Needed for completion of the human genome: hypothesis driven experiments and biologically realistic mathematical models

With the sponsorship of ``Fundacio La Caixa'' we met in Barcelona, November 21st and 22nd, to analyze the reasons why, after the completion of the human genome sequence, the identification all protein coding genes and their variants remains a distant goal. Here we report on our discussions and summarize some of the major challenges that need to be overcome in order to complete the human gene catalog.Comment: Report and discussion resulting from the `Fundacio La Caixa' gene finding meeting held November 21 and 22 2003 in Barcelon

Nucleosome rotational setting is associated with transcriptional regulation in promoters of tissue-specific human genes

Human genes contain a 10 bp repeat of RR dinucleotides focused around the first nucleosome position suggesting a role in transcriptional control

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Solving an enigma in the tree of life, at the origins of teleost fishes

Tracing the phylogenetic relationships between species is one of the fundamental objectives of evolutionary biology. Since Charles Darwin's seminal work in the 19th century, considerable progress has been made towards establishing a tree of life that summarises the evolutionary history of species. Nevertheless, substantial uncertainties still remain. Specifically, the relationships at the origins of teleost fishes have been the subject of extensive debate over the last 50 years. This question has major implications for various research fields: there are almost 30,000 species in the teleost group, which includes invaluable model organisms for biomedical, evolutionary and ecological studies. Here, we present the work in which we solved this enigma. We demonstrated that eels are more closely related to bony-tongued fishes than to the rest of teleost fishes. We achieved this by taking advantage of new genomic data and leveraging innovative phylogenetic markers. Notably, in addition to traditional molecular phylogeny methods based on the evolution of gene sequences, we also considered the evolution of gene order along the DNA molecule. We discuss the challenges and opportunities that these new markers represent for the field of molecular phylogeny, and in particular the possibilities they offer for re-examining other controversial branches in the tree of life

Factors influencing the accuracy and precision in dating single gene trees

Molecular dating is the inference of divergence time from genetic sequences. Knowing the time of appearance of a taxon sets the evolutionary context by connecting it with past ecosystems and species. Knowing the divergence times of gene lineages would provide a context to understand adaptation at the genomic level. However, molecular clock inference faces uncertainty due to the variability of the rate of substitution between species, between genes, and between sites within genes. When dating speciations, per-lineage rate variability can be informed by fossil calibrations, and gene-specific rates can be either averaged out or modeled by concatenating multiple genes. By contrast, when dating gene-specific events, fossil calibrations only inform about speciation nodes, and concatenation does not apply to divergences other than speciations. This study aims to benchmark the accuracy of molecular dating applied to single gene trees and identify how it is affected by gene tree characteristics. We analyze 5205 alignments of genes from 21 Primates in which no duplication or loss is observed. We also simulated alignments based on characteristics from Primates under a relaxed clock model to analyze the dating accuracy. Divergence times were estimated with the Bayesian program Beast2. From the empirical dataset, we find that the date estimates deviate more from the median age with shorter alignments, high rate heterogeneity between branches, and low average rate, features that underlie the amount of dating information in alignments, hence, statistical power. The smallest deviation is associated with core biological functions such as ATP binding and cellular organization, categories that are expected to be under strong negative selection. We then investigated the accuracy of dating with simulated alignments, by controlling the three above parameters separately. It confirmed the factors of precision, but also revealed biases when branch rates are highly heterogeneous. This suggests that in the case of the relaxed uncorrelated molecular clock, biases arise from the tree prior when calibrations are lacking and rate heterogeneity is high. Our study finally reports the scale of the gene tree features that influence the dating consistency with median ages, so that comparisons can be made with other genes and taxa. To tackle the molecular dating of events only observed in single gene trees, like deep coalescence, horizontal gene transfers, and gene duplications, future models should overcome the lack of power due to limited information from single genes

An atlas of fish genome evolution reveals delayed rediploidization following the teleost whole-genome duplication

Teleost fishes are ancient tetraploids descended from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions evolutionary processes by which duplicated genomes return to diploid meiotic pairing, and subsequent genetic divergence of duplicated genes (cytological and genetic rediploidization). How teleosts became tetraploid remains unresolved, leaving a fundamental gap in the interpretation of their functional evolution. As a result of the whole-genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with a state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate how rediploidization occurred in teleosts at the genome-wide level. We uncover that some duplicated regions maintained tetraploidy for more than 60 million years, with three chromosome pairs diverging genetically only after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, we find evidence for biased gene retention along several duplicated chromosomes, contradicting current paradigms that asymmetrical evolution is specific to allopolyploids. Altogether, our results offer novel insights into genome evolutionary dynamics following ancient polyploidizations in vertebrates

Genomicus: a database and a browser to study gene synteny in modern and ancestral genomes

Summary: Comparative genomics remains a pivotal strategy to study the evolution of gene organization, and this primacy is reinforced by the growing number of full genome sequences available in public repositories. Despite this growth, bioinformatic tools available to visualize and compare genomes and to infer evolutionary events remain restricted to two or three genomes at a time, thus limiting the breadth and the nature of the question that can be investigated. Here we present Genomicus, a new synteny browser that can represent and compare unlimited numbers of genomes in a broad phylogenetic view. In addition, Genomicus includes reconstructed ancestral gene organization, thus greatly facilitating the interpretation of the data