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: For example, this paper found that genes and capabilities that evolve in one lineage are often stably acquired by another lineage, and that direct gene transfer between species has occurred at some level in all major groups, but it appears to be far more frequent in prokaryotes than in multicellular eukaryotes.
Abstract: Genomics has revealed that inheritance systems of separate species are often not well segregated: genes and capabilities that evolve in one lineage are often stably acquired by another lineage. Although direct gene transfer between species has occurred at some level in all major groups, it appears to be far more frequent in prokaryotes than in multicellular eukaryotes. An alternative to incorporating novel genes into a recipient genome is acquiring a stable, possibly heritable, symbiotic association and thus enjoying benefits of complementary metabolic capabilities. These kinds of symbioses have arisen frequently in animals; for example, many insect groups have diversified on the basis of symbiotic associations acquired early in their evolutionary histories. The resulting associations are highly complex, often involving specialized cell types and organs, developmental mechanisms that ensure transfer of symbionts between generations, and mechanisms for controlling symbiont proliferation and location. The genomes of long-term obligate symbionts often undergo irreversible gene loss and deterioration even as hosts evolve dependence on them. In some cases, animal genomes may have acquired genes from symbionts, mirroring the gene uptake from mitochondrial and plastid genomes. Multiple symbionts often coexist in the same host, resulting in coadaptation among several phylogenetically distant genomes.
446 citations
TL;DR: A mechanism that governs 3′ splice-site selection in these exons during alternative splicing is revealed, and mutations that activated the exonization of a silent intronic Alu are identified.
Abstract: Alu repetitive elements can be inserted into mature messenger RNAs via a splicing-mediated process termed exonization. To understand the molecular basis and the regulation of the process of turning intronic Alus into new exons, we compiled and analyzed a data set of human exonized Alus. We revealed a mechanism that governs 3' splice-site selection in these exons during alternative splicing. On the basis of these findings, we identified mutations that activated the exonization of a silent intronic Alu.
446 citations
TL;DR: This work adopts the perspective of biophysicists interested in light-dependent signal transduction in nature and the three-dimensional structures that underpin signaling.
Abstract: Signaling photoreceptors use the information contained in the ab- sorption of a photon to modulate biological activity in plants and a wide range of organisms. The fundamental—and as yet imperfectly answered—question is, how is this achieved at the molecular level? We adopt the perspective of biophysicists interested in light-dependent sig- nal transduction in nature and the three-dimensional structures that underpin signaling. Six classes of photoreceptors are known: light- oxygen-voltage (LOV) sensors, xanthopsins, phytochromes, blue-light sensors using flavin adenine dinucleotide (BLUF), cryptochromes, and rhodopsins. All are water-soluble proteins except rhodopsins, which are integral membrane proteins; all are based on a modular architec- ture except cryptochromes and rhodopsins; and each displays a distinct, light-dependent chemical process based on the photochemistry of their nonprotein chromophore, such as isomerization about a double bond (xanthopsins, phytochromes, and rhodopsins), formation or rupture of a covalent bond (LOV sensors), or electron transfer (BLUF sensors and cryptochromes).
444 citations
TL;DR: This review examines these active human transposons and explores mechanistic factors that influence their mobilization and genetic diversity in human populations and cause human diseases by integrating into genes.
443 citations
TL;DR: Comparison of K across species reveals that it is an essential factor in metazoans, but not in yeast, and the greater diversity of mammalian K protein interactions and function may reflect gain of novel docking sites and expansion evolutionary of gene expression networks.
Abstract: Since its original identification as a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex, K protein has been found not only in the nucleus but also in the cytoplasm and mitochondria and is implicated in chromatin remodeling, transcription, splicing and translation processes. K protein contains multiple modules that, on one hand, bind kinases while, on the other hand, recruit chromatin, transcription, splicing and translation factors. Moreover, the K- protein-mediated interactions are regulated by signaling cascades. These observations are consistent with K protein acting as a docking platform to integrate signaling cascades by facilitating cross-talk between kinases and factors that mediate nucleic-acid-directed processes. Comparison of K across species reveals that it is an essential factor in metazoans, but not in yeast. Although some of the K protein interactions and functions are conserved in eukaryotes from yeast to man, the mammalian protein seems to play a wider role. The greater diversity of mammalian K protein interactions and function may reflect gain of novel docking sites and expansion evolutionary of gene expression networks.
442 citations
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