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Journal ArticleDOI

Initial sequencing and analysis of the human genome.

Eric S. Lander1, Lauren Linton1, Bruce W. Birren1, Chad Nusbaum1  +245 moreInstitutions (29)
15 Feb 2001-Nature (Nature Publishing Group)-Vol. 409, Iss: 6822, pp 860-921
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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Citations
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Journal ArticleDOI
TL;DR: How BLAT was optimized is described, which is more accurate and 500 times faster than popular existing tools for mRNA/DNA alignments and 50 times faster for protein alignments at sensitivity settings typically used when comparing vertebrate sequences.
Abstract: Analyzing vertebrate genomes requires rapid mRNA/DNA and cross-species protein alignments A new tool, BLAT, is more accurate and 500 times faster than popular existing tools for mRNA/DNA alignments and 50 times faster for protein alignments at sensitivity settings typically used when comparing vertebrate sequences BLAT's speed stems from an index of all nonoverlapping K-mers in the genome This index fits inside the RAM of inexpensive computers, and need only be computed once for each genome assembly BLAT has several major stages It uses the index to find regions in the genome likely to be homologous to the query sequence It performs an alignment between homologous regions It stitches together these aligned regions (often exons) into larger alignments (typically genes) Finally, BLAT revisits small internal exons possibly missed at the first stage and adjusts large gap boundaries that have canonical splice sites where feasible This paper describes how BLAT was optimized Effects on speed and sensitivity are explored for various K-mer sizes, mismatch schemes, and number of required index matches BLAT is compared with other alignment programs on various test sets and then used in several genome-wide applications http://genomeucscedu hosts a web-based BLAT server for the human genome

8,326 citations

Journal ArticleDOI
06 Dec 2002-Science
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

7,486 citations

Journal ArticleDOI
TL;DR: The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
Abstract: The character of a cell is defined by its constituent proteins, which are the result of specific patterns of gene expression. Crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (e.g., Cosma et al. 1999). But the types of transcription factors present in a cell are not alone sufficient to define its spectrum of gene activity, as the transcriptional potential of a genome can become restricted in a stable manner during development. The constraints imposed by developmental history probably account for the very low efficiency of cloning animals from the nuclei of differentiated cells (Rideout et al. 2001; Wakayama and Yanagimachi 2001). A “transcription factors only” model would predict that the gene expression pattern of a differentiated nucleus would be completely reversible upon exposure to a new spectrum of factors. Although many aspects of expression can be reprogrammed in this way (Gurdon 1999), some marks of differentiation are evidently so stable that immersion in an alien cytoplasm cannot erase the memory. The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zygote from which it is descended (mammalian B and T cells being an obvious exception). This means that the marks of developmental history are unlikely to be caused by widespread somatic mutation. Processes less irrevocable than mutation fall under the umbrella term “epigenetic” mechanisms. A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Russo et al. 1996). There are two epigenetic systems that affect animal development and fulfill the criterion of heritability: DNA methylation and the Polycomb-trithorax group (Pc-G/trx) protein complexes. (Histone modification has some attributes of an epigenetic process, but the issue of heritability has yet to be resolved.) This review concerns DNA methylation, focusing on the generation, inheritance, and biological significance of genomic methylation patterns in the development of mammals. Data will be discussed favoring the notion that DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo. Embryonic transcription, on the other hand, may cause the exclusion of the DNA methylation machinery. The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development. Indeed, the possibility will be discussed that DNA methylation and Pc-G/trx may represent alternative systems of epigenetic memory that have been interchanged over evolutionary time. Animal DNA methylation has been the subject of several recent reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; Costello and Plass 2001; Jones and Takai 2001). For recent reviews of plant and fungal DNA methylation, see Finnegan et al. (2000), Martienssen and Colot (2001), and Matzke et al. (2001).

6,691 citations

Journal ArticleDOI
Robert H. Waterston1, Kerstin Lindblad-Toh2, Ewan Birney, Jane Rogers3  +219 moreInstitutions (26)
05 Dec 2002-Nature
TL;DR: The results of an international collaboration to produce a high-quality draft sequence of the mouse genome are reported and an initial comparative analysis of the Mouse and human genomes is presented, describing some of the insights that can be gleaned from the two sequences.
Abstract: The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

6,643 citations

Journal ArticleDOI
John W. Belmont1, Paul Hardenbol, Thomas D. Willis, Fuli Yu1, Huanming Yang2, Lan Yang Ch'Ang, Wei Huang3, Bin Liu2, Yan Shen3, Paul K.H. Tam4, Lap-Chee Tsui4, Mary M.Y. Waye5, Jeffrey Tze Fei Wong6, Changqing Zeng2, Qingrun Zhang2, Mark S. Chee7, Luana Galver7, Semyon Kruglyak7, Sarah S. Murray7, Arnold Oliphant7, Alexandre Montpetit8, Fanny Chagnon8, Vincent Ferretti8, Martin Leboeuf8, Michael S. Phillips8, Andrei Verner8, Shenghui Duan9, Denise L. Lind10, Raymond D. Miller9, John P. Rice9, Nancy L. Saccone9, Patricia Taillon-Miller9, Ming Xiao10, Akihiro Sekine, Koki Sorimachi, Yoichi Tanaka, Tatsuhiko Tsunoda, Eiji Yoshino, David R. Bentley11, Sarah E. Hunt11, Don Powell11, Houcan Zhang12, Ichiro Matsuda13, Yoshimitsu Fukushima14, Darryl Macer15, Eiko Suda15, Charles N. Rotimi16, Clement Adebamowo17, Toyin Aniagwu17, Patricia A. Marshall18, Olayemi Matthew17, Chibuzor Nkwodimmah17, Charmaine D.M. Royal16, Mark Leppert19, Missy Dixon19, Fiona Cunningham20, Ardavan Kanani20, Gudmundur A. Thorisson20, Peter E. Chen21, David J. Cutler21, Carl S. Kashuk21, Peter Donnelly22, Jonathan Marchini22, Gilean McVean22, Simon Myers22, Lon R. Cardon22, Andrew P. Morris22, Bruce S. Weir23, James C. Mullikin24, Michael Feolo24, Mark J. Daly25, Renzong Qiu26, Alastair Kent, Georgia M. Dunston16, Kazuto Kato27, Norio Niikawa28, Jessica Watkin29, Richard A. Gibbs1, Erica Sodergren1, George M. Weinstock1, Richard K. Wilson9, Lucinda Fulton9, Jane Rogers11, Bruce W. Birren25, Hua Han2, Hongguang Wang, Martin Godbout30, John C. Wallenburg8, Paul L'Archevêque, Guy Bellemare, Kazuo Todani, Takashi Fujita, Satoshi Tanaka, Arthur L. Holden, Francis S. Collins24, Lisa D. Brooks24, Jean E. McEwen24, Mark S. Guyer24, Elke Jordan31, Jane Peterson24, Jack Spiegel24, Lawrence M. Sung32, Lynn F. Zacharia24, Karen Kennedy29, Michael Dunn29, Richard Seabrook29, Mark Shillito, Barbara Skene29, John Stewart29, David Valle21, Ellen Wright Clayton33, Lynn B. Jorde19, Aravinda Chakravarti21, Mildred K. Cho34, Troy Duster35, Troy Duster36, Morris W. Foster37, Maria Jasperse38, Bartha Maria Knoppers39, Pui-Yan Kwok10, Julio Licinio40, Jeffrey C. Long41, Pilar N. Ossorio42, Vivian Ota Wang33, Charles N. Rotimi16, Patricia Spallone29, Patricia Spallone43, Sharon F. Terry44, Eric S. Lander25, Eric H. Lai45, Deborah A. Nickerson46, Gonçalo R. Abecasis41, David Altshuler47, Michael Boehnke41, Panos Deloukas11, Julie A. Douglas41, Stacey Gabriel25, Richard R. Hudson48, Thomas J. Hudson8, Leonid Kruglyak49, Yusuke Nakamura50, Robert L. Nussbaum24, Stephen F. Schaffner25, Stephen T. Sherry24, Lincoln Stein20, Toshihiro Tanaka 
18 Dec 2003-Nature
TL;DR: The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance the ability to choose targets for therapeutic intervention.
Abstract: The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

5,926 citations

References
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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
J. Craig Venter1, Mark Raymond Adams1, Eugene W. Myers1, Peter W. Li1  +269 moreInstitutions (12)
16 Feb 2001-Science
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

Journal ArticleDOI
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

Journal ArticleDOI
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