Initial sequencing and analysis of the human genome.
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
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TL;DR: Type of odorant structures that may be recognized by some subfam families were predicted by identifying subfamilies that contain ORs with known odor ligands or human homologs of such ORs, and most subfam Families are encoded by a single chromosomal locus.
Abstract: Humans perceive an immense variety of chemicals as having distinct odors. Odor perception initiates in the nose, where odorants are detected by a large family of olfactory receptors (ORs). ORs have diverse protein sequences but can be assigned to subfamilies on the basis of sequence relationships. Members of the same subfamily have related sequences and are likely to recognize structurally related odorants. To gain insight into the mechanisms underlying odor perception, we analyzed the human OR gene family. By searching the human genome database, we identified 339 intact OR genes and 297 OR pseudogenes. Determination of their genomic locations showed that OR genes are unevenly distributed among 51 different loci on 21 human chromosomes. Sequence comparisons showed that the human OR family is composed of 172 subfamilies. Types of odorant structures that may be recognized by some subfamilies were predicted by identifying subfamilies that contain ORs with known odor ligands or human homologs of such ORs. Analysis of the chromosomal locations of members of each OR subfamily revealed that most subfamilies are encoded by a single chromosomal locus. Moreover, many loci encode only one or a few subfamilies, suggesting that different parts of the genome may, to some extent, be involved in the detection of different types of odorant structural motifs.
551 citations
TL;DR: The plasticity of the 5′ splice sites of multicellular eukaryotes means that these sites can be used in both constitutive and alternative splicing, and for the regulation of the inclusion/skipping ratio in alternativesplicing.
Abstract: Alternative splicing creates transcriptome diversification, possibly leading to speciation. A large fraction of the protein-coding genes of multicellular organisms are alternatively spliced, although no regulated splicing has been detected in unicellular eukaryotes such as yeasts. A comparative analysis of unicellular and multicellular eukaryotic 5' splice sites has revealed important differences - the plasticity of the 5' splice sites of multicellular eukaryotes means that these sites can be used in both constitutive and alternative splicing, and for the regulation of the inclusion/skipping ratio in alternative splicing. So, alternative splicing might have originated as a result of relaxation of the 5' splice site recognition in organisms that originally could support only constitutive splicing.
550 citations
TL;DR: How recent genomic profiling of transcription factors gives insight into how binding specificity is achieved and what features of chromatin influence the ability of transcription factor to interact with the genome is discussed.
Abstract: A crucial question in the field of gene regulation is whether the location at which a transcription factor binds influences its effectiveness or the mechanism by which it regulates transcription. Comprehensive transcription factor binding maps are needed to address these issues, and genome-wide mapping is now possible thanks to the technological advances of ChIP-chip and ChIP-seq. This Review discusses how recent genomic profiling of transcription factors gives insight into how binding specificity is achieved and what features of chromatin influence the ability of transcription factors to interact with the genome. It also suggests future experiments that may further our understanding of the causes and consequences of transcription factor-genome interactions.
550 citations
TL;DR: Recent reports that update the understanding of human L1 retrotransposons and their role in disease are highlighted and shed light on not just when, but where, retrotransposition occurs and its part in genetic variation.
549 citations
University of California, Santa Cruz1, University of California, Davis2, Agency for Science, Technology and Research3, National University of Singapore4, Wellcome Trust Sanger Institute5, European Bioinformatics Institute6, University of Porto7, Joint Genome Institute8, Centre national de la recherche scientifique9, French Institute for Research in Computer Science and Automation10, Cold Spring Harbor Laboratory11, University of Maryland, College Park12, Monsanto13, Howard Hughes Medical Institute14, University of California, San Francisco15, Royal Holloway, University of London16, Sainsbury Laboratory17, Beijing Genomics Institute18, Broad Institute19
TL;DR: The Assemblathon 1 competition is described, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies, and it is established that it is possible to assemble the genome to a high level of coverage and accuracy.
Abstract: Low-cost short read sequencing technology has revolutionized genomics, though it is only just becoming practical for the high-quality de novo assembly of a novel large genome We describe the Assemblathon 1 competition, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies In a collaborative effort, teams were asked to assemble a simulated Illumina HiSeq data set of an unknown, simulated diploid genome A total of 41 assemblies from 17 different groups were received Novel haplotype aware assessments of coverage, contiguity, structure, base calling, and copy number were made We establish that within this benchmark: (1) It is possible to assemble the genome to a high level of coverage and accuracy, and that (2) large differences exist between the assemblies, suggesting room for further improvements in current methods The simulated benchmark, including the correct answer, the assemblies, and the code that was used to evaluate the assemblies is now public and freely available from http://wwwassemblathonorg/
548 citations
Cites background or methods from "Initial sequencing and analysis of ..."
...…exceptions (e.g., MacCallum et al. 2009; Gnerre et al. 2011) is de rigueur when introducing new de novo assembly software (e.g., (Myers et al. 2000; Lander et al. 2001; Venter et al. 2001; Batzoglou et al. 2002; Dohm et al. 2007; Jeck et al. 2007; Warren et al. 2007; Butler et al. 2008; Chaisson…...
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...…GigAssembler (Kent and Haussler 2000), Celera (Myers et al. 2000; Venter et al. 2001), ARACHNE (Batzoglou et al. 2002), and Phusion (Mullikin and Ning 2003), which were used for numerous highquality assemblies such as human (Lander et al. 2001) and mouse (Waterston et al. 2002)....
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References
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TL;DR: A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original.
Abstract: The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSIBLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.
70,111 citations
TL;DR: The definition and use of family-specific, manually curated gathering thresholds are explained and some of the features of domains of unknown function (also known as DUFs) are discussed, which constitute a rapidly growing class of families within Pfam.
Abstract: Pfam is a widely used database of protein families and domains. This article describes a set of major updates that we have implemented in the latest release (version 24.0). The most important change is that we now use HMMER3, the latest version of the popular profile hidden Markov model package. This software is approximately 100 times faster than HMMER2 and is more sensitive due to the routine use of the forward algorithm. The move to HMMER3 has necessitated numerous changes to Pfam that are described in detail. Pfam release 24.0 contains 11,912 families, of which a large number have been significantly updated during the past two years. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/).
14,075 citations
TL;DR: Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems are indicated.
Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
12,098 citations
TL;DR: This letter extends the heuristic homology algorithm of Needleman & Wunsch (1970) to find a pair of segments, one from each of two long sequences, such that there is no other Pair of segments with greater similarity (homology).
10,262 citations
09 Apr 1981
TL;DR: The complete sequence of the 16,569-base pair human mitochondrial genome is presented and shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.
Abstract: The complete sequence of the 16,569-base pair human mitochondrial genome is presented. The genes for the 12S and 16S rRNAs, 22 tRNAs, cytochrome c oxidase subunits I, II and III, ATPase subunit 6, cytochrome b and eight other predicted protein coding genes have been located. The sequence shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.
8,783 citations