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Gill Bejerano

Publications and source records attributed to Gill Bejerano.

11 recordsLinked to original sources
PubMed2006

Forces shaping the fastest evolving regions in the human genome.

Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.

Animals↗
PubMed2006

Branch and bound computation of exact p-values.

UNLABELLED: P-value computation is often used in bioinformatics to quantify the surprise, or significance, associated with a given observation. An implementation is provided that computes the exact p-value associated with any observed sample, against a null multinomial distribution, using the likelihood-ratio statistic. The efficient branch and bound code, far exceeding the full enumeration implemented by commercial packages, is especially useful with small sample, sparse data and rare events, common scenarios in bioinformatics, where approximations are often inaccurate and inappropriate. This code base can also be adapted to compute exact p-values of other statistics in diverse sampling scenarios. AVAILABILITY: Freely available at http://www.soe.ucsc.edu/~jill/src/.

Algorithms↗
PubMed2006

Identification and classification of conserved RNA secondary structures in the human genome.

The discoveries of microRNAs and riboswitches, among others, have shown functional RNAs to be biologically more important and genomically more prevalent than previously anticipated. We have developed a general comparative genomics method based on phylogenetic stochastic context-free grammars for identifying functional RNAs encoded in the human genome and used it to survey an eight-way genome-wide alignment of the human, chimpanzee, mouse, rat, dog, chicken, zebra-fish, and puffer-fish genomes for deeply conserved functional RNAs. At a loose threshold for acceptance, this search resulted in a set of 48,479 candidate RNA structures. This screen finds a large number of known functional RNAs, including 195 miRNAs, 62 histone 3'UTR stem loops, and various types of known genetic recoding elements. Among the highest-scoring new predictions are 169 new miRNA candidates, as well as new candidate selenocysteine insertion sites, RNA editing hairpins, RNAs involved in transcript auto regulation, and many folds that form singletons or small functional RNA families of completely unknown function. While the rate of false positives in the overall set is difficult to estimate and is likely to be substantial, the results nevertheless provide evidence for many new human functional RNAs and present specific predictions to facilitate their further characterization.

3' Untranslated Regions↗
PubMed2006

A distal enhancer and an ultraconserved exon are derived from a novel retroposon.

Hundreds of highly conserved distal cis-regulatory elements have been characterized so far in vertebrate genomes. Many thousands more are predicted on the basis of comparative genomics. However, in stark contrast to the genes that they regulate, in invertebrates virtually none of these regions can be traced by using sequence similarity, leaving their evolutionary origins obscure. Here we show that a class of conserved, primarily non-coding regions in tetrapods originated from a previously unknown short interspersed repetitive element (SINE) retroposon family that was active in the Sarcopterygii (lobe-finned fishes and terrestrial vertebrates) in the Silurian period at least 410 million years ago (ref. 4), and seems to be recently active in the 'living fossil' Indonesian coelacanth, Latimeria menadoensis. Using a mouse enhancer assay we show that one copy, 0.5 million bases from the neuro-developmental gene ISL1, is an enhancer that recapitulates multiple aspects of Isl1 expression patterns. Several other copies represent new, possibly regulatory, alternatively spliced exons in the middle of pre-existing Sarcopterygian genes. One of these, a more than 200-base-pair ultraconserved region, 100% identical in mammals, and 80% identical to the coelacanth SINE, contains a 31-amino-acid-residue alternatively spliced exon of the messenger RNA processing gene PCBP2 (ref. 6). These add to a growing list of examples in which relics of transposable elements have acquired a function that serves their host, a process termed 'exaptation', and provide an origin for at least some of the many highly conserved vertebrate-specific genomic sequences.

Animals↗
PubMed2005

Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.

We have conducted a comprehensive search for conserved elements in vertebrate genomes, using genome-wide multiple alignments of five vertebrate species (human, mouse, rat, chicken, and Fugu rubripes). Parallel searches have been performed with multiple alignments of four insect species (three species of Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven species of Saccharomyces. Conserved elements were identified with a computer program called phastCons, which is based on a two-state phylogenetic hidden Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by maximum likelihood, subject to constraints designed to calibrate the model across species groups, and then predicting conserved elements based on this model. The predicted elements cover roughly 3%-8% of the human genome (depending on the details of the calibration procedure) and substantially higher fractions of the more compact Drosophila melanogaster (37%-53%), Caenorhabditis elegans (18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to vertebrates, in order of increasing genome size and general biological complexity, increasing fractions of conserved bases are found to lie outside of the exons of known protein-coding genes. In all groups, the most highly conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases long. These elements share certain properties with ultraconserved elements, but they tend to be longer and less perfectly conserved, and they overlap genes of somewhat different functional categories. In vertebrates, HCEs are associated with the 3' UTRs of regulatory genes, stable gene deserts, and megabase-sized regions rich in moderately conserved noncoding sequences. Noncoding HCEs also show strong statistical evidence of an enrichment for RNA secondary structure.

3' Untranslated Regions↗
PubMed2005

Ultraconserved elements in insect genomes: a highly conserved intronic sequence implicated in the control of homothorax mRNA splicing.

Recently, we identified a large number of ultraconserved (uc) sequences in noncoding regions of human, mouse, and rat genomes that appear to be essential for vertebrate and amniote ontogeny. Here, we used similar methods to identify ultraconserved genomic regions between the insect species Drosophila melanogaster and Drosophila pseudoobscura, as well as the more distantly related Anopheles gambiae. As with vertebrates, ultraconserved sequences in insects appear to occur primarily in intergenic and intronic sequences, and at intron-exon junctions. The sequences are significantly associated with genes encoding developmental regulators and transcription factors, but are less frequent and are smaller in size than in vertebrates. The longest identical, nongapped orthologous match between the three genomes was found within the homothorax (hth) gene. This sequence spans an internal exon-intron junction, with the majority located within the intron, and is predicted to form a highly stable stem-loop RNA structure. Real-time quantitative PCR analysis of different hth splice isoforms and Northern blotting showed that the conserved element is associated with a high incidence of intron retention in hth pre-mRNA, suggesting that the conserved intronic element is critically important in the post-transcriptional regulation of hth expression in Diptera.

Animals↗
PubMed2004

Into the heart of darkness: large-scale clustering of human non-coding DNA.

MOTIVATION: It is currently believed that the human genome contains about twice as much non-coding functional regions as it does protein-coding genes, yet our understanding of these regions is very limited. RESULTS: We examine the intersection between syntenically conserved sequences in the human, mouse and rat genomes, and sequence similarities within the human genome itself, in search of families of non-protein-coding elements. For this purpose we develop a graph theoretic clustering algorithm, akin to the highly successful methods used in elucidating protein sequence family relationships. The algorithm is applied to a highly filtered set of about 700 000 human-rodent evolutionarily conserved regions, not resembling any known coding sequence, which encompasses 3.7% of the human genome. From these, we obtain roughly 12 000 non-singleton clusters, dense in significant sequence similarities. Further analysis of genomic location, evidence of transcription and RNA secondary structure reveals many clusters to be significantly homogeneous in one or more characteristics. This subset of the highly conserved non-protein-coding elements in the human genome thus contains rich family-like structures, which merit in-depth analysis. AVAILABILITY: Supplementary material to this work is available at http://www.soe.ucsc.edu/~jill/dark.html

Animals↗
PubMed2004

Ultraconserved elements in the human genome.

There are 481 segments longer than 200 base pairs (bp) that are absolutely conserved (100% identity with no insertions or deletions) between orthologous regions of the human, rat, and mouse genomes. Nearly all of these segments are also conserved in the chicken and dog genomes, with an average of 95 and 99% identity, respectively. Many are also significantly conserved in fish. These ultraconserved elements of the human genome are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in the regulation of transcription and development. Along with more than 5000 sequences of over 100 bp that are absolutely conserved among the three sequenced mammals, these represent a class of genetic elements whose functions and evolutionary origins are yet to be determined, but which are more highly conserved between these species than are proteins and appear to be essential for the ontogeny of mammals and other vertebrates.

Alternative Splicing↗
PubMed2004

Algorithms for variable length Markov chain modeling.

UNLABELLED: We present a general purpose implementation of variable length Markov models. Contrary to fixed order Markov models, these models are not restricted to a predefined uniform depth. Rather, by examining the training data, a model is constructed that fits higher order Markov dependencies where such contexts exist, while using lower order Markov dependencies elsewhere. As both theoretical and experimental results show, these models are capable of capturing rich signals from a modest amount of training data, without the use of hidden states. AVAILABILITY: The source code is freely available at http://www.soe.ucsc.edu/~jill/src/

Algorithms↗
PubMed2004

Efficient exact p-value computation for small sample, sparse, and surprising categorical data.

A major obstacle in applying various hypothesis testing procedures to datasets in bioinformatics is the computation of ensuing p-values. In this paper, we define a generic branch-and-bound approach to efficient exact p-value computation and enumerate the required conditions for successful application. Explicit procedures are developed for the entire Cressie-Read family of statistics, which includes the widely used Pearson and likelihood ratio statistics in a one-way frequency table goodness-of-fit test. This new formulation constitutes a first practical exact improvement over the exhaustive enumeration performed by existing statistical software. The general techniques we develop to exploit the convexity of many statistics are also shown to carry over to contingency table tests, suggesting that they are readily extendible to other tests and test statistics of interest. Our empirical results demonstrate a speed-up of orders of magnitude over the exhaustive computation, significantly extending the practical range for performing exact tests. We also show that the relative speed-up gain increases as the null hypothesis becomes sparser, that computation precision increases with increase in speed-up, and that computation time is very moderately affected by the magnitude of the computed p-value. These qualities make our algorithm especially appealing in the regimes of small samples, sparse null distributions, and rare events, compared to the alternative asymptotic approximations and Monte Carlo samplers. We discuss several established bioinformatics applications, where small sample size, small expected counts in one or more categories (sparseness), and very small p-values do occur. Our computational framework could be applied in these, and similar cases, to improve performance.

Computational Biology↗