equilibrium were obtained using PBAT. Abbreviations: HW = Hardy Weinberg equilibrium; Allele = minor allele; Freq = minor allele frequency. (DOC)

The top results for association with schizophrenia (p<1×10−3) in the 10q24-26 region, by using the additive model (adapted from Alkelai et al, 2011 [11]). P-values were obtained using PBAT. The overlapping best results (p<1×10−3) with the dominant model are represented in bold. (DOC)

Large numbers of mass spectrometry proteomics studies are being conducted to understand all types of biological processes. The size and complexity of proteomics data hinders efforts to easily share, integrate, query and compare the studies. The Model Organism Protein Expression Database (MOPED, htttp://moped.proteinspire.org) is a new and expanding...

Since 1998, the bioinformatics, systems biology, genomics and medical communities have enjoyed a synergistic relationship with the GeneCards database of human genes (http://www.genecards.org). This human gene compendium was created to help to introduce order into the increasing chaos of information flow. As a consequence of viewing details and deep...

We present a new embodiment of the graded autocatalysis replication domain (GARD) for the growth, replication and evolution of lipid vesicles based on a semi-empirical foundation using experimentally measured kinetic values of selected extant lipid species. Extensive simulations using this formalism elucidated the details of the dependence of the r...

While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide li...

We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensi...

It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a ch...

For diseases with complex phenotype such as diabetic nephropathy (DN), integration of multiple Omics sources promises an improved description of the disease pathophysiology, being the basis for novel diagnostics and therapy, but equally important personalization aspects. Molecular features on DN were retrieved from public domain Omics studies and b...

Technological Omics breakthroughs, including next generation sequencing, bring avalanches of data which need to undergo effective data management to ensure integrity, security, and maximal knowledge-gleaning. Data management system requirements include flexible input formats, diverse data entry mechanisms and views, user friendliness, attention to...

The pattern-forming bacterium Paenibacillus vortex is notable for its advanced social behavior, which is reflected in development of colonies with highly intricate architectures. Prior to this study, only two other Paenibacillus species (Paenibacillus sp. JDR-2 and Paenibacillus larvae) have been sequenced. However, no genomic data is available on...

Detailed supplementary information. This file includes additional information on P. vortex physiology, comparison of sequencing methods, validation of P. vortex annotation and materials and methods.

Early stage of colony organization including the formation of vortices and moving groups of bacteria. The magnification is 50× magnification and 60× rate.

Dynamic imaging of swarming by light microscopy. Single branch of a swarming culture moving on MH (1.5% w/v) agar is presented. Magnification 400× and 4 times the actual speed.

A subset of 50 soil bacterial genomes with genome size 4-8 Mbp (closer to the P. vortex genome size), that were used in the comparative genome analysis.

Effect of extracellular material derived from plates containing swarming cells on P. vortex swarming. Light microscopy of P. vortex moving on MH agar (0.3% w/v), extending into an area where extracellular material derived from washes of swarming cells was delivered by toothpick and allowed to soak into the agar. (A) Cell mass starts to disperse as...

A compiled list of Pfam domains that was used to identify Two-Component System genes is presented.

Movement of a single vortex, 500× magnification and twice the real speed.

Effect of number of extracellular materials derived from plates containing swarming cells on P. vortex swarming. Light microscopy of P. vortex moving on MH agar (0.3% w/v), extending into an area where extracellular material derived from washes of swarming cells. (A) Cell mass is evaluating the gradient and starts move towards the area with the ext...

A set of 500 complete bacterial genomes of 2-10 Mbp genome size, which were used in the detailed comparative genomic analysis with the P. vortex genome.

List of conserved PFAM domains, TIGR domains, COG categories or KEGG pathways associated with sporulation that were used in identification of sporularion genes in P. vortex.

A compiled list of Pfam domains that was used to identify Transcription Factor genes is presented.

A compiled list of COG categories that was used to identify defense related genes is presented.

List of 153 sporulation genes encoded by the P. vortex genome that are responsible for cell division, engulfment, cortex and coat synthesis, maturation and germination processes.

A compiled list of COG categories that was used to identify transport related genes is presented.

False discovery rate (FDR) threshold in the initial CNV identification step. The figure displays the recall rate for 11 OR loci on the X-chromosome, which were assessed in 57 male samples as a function of different Q-value (FDR) cutoffs in CopySeq's CNV identification step (see Materials and Methods). The recall rate was calculated, assuming that O...

Enrichment of segmental duplications in high copy-number genotype calls. Fraction of 118,650 (791 autosomal loci times 150 samples) OR copy-number genotype calls intersecting annotated SDs (i.e., assessed by requiring a > = 51% overlap of the OR locus with SDs, based on the UCSC genome browser track ‘Segmental Dups’) (0.24 MB TIF)

Approximately linear dependency between locus copy-number and read-depth ratio. This figure shows the distribution of adjusted read-depth ratios for 99 CNV loci on chromosome 1 among 118 individuals for which we had prior information in terms of copy-number genotype assignments [2], i.e., individual densities were generated by using the previously...

Outcomes copy-number genotyping integrated with paired-end mapping on chromosome 1 benchmark set. (0.04 MB DOC)

Concordance of CopySeq copy-number genotypes and copy-number genotypes from the microarray-based study by Conrad et al. Comparison of >7,000 CopySeq-based locus copy-number assignments in OR loci with microarray-based copy-number genotypes from Conrad and co-workers [1]. The comparison is based on 51 OR loci, assessed in 149 individuals. Circle siz...

Locus-specific genotyping concordance for 500 benchmark CNVs on chromosome 1. The plots show the locus-specific genotyping concordance for 99 CNV loci on chromosome 1 taken from McCarroll et al. (A) and 401 CNV loci on chromosome 1 taken from Conrad et al. (B). Values are sorted by increasing concordance. While the vast majority of loci showed high...

Table of copy-number genotype calls in 150 samples and 808 OR loci. (0.81 MB XLS)

Summary of detected CNVs affecting OR loci. (0.03 MB DOC)

Poisson variance over-dispersion before and after G+C-content normalization. Boxplot of Poisson variance over-dispersion as assessed by control regions in 170 samples before (‘Pre’) and after (‘Post’) G+C content bias correction. Over-dispersion is defined as the n-fold variance as compared to the theoretical variance expected from random sequencin...

Principal component analysis (PCA) on 265 bi-allelic OR loci and 150 individuals. Population-specific copy-number variation of OR loci displayed by principle component analysis (PCA). PCA analysis was carried out on 265 bi-allelic OR loci in 150 individuals explaining 39% of the total variance (PC1 = 18.9%; PC2 = 12.6%; PC3 = 7.5%). Individuals are...