Showing papers by "Manolis Kellis published in 2005"

Genome sequence, comparative analysis and haplotype structure of the domestic dog

Abstract: Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.

Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals

Abstract: Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.

Large-scale discovery and validation of functional elements in the human genome.

Abstract: A report on the genomics workshop 'Identification of Functional Elements in Mammalian Genomes', Cold Spring Harbor, New York, 11-13 November 2004.

Gene finding using multiple related species: a classification approach

Abstract: Three years after the initial sequencing of the human genome, the actual number of functional human genes remains uncertain. Several expression-based analyses still argue for a hundred thousand transcribed genes, whereas more conservative estimates range between 20 000 and 25 000 genes. The central question in such debates still remains: what constitutes a real gene? In this paper, we address this question and present a comparative genomics approach for systematic gene identification, which observes gene-specific signatures of evolutionary selection across multiple related species. First, we formulate the gene identification problem as a classification problem between genes and noncoding regions, on the basis of their distinct patterns of nucleotide change. We then summarize the results of applying this approach to reannotate the yeast genome, with changes affecting nearly 15% of all genes, and the rejection of more than 500 previously annotated genes. Finally, we discuss the implications of this analysis on understanding the human genome, and strategies for the systematic reannotation of higher eukaryotes. Keywords: comparative genomics; evolutionary signatures; systematic reannotation; defining real genes; genome analysis