Liran Carmel

• Hebrew University of Jerusalem

Recent advances in ancient DNA extraction and high-throughput sequencing technologies enabled the high-quality sequencing of archaic genomes, including the Neanderthal and the Denisovan. While comparisons with modern humans revealed both archaic-specific and human-specific sequence changes, in the absence of gene expression information, understandi...

We report genome-wide DNA data for 73 individuals from five archaeological sites across the Bronze and Iron Ages Southern Levant. These individuals, who share the “Canaanite” material culture, can be modeled as descending from two sources: (1) earlier local Neolithic populations and (2) populations related to the Chalcolithic Zagros or the Bronze A...

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chim...

High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, archaic humans, and chimpanzees revealed 87...

The 3’-end of the coding sequence in several species is known to show specific codon usage bias. Several factors have been suggested to underlie this phenomenon, including selection against translation efficiency, selection for translation accuracy, and selection against RNA folding. All are supported by some evidence, but there is no general agree...

Regulatory changes are broadly accepted as key drivers of phenotypic divergence. However, identifying regulatory changes that underlie human-specific traits has proven very challenging. Here, we use 63 DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that emerged in m...

DNA is a central component in the cells of all living organisms, which contains information that is critical for building the body and maintaining its biological processes. Today, owing to new technological developments, scientists can obtain DNA directly from remains of humans and other organisms that died a long time ago. The ability to read anci...

MicroRNAs (miRNAs) are short non-coding RNAs that negatively regulate the expression and translation of genes in healthy and diseased tissues. Herein, we characterize short RNAs from human HeLa cells found in the supraspliceosome, a nuclear dynamic machine in which pre-mRNA processing occurs. We sequenced small RNAs (<200 nt) extracted from the sup...

In mammals, transposable elements are largely silenced, but under fortuitous circumstances may be co-opted to play a functional role. Here, we show that when Alu elements are inserted within or nearby genes in sense orientation, they may contribute to the transcriptome diversity by forming new cleavage and polyadenylation sites. We mapped these new...

Primate-specific Alu short interspersed elements (SINEs) as well as rodent-specific B and ID (B/ID) SINEs can promote Staufen-mediated decay (SMD) when present in mRNA 3'-untranslated regions (3'-UTRs). The transposable nature of SINEs, their presence in long noncoding RNAs, their interactions with Staufen, and their rapid divergence in different e...

Analyzing the conditions in which past individuals lived is key to understanding the environments and cultural transitions to which humans had to adapt. Here, we suggest a methodology to probe into past environments, using reconstructed premortem DNA methylation maps of ancient individuals. We review a large body of research showing that differenti...

Many human introns carry out a function, in the sense that they are critical to maintain normal cellular activity. Their identification is fundamental to understanding cellular processes and disease. However, being noncoding elements, such functional introns are poorly predicted based on traditional approaches of sequence and structure conservation...

One of the biggest challenges in studying how genes work is understanding their effect on the physiology and anatomy of the body. Existing tools try to address this using indirect features, such as expression levels and biochemical pathways. Here, we present Gene ORGANizer (geneorganizer.huji.ac.il), a phenotype-based tool that directly links human...

One of the biggest challenges in studying how genes work is understanding their effect on the physiology and anatomy of the body. Existing tools try to address this using indirect features, such as expression levels and biochemical pathways. Here, we present Gene ORGANizer (geneorganizer.huji.ac.il), a phenotype-based tool that directly links human...

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using SNP chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likel...

Background It is not fully understood how a termination codon is recognized as premature (PTC) by the nonsense-mediated decay (NMD) machinery. This is particularly true for transcripts lacking an exon junction complex (EJC) along their 3’ untranslated region (3’UTR), and thus degrade through the EJC-independent NMD pathway. ResultsHere, we analyzed...

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using SNP chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likel...

Recent years have witnessed the rise of ancient DNA (aDNA) technology, allowing comparative genomics to be carried out at unprecedented time resolution. While it is relatively straightforward to use aDNA to identify recent genomic changes, it is much less clear how to utilize it to study changes in epigenetic regulation. Here we review recent works...

Recessive CRB2 mutations were recently reported to cause both steroid resistant nephrotic syndrome and prenatal onset ventriculomegaly with kidney disease. We report two Ashkenazi Jewish siblings clinically diagnosed with ciliopathy. Both presented with severe congenital hydrocephalus and mild urinary tract anomalies. One affected sibling also has...

RNA-seq is becoming a preferred tool for genomics studies of model and non-model organisms. However, DNA-based analysis of organisms lacking sequenced genomes cannot rely on RNA-seq data alone to isolate most genes of interest, as DNA codes both exons and introns. With this in mind, we designed a novel tool, LEMONS, that exploits the evolutionary c...

Intron positions upon the mRNA transcript are sometimes remarkably conserved even across distantly related eukaryotic species. This has made the comparison of intron–exon architectures across orthologous transcripts a very useful tool for studying various evolutionary processes. Moreover, the wide range of functions associated with introns may conf...

Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mu...

Ancient DNA sequencing has recently provided high-coverage archaic human genomes. However, the evolution of epigenetic regulation along the human lineage remains largely unexplored. We reconstructed the full DNA methylation maps of the Neandertal and the Denisovan by harnessing the natural degradation processes of methylated and unmethylated cytosi...

An appreciable fraction of introns is thought to have some function, but there is no obvious way to predict which specific intron is likely to be functional. We hypothesize that functional introns experience a different selection regime than non-functional ones and will therefore show distinct evolutionary histories. In particular, we expect functi...

Frequency of the editing statuses. (blue) human subjects with major depression; (cyan) normal human controls; (orange) transacted rats; (red) normal rat controls. (DOC)

a) AIC score, and b) Bayesian score for human models to . The pDAGs associated with each model are identical to those obtained by the BIC score (Figure 2). (DOC)

pDAG for the rat model. a) as obtained from the BIC and from the Bayes scores; b) as obtained from the AIC score. The difference is in the single edge connecting C to D in the BIC and Bayes scores, which is replaced by an edge connecting C and E in the AIC score. (DOC)

Level of support of each edge in all individual best-fitting models with fixed number of edges. The results are for Bayes scores in human. (DOC)

Level of support of each edge in all individual best-fitting models with fixed number of edges. The results are for AIC scores in rat. (DOC)

Number and composition of the mRNA molecules collected for human and rat. (DOC)

The -coefficient between the editing sites for (a) human, and (b) rat. All coefficients are significant (FDR corrected), except for the pair (D,E) in human and (A,E) in rat. Errors are standard deviations. (DOC)

The estimated parameters of the best-fitting models in rat. The models are shown in Figure 3. (XLS)

a) AIC score, and b) Bayesian score for rat models to . The pDAGs associated with each model are identical to those obtained by the BIC score (Figure 3), except for the model under the AIC scores, which is depicted in Figure S5. (DOC)

Level of support of each edge in all individual best-fitting models with fixed number of edges. The results are for AIC scores in human. (DOC)

Level of support of each edge in all individual best-fitting models with fixed number of edges. The results are for Bayes scores in rat. (DOC)

The estimated parameters of the best-fitting models in human. The models are shown in Figure 2. (XLS)

Statistics on the individual best-models for AIC scores in human. The statistics for AIC is very similar to BIC, and we report here only those models for which the AIC scores behave differently from the BIC scores (changes are in red). The models are shown in Figure 3. (DOC)

Clustering of the five editing sites using Dice distance. (a) human; (b) rat. (DOC)

Statistics on the individual best-models for Bayes scores in human. The statistics for Bayes score is very similar to BIC, and we report here only those models for which the Bayes scores behave differently from the BIC scores (changes are in red). (DOC)

Statistics on the individual best-models for BIC scores in rat. For each family of models with the same number of edges, we report all significantly enriched best-models found among all 19 individuals. The ID of the model is its rank (asterisk marks the best model found in the pooled analysis, see Figure 3). The support is the number of individuals...

Statistics on the individual best-models for AIC scores in rat. The statistics for AIC is very similar to BIC, and we report here only those models for which the AIC scores behave differently from the BIC scores (changes are in red). (DOC)

Statistics on the individual best-models for Bayes scores in rat. The statistics for Bayes score is very similar to BIC, and we report here only those models for which the Bayes scores behave differently from the BIC scores (changes are in red). (DOC)

The serotonin 2C receptor (5-HT(2C)R)-a key regulator of diverse neurological processes-exhibits functional variability derived from editing of its pre-mRNA by site-specific adenosine deamination (A-to-I pre-mRNA editing) in five distinct sites. Here we describe a statistical technique that was developed for analysis of the dependencies among the e...

Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic...

Evolution of exon-intron structure of eukaryotic genes has been a matter of long-standing, intensive debate. The introns-early concept, later rebranded 'introns first' held that protein-coding genes were interrupted by numerous introns even at the earliest stages of life's evolution and that introns played a major role in the origin of proteins by...

The intron–exon architecture of many eukaryotic genes raises the intriguing question of whether this unique organization serves any function, or is it simply a result of the spread of functionless introns in eukaryotic genomes. In this review, we show that introns in contemporary species fulfill a broad spectrum of functions, and are involved in vi...

XX female gonadal dysgenesis (XX-GD) is a rare, genetically heterogeneous disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads. Most cases are unexplained but thought to be autosomal recessive. We elucidated the genetic basis of XX...

Intron density is highly variable across eukaryotic species. It seems that different lineages have experienced considerably different levels of intron gain and loss events, but the reasons for this are not well known. A large number of mechanisms for intron loss and gain have been suggested, and most of them have at least some level of indirect sup...

We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia’s genes have no detectable homologs in any other available proteome, and the m...

We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia’s genes have no detectable homologs in any other available proteome, and the m...

Evolutionary binary characters are features of species or genes, indicating the absence (value zero) or presence (value one) of some property. Examples include eukaryotic gene architecture (the presence or absence of an intron in a particular locus), gene content, and morphological characters. In many studies, the acquisition of such binary charact...

Analysis of gene architecture and expression levels of four organisms, Homo sapiens, Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana, reveals a surprising, nonmonotonic, universal relationship between expression level and gene compactness. With increasing expression level, the genes tend at first to become longer but, from...

Enteric neural crest-derived cells (ENCCs) migrate along the intestine to form a highly organized network of ganglia that comprises the enteric nervous system (ENS). The signals driving the migration and patterning of these cells are largely unknown. Examining the spatiotemporal development of the intestinal neurovasculature in avian embryos, we fi...

Spliceosomal introns are one of the principal distinctive features of eukaryotes. Nevertheless, different large-scale studies disagree about even the most basic features of their evolution. In order to come up with a more reliable reconstruction of intron evolution, we developed a model that is far more comprehensive than previous ones. This model...

To realize the promise of stem cell biology, it is important to identify the precise time in the history of the cell when developmental potential is restricted. To achieve this goal, we developed a real-time imaging system that captures the transitions in fate, generating neurons, astrocytes, and oligodendrocytes from single CNS stem cells in vitro...

Enteric neural crest-derived cells (ENCCs) migrate along the intestine to form a highly organized network of ganglia that comprises the enteric nervous system (ENS). The signals driving the directed migration of these cells are largely unknown. We examined the intestinal neurovasculature in avian embryos and find that endothelial cells are present...

Numerous eukaryotic proteins contain multiple domains. Certain domains show a tendency to occur in diverse domain architectures and can be considered "promiscuous." These promiscuous domains are, typically, involved in protein-protein interactions and play crucial roles in interaction networks, particularly those that contribute to signal transduct...

Time estimates of the nematodes-insects-vertebrates divergence.

Author Summary A key goal in biology is to identify specific ligands for specific receptors. One example is where the ligand is a drug. In turn, in the olfactory system the ligand is the odorant that binds to olfactory receptors. There are many olfactory receptor types, and which odorants will activate which receptors remains largely unknown. One...

We introduce a novel technique to determine the expression state of a gene from quantitative information measuring its expression. Adopting a productive abstraction from current thinking in molecular biology, we consider two expression states for a gene--Up or Down. We determine this state by using a statistical model that assumes the data behaves...

Rare genomic changes (RGCs) that are thought to comprise derived shared characters of individual clades are becoming an increasingly important class of markers in genome-wide phylogenetic studies. Recently, we proposed a new type of RGCs designated RGC_CAMs (after Conserved Amino acids-Multiple substitutions) that were inferred using genome-wide id...

The recent analysis of a novel class of rare genomic changes, RGC_CAMs (after conserved amino acids-multiple substitutions), supported the Coelomata clade of animals as opposed to the Ecdysozoa clade (Rogozin et al. 2007). A subsequent reanalysis, with the sequences from the sea anemone Nematostella vectensis included in the set of outgroup species...

Pattern-by-pattern analysis of parallel gains. The order of species in each pattern is Dicdi, Caeel, Strpu, Cioin, Danre, Galga, Homsa, Roden, Drome, Anoga, Cryne, Schpo, Sacce, Aspfu, Neucr, Arath, Orysa, Thepa, and Plafa. The frequency of a pattern is the number of times it was observed in our data.

The phylogenetic tree of eukaryotes used in the present study. Species and lineage abbreviations: Caeel (Caenorhabditis elegans), Strpu (Strongylocentrotus purpuratus), Cioin (Ciona intestinalis), Danre (Danio rerio), Galga (Gallus gallus), Homsa (Homo sapiens), roden (Mus musculus and Rattus norvegicus combined), Drome (Drosophila melanogaster), A...

Evolution of protein sequences is largely governed by purifying selection, with a small fraction of proteins evolving under positive selection. The evolution at synonymous positions in protein-coding genes is not nearly as well understood, with the extent and types of selection remaining, largely, unclear. A statistical test to identify purifying a...

7 Arrays of chemical sensors, known as electronic noses, yield a unique pattern for a given mixture of odors. Recently, there has been increasing interest in trying to mix odors such as to generate a desired response in the electronic nose. For the time being, this intriguing problem had been tackled only experimentally with the aid of specific app...

Introns that interrupt eukaryotic protein-coding sequences are generally thought to be nonfunctional. However, for reasons still poorly understood, positions of many introns are highly conserved in evolution. Previous reconstructions of intron gain and loss events during eukaryotic evolution used a variety of simplified evolutionary models that yie...

Several contrasting scenarios have been proposed for the origin and evolution of spliceosomal introns, a hallmark of eukaryotic genes. A comprehensive probabilistic model to obtain a definitive reconstruction of intron evolution was developed and applied to 391 sets of conserved genes from 19 eukaryotic species. It is inferred that a relatively hig...

As the number of sequenced genomes from diverse walks of life rapidly increases, phylogenetic analysis is entering a new era: reconstruction of the evolutionary history of organisms on the basis of full-scale comparison of their genomes. In addition to brute force, genome-wide analysis of alignments, rare genomic changes (RGCs) that are thought to...

The presence of introns in protein-coding genes is a universal feature of eukaryotic genome organization, and the genes of multicellular eukaryotes, typically, contain multiple introns, a substantial fraction of which share position in distant taxa, such as plants and animals. Depending on the methods and data sets used, researchers have reached op...

A u t h o r ' s p e r s o n a l c o p y Abstract The Lorentzian model is a powerful feature extraction technique for electronic noses. In a previous work, it was applied to single-peak transient signals and was shown to achieve lower classification error rate than other feature extraction techniques. Here, we generalize the Lorentzian model by show...

Haloacid dehalogenase (HAD)-like hydrolases are a vast superfamily of largely uncharacterized enzymes, with a few members shown to possess phosphatase, β-phosphoglucomutase, phosphonatase, and dehalogenase activities. Using a representative set of 80 phosphorylated substrates, we characterized the substrate specificities of 23 soluble HADs encoded...

Recent genome analyses revealed intriguing correlations between variables characterizing the functioning of a gene, such as expression level (EL), connectivity of genetic and protein-protein interaction networks, and knockout effect, and variables describing gene evolution, such as sequence evolution rate (ER) and propensity for gene loss. Typicall...

To identify the underlying gene expression profiles of unexplained chronic fatigue subjects classified into five or six class solutions by principal component (PCA) and latent class analyses (LCA). Microarray expression data were available for 15,315 genes and 111 female subjects enrolled from a population-based study on chronic fatigue syndrome. A...

In addition to multiple, complete genome sequences, genome-wide data on biological properties of genes, such as knockout effect, expression levels, protein-protein interactions, and others, are rapidly accumulating. Numerous attempts were made by many groups to examine connections between these properties and quantitative measures of gene evolution...

We propose a detailed model of evolution of exon-intron structure of eukaryotic genes that takes into account gene-specific in- tron gain and loss rates, branch-specific gain and loss coefficients, invari- ant sites incapable of intron gain, and rate variability of both gain and loss which is gamma-distributed across sites. We develop an expectatio...

When measuring over-concentrated stimuli, chemical sensors tend to exhibit corrupted time signals, which are normally categorized as missing data. Such a failure of one or more sensors occurs frequently in applications where an eNose is exposed to a diverse repertoire of chemicals. As a rule, missing data are removed from the dataset by leaving a p...

A fundamental question in studying odor patterns in electronic noses is how to estimate the response to a mixture, given the response curves of the pure chemicals. We study this question by proposing two mixture-predicting models, and verify them against real data collected using quartz microbalance sensors. We find that a simple additive law expla...

We consider the task of finding a mapping between two eNoses that employ two different sensor technologies, quartz microbalance and conducting polymers. Such a mapping is a model that predicts the response of one eNose based on the response of the other. eNose mappings are important for odor communication and synthesis, as well as for eNose data in...

We present a novel family of data-driven linear transformations, aimed at finding low-dimensional embeddings of multivariate data, in a way that optimally preserves the structure of the data. The well-studied PCA and Fisher's LDA are shown to be special members in this family of transformations, and we demonstrate how to generalize these two method...

We present an algorithm for drawing directed graphs which is based on rapidly solving a unique one-dimensional optimization problem for each of the axes. The algorithm results in a clear description of the hierarchy structure of the graph. Nodes are not restricted to lie on fixed horizontal layers, resulting in layouts that convey the symmetries of...

We propose a new feature extraction method for use with chemical sensors. It is based on fitting a parametric analytic model of the sensor’s response over time to the measured signal, and taking the set of best-fitting parameters as the features. The process of finding the features is fast and robust, and the resulting set of features is shown to s...

We present a novel family of data-driven linear transformations, aimed at visualizing multivariate data in a low-dimensional space in a way that optimally preserves the structure of the data. The well-studied PCA and Fisher's LDA are shown to be special members in this family of transformations, and we demonstrate how to generalize these two method...

We propose a setup for an odor communication system. Its different parts are described, and ways to realize them are outlined. Our scheme enables an output device-the whiffer-to release an imitation of an odorant read in by an input device-the sniffer-upon command. The heart of the system is the novel algorithmic scheme that makes the scheme feasib...

The Lorentzian model is an analytic expression that describes the time response of electronic nose sensors. We show how this model can be utilized to calculate a normal- ized similarity index between any two measurements. The set of similarity indices is then used for two purposes: visualization of the data, and classification of new samples. The v...

We present an extremely fast graph drawing algorithm for very large graphs, which we term ACE (for Algebraic multigrid Computation of Eigenvectors). ACE exhibits a vast improvement over the fastest algorithms we are currently aware of; using a serial PC, it draws graphs of millions of nodes in less than a minute. ACE finds an optimal drawing by min...

We propose an algorithm for use with multisensor systems that is capable of the following: (a) identify an analyte independently of its concentration; (b) estimate the concentration of the analyte, even if the system was not previously exposed to this concentration; (c) tell when an analyte is of a chemical type not previously presented to the syst...

We present an algorithm for drawing directed graphs, which is based on rapidly solving a unique one-dimensional optimization problem for each of the axes. The algorithm results in a clear description of the hierarchy structure of the graph. Nodes are not restricted to lie on .xed horizontal layers, resulting in layouts that convey the symmetries of...

We present an extremely fast graph drawing algorithm for very large graphs, which we term ACE (for Algebraic multigrid Computation of Eigenvectors). ACE exhibits an improvement of something like two orders of magnitude over the fastest algorithms we are aware of; it draws graphs of millions of nodes in less than a minute. ACE finds an optimal drawi...

We present an extremely fast graph drawing algorithm for very large graphs, which we term ACE (for Algebraic multigrid Computation of Eigenvectors). ACE exhibits an improvement of something like two orders of magnitude over the fastest algorithms we are aware of; it draws graphs of millions of nodes in less than a minute. ACE finds an optimal drawi...

The concept of shape space, which has been successfully implemented in immunology, is used here to construct a model for the discrimination power of the olfactory system. Using reasonable assumptions on the behaviour of the biological system, we are able to estimate the number of distinct olfactory receptor types. Our estimated value of around 1000...

Two-level systems were shown to be fully described by a single function, known sometimes as the Stueckelberg parameter. Using concepts from differential geometry, we give geometrical meaning to the Stueckelberg parameter and to other related quantities. As a result, a generalization of the Stueckelberg parameter is introduced, and a relation obtain...