User:Estevezj/sandbox/Genomics

From Wikipedia, the free encyclopedia
This page is about the scientific field. For the journal, see Genomics (journal).

Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes (the complete set of DNA within a single cell of an organism).[1][2] The field includes efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping. The field also includes studies of intragenomic phenomena such as heterosis, epistasis, pleiotropy and other interactions between loci and alleles within the genome.[3] In contrast, the investigation of the roles and functions of single genes is a primary focus of molecular biology or genetics and is a common topic of modern medical and biological research. Research of single genes does not fall into the definition of genomics unless the aim of this genetic, pathway, and functional information analysis is to elucidate its effect on, place in, and response to the entire genome's networks.[4]

History[edit]

Etymology[edit]

While the word 'genome' (from the German Genom, attributed to Hans Winkler) was in use in English as early as 1926, [5] the term 'genomics' was coined by Dr. Tom Roderick, a geneticist at the Jackson Laboratory (Bar Harbor, ME) over beer at a meeting held in Maryland on the mapping of the human genome in 1986. [6]

Early sequencing efforts[edit]

Following James D. Watson and Francis Crick's discovery of the structure of DNA in 1953 and Fred Sanger's publication of the Amino acid sequence of insulin in 1955, nucleic acid sequencing became a major target of early molecular biologists.[7] In 1964, Robert W. Holley and colleagues published the first nucleic acid sequence ever determined, the ribonucleotide sequence of alanine transfer RNA.[8][9] Extending this work, Marshall Nirenberg and Philip Leder revealed the triplet nature of the genetic code and were able to determine the sequences of 54 out of 64 codons in their experiments.[10] In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.[11] Fiers' group expanded on their MS2 coat protein work, determining the complete nucleotide-sequence of bacteriophage MS2-RNA (whose genome encodes just four genes in 3569 base pairs [bp]) and Simian virus 40 in 1976 and 1978, respectively.[12][13]

DNA sequencing technology developed[edit]

Frederick Sanger
Walter Gilbert
Frederick Sanger and Walter Gilbert shared half of the 1980 Nobel Prize in chemistry for independently developing methods for the sequencing of DNA.

In addition to his seminal work on the amino acid sequence of insulin, Frederick Sanger and his colleagues played a key role in the development of DNA sequencing techniques that enabled the establishment of comprehensive genome sequencing projects.[3] In 1975, he and Alan Coulson published a sequencing procedure using DNA polymerase with radiolabelled nucleotides that he called the Plus and Minus technique.[14][15] This involved two closely related methods that generated short oligonucleotides with defined 3' termini. These could be fractionated by electrophoresis on a polyacrylamide gel and visualised using autoradiography. The procedure could sequence up to 80 nucleotides in one go and was a big improvement on what gone before but was still very laborious. Nevertheless, in 1977 his group was able to sequence most of the 5,386 nucleotides of the single-stranded bacteriophage φX174, completing the first fully sequenced DNA-based genome.[16] The refinement of the Plus and Minus method resulted in the chain-termination, or Sanger method, which formed the basis of the techniques of DNA sequencing, genome mapping, data storage, and bioinformatic analysis most widely used in the following quarter-century of research.[17][18] In the same year Walter Gilbert and Allan Maxam of Harvard University independently developed the Maxam-Gilbert method (also known as the chemical method) of DNA sequencing, involving the preferential cleavage of DNA at known bases, a less efficient method.[19][20] For their groundbreaking work in the sequencing of nucleic acids, Gilbert and Sanger shared half the 1980 Nobel Prize in chemistry with Paul Berg (recombinant DNA).

Complete genomes[edit]

The advent of these technologies resulted in a rapid intensification in the scope and speed of completion of genome sequencing projects. The first complete genome sequence of an eukaryotic organelle, the human mitochondrion (16,568 bp, about 16.6 kb [kilobase]), was reported in 1981,[21] and the first chloroplast genomes followed in 1986.[22][23] In 1992, the first eukaryotic chromosome, chromosome III of brewer's yeast Saccharomyces cerevisiae (315 kb) was sequenced.[24] The first free-living organism to be sequenced was that of Haemophilus influenzae (1.8 Mb [megabase]) in 1995.[25] The following year a consortium of researchers from laboratories across North America, Europe, and Japan announced the completion of the first complete genome sequence of an eukaryote, S. cerevisiae (12.1 Mb) was completed the following year and since then genomes have continued being sequenced at an exponentially growing pace.[26] As of October 2011, the complete sequences are available for: 2719 viruses, 1115 archaea and bacteria, and 36 eukaryotes, of which about half are fungi.[27] [28]

"Hockey stick" graph showing the exponential growth of public sequence databases.
The number of genome projects has increased as technological improvements continue to lower the cost of sequencing. (A) Exponential growth of genome sequence databases since 1995. (B) The cost in US Dollars (USD) to sequence one million bases. (C) The cost in USD to sequence a 3,000 Mb (human-sized) genome on a log-transformed scale.

Most of the microorganisms whose genomes have been completely sequenced are problematic pathogens, such as Haemophilus influenzae, which has resulted in a pronounced bias in their phylogenetic distribution compared to the breadth of microbial diversity.[29][30] Of the other sequenced species, most were chosen because they were well-studied model organisms or promised to become good models. Yeast (Saccharomyces cerevisiae) has long been an important model organism for the eukaryotic cell, while the fruit fly Drosophila melanogaster has been a very important tool (notably in early pre-molecular genetics). The worm Caenorhabditis elegans is an often used simple model for multicellular organisms. The zebrafish Brachydanio rerio is used for many developmental studies on the molecular level and the flower Arabidopsis thaliana is a model organism for flowering plants. The Japanese pufferfish (Takifugu rubripes) and the spotted green pufferfish (Tetraodon nigroviridis) are interesting because of their small and compact genomes, containing very little non-coding DNA compared to most species.[31][32] The mammals dog (Canis familiaris), [33] brown rat (Rattus norvegicus), mouse (Mus musculus), and chimpanzee (Pan troglodytes) are all important model animals in medical research. [20]

A rough draft of the human genome was completed by the Human Genome Project in early 2001, creating much fanfare.[34] This project, completed in 2003, sequenced the entire genome for one specific person, and by 2007 this sequence was declared "finished" (less than one error in 20,000 bases and all chromosomes assembled).[34] In the years since then, the genomes of many other individual people have been sequenced, partly under the auspices of the 1000 Genomes Project, which announced the sequencing of 1,092 genomes in October 2012.[35] Completion of this project was made possible by the development of dramatically more efficient sequencing technologies and required the commitment of significant bioinformatics resources from large international collaboration.[36] The continued analysis of human genomic data has profound political and social repercussions for human societies.[37]

Next-generation sequencing[edit]

[38]


Size comparison of selected genomes.[39] [40]
Latin Name Common Name Genome Size
Eukaryotes
Lilium longiflorum Easter lily 90,000,000 Kb
Homo sapiens Human 3,200,000 Kb
Oryza sativa Rice 420,000 Kb
Drosophila melanogaster Fruit fly 137,000 Kb
Arabidopsis thaliana Mustard cress 115,428 Kb
Caenorhabditis elegans Roundworm 97,000 Kb
Saccharomyces cerevisiae Yeast 12,069 Kb
Eubacteria
Haemophilus influenzae Pfeiffer's bacillus 1,830 Kb
Escherichia coli Human colon bacterium 4,639 Kb
Helicobacter pylori Stomach ulcer bacterium 1,667 Kb
Mycobacterium tuberculosis Tuberculosis 4,411 Kb
Yersinia pestis Plague 4,653 Kb
Archaea
Halobacterium Salt-tolerant archaean 2,014 Kb
Methanobacterium thermoautotrophicum Methane-producing archaean 1,751 Kb

Genome analysis[edit]

Main article: Genome project

After an organism has been selected, genome projects involve three components: the sequencing of DNA, the assembly of that sequence to create a representation of the original chromosome, and the annotation and analysis of that representation.[3]

Overview of a genome project. First, the genome must be selected, which involves several factors including cost and relevance. Second, the sequence is generated and assembled at a given sequencing center (such as BGI or JGI). Third, the genome sequence is annotated at several levels: DNA, protein, gene pathways, or comparatively.

Sequencing[edit]

Main article: DNA Sequencing

Historically, sequencing was done in sequencing centers, centralized facilities (ranging from large independent institutions such as Joint Genome Institute which sequence dozens of terabases a year, to local molecular biology core facilities) which contain research laboratories with the costly instrumentation and technical support necessary. As sequencing technology continues to improve, however, a new generation of effective fast turnaround benchtop sequencers has come within reach of the average academic laboratory.[41][42] On the whole, genome sequencing approaches fall into two broad categories, shotgun and high-throughput (aka next-generation) sequencing.[3]

Shotgun sequencing[edit]
An ABI PRISM 3100 Genetic Analyzer. Such capillary sequencers automated the early efforts of sequencing genomes.
Main article: Sanger sequencing

Shotgun sequencing (Sanger sequencing is used interchangably) is a sequencing method designed for analysis of DNA sequences longer than 1000 base pairs, up to and including entire chromosomes.[43] It is named by analogy with the rapidly-expanding, quasi-random firing pattern of a shotgun. Since the chain termination method of DNA sequencing can only be used for fairly short strands (100 to 1000 basepairs), longer DNA sequences must be broken into random small segments which are then sequenced to obtain reads. Multiple overlapping reads for the target DNA are obtained by performing several rounds of this fragmentation and sequencing. Computer programs then use the overlapping ends of different reads to assemble them into a continuous sequence.[43][44]

The technology underlying shotgun sequencing is the classical chain-termination method, which is based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication.[45][16] Developed by Frederick Sanger and colleagues in 1977, it was the most widely-used sequencing method for approximately 25 years. More recently, Sanger sequencing has been supplanted by "Next-Gen" sequencing methods, especially for large-scale, automated genome analyses. However, the Sanger method remains in wide use in 2012, primarily for smaller-scale projects and for obtaining especially long contiguous DNA sequence reads (>500 nucleotides).[46] Chain-termination methods require a single-stranded DNA template, a DNA primer, a DNA polymerase, normal deoxynucleotidetriphosphates (dNTPs), and modified nucleotides (dideoxyNTPs) that terminate DNA strand elongation. These chain-terminating nucleotides lack a 3'-OH group required for the formation of a phosphodiester bond between two nucleotides, causing DNA polymerase to cease extension of DNA when a ddNTP is incorporated. The ddNTPs may be radioactively or fluorescently labelled for detection in automated sequencing machines.[3] Typically, these automated DNA-sequencing instruments (DNA sequencers) can sequence up to 96 DNA samples in a single batch (run) in up to 48 runs a day.[47]

High-throughput sequencing[edit]

The high demand for low-cost sequencing has driven the development of high-throughput sequencing (or next-generation sequencing [NGS]) technologies that parallelize the sequencing process, producing thousands or millions of sequences at once.[48][49] High-throughput sequencing technologies are intended to lower the cost of DNA sequencing beyond what is possible with standard dye-terminator methods. In ultra-high-throughput sequencing as many as 500,000 sequencing-by-synthesis operations may be run in parallel.[50][51]

While NGS methods' high throughput are associated with the sequencing of large eukaryotic genomes, their scalability gives them applications in the sequencing of smaller prokaryotic genomes.[47] In a December 2012 comparison of NGS technologies, researchers from the Integrated Microbial Genomes project found comparison [46]


454 pyrosequencing[edit]
Illumina (Solexa) sequencing[edit]
Illumina Genome Analyzer II System. Illumina technologies have set the standard for high throughput massively parallel sequencing.[41]

Solexa, now part of Illumina, developed a sequencing method based on reversible dye-terminators technology acquired from Manteia Predictive Medicine in 2004. This technology had been invented and developed in late 1996 at Glaxo-Welcome's Geneva Biomedical Research Institute (GBRI), by Dr. Pascal Mayer and Dr Laurent Farinelli.[52] In this method, DNA molecules and primers are first attached on a slide and amplified with polymerase so that local clonal colonies, initially coined "DNA colonies", are formed. To determine the sequence, four types of reversible terminator bases (RT-bases) are added and non-incorporated nucleotides are washed away. Unlike pyrosequencing, the DNA chains are extended one nucleotide at a time and image acquisition can be performed at a delayed moment, allowing for very large arrays of DNA colonies to be captured by sequential images taken from a single camera.

Decoupling the enzymatic reaction and the image capture allows for optimal throughput and theoretically unlimited sequencing capacity. With an optimal configuration, the ultimately reachable instrument throughput is thus dictated solely by the analogic-to-digital conversion rate of the camera, multiplied by the number of cameras and divided by the number of pixels per DNA colony required for visualizing them optimally (approximately 10 pixels/colony). In 2012, with cameras operating at more than 10 MHz A/D conversion rates and available optics, fluidics and enzymatics, throughput can be multiples of 1 million nucleotides/second, corresponding roughly to 1 human genome equivalent at 1x coverage per hour per instrument, and 1 human genome re-sequenced (at approx. 30x) per day per instrument (equipped with a single camera). The camera takes images of the fluorescently labeled nucleotides, then the dye along with the terminal 3' blocker is chemically removed from the DNA, allowing the next cycle.[53]


Single cell genomics[edit]

Assembly[edit]

Main article: Sequence assembly
Overlapping reads form contigs; contigs and gaps of known length form scaffolds.
Paired end reads of next generation sequencing data mapped to a reference genome.
Multiple, fragmented sequence reads must be assembled together on the basis of their overlapping areas.

When are genomes finished?

  • genome standards [58]
  • Coverage?

Challenges[edit]

  • challenges reviewed:
    • NGS and, [59]
    • Mammalian assembly and, [60]
  • Assembler performance compared (2011) [61][62]
Algorithms[edit]

Scaffolding[edit]

De-novo vs. mapping assembly[edit]

Finishing[edit]

Annotation[edit]

The DNA sequence alone is of little value without additional analysis.[3] Genome annotation is the process of attaching biological information to sequences, and consists of three main steps:[63]

  1. identifying portions of the genome that do not code for proteins
  2. identifying elements on the genome, a process called gene prediction, and
  3. attaching biological information to these elements.

Automatic annotation tools try to perform these steps in silico, as opposed to manual annotation (a.k.a. curation) which involves human expertise and potential experimental verification.[64] Ideally, these approaches co-exist and complement each other in the same annotation pipeline (also see below).

Traditionally, the basic level of annotation is using BLAST for finding similarities, and then annotating genomes based on homolouges.[3] More recently, additional information is added to the annotation platform. The additional information allows manual annotators to deconvolute discrepancies between genes that are given the same annotation. Some databases use genome context information, similarity scores, experimental data, and integrations of other resources to provide genome annotations through their Subsystems approach. Other databases (e.g. Ensembl) rely on both curated data sources as well as a range of different software tools in their automated genome annotation pipeline.[65] Structural annotation consists of the identification of genomic elements, primarily ORFs and their localisation, or gene structure. Functional annotation consists of attaching biological information to genomic elements.

Sequencing pipelines and databases[edit]

Genome analysis tools in Integrated Microbial Genomes (v. 2.9) pipeline.

The need for reproducibility and efficient management of large amount of data associated with genome projects mean that computational pipelines have important applications in genomics.[66]

Research areas[edit]

Functional genomics[edit]

Main article: Functional genomics

Functional genomics is a field of molecular biology that attempts to make use of the vast wealth of data produced by genomic projects (such as genome sequencing projects) to describe gene (and protein) functions and interactions. Functional genomics focuses on the dynamic aspects such as gene transcription, translation, and protein–protein interactions, as opposed to the static aspects of the genomic information such as DNA sequence or structures. Functional genomics attempts to answer questions about the function of DNA at the levels of genes, RNA transcripts, and protein products. A key characteristic of functional genomics studies is their genome-wide approach to these questions, generally involving high-throughput methods rather than a more traditional “gene-by-gene” approach.

A major branch of genomics is still concerned with sequencing the genomes of various organisms, but the knowledge of full genomes has created the possibility for the field of functional genomics, mainly concerned with patterns of gene expression during various conditions. The most important tools here are microarrays and bioinformatics.

Evolutionary genomics[edit]

Structural genomics[edit]

Main article: Structural genomics
An example of a protein structure determined by the Midwest Center for Structural Genomics.

Structural genomics seeks to describe the 3-dimensional structure of every protein encoded by a given genome.[67][68] This genome-based approach allows for a high-throughput method of structure determination by a combination of experimental and modeling approaches. The principal difference between structural genomics and traditional structural prediction is that structural genomics attempts to determine the structure of every protein encoded by the genome, rather than focusing on one particular protein. With full-genome sequences available, structure prediction can be done more quickly through a combination of experimental and modeling approaches, especially because the availability of large number of sequenced genomes and previously-solved protein structures allows scientists to model protein structure on the structures of previously solved homologs. Structural genomics involves taking a large number of approaches to structure determination, including experimental methods using genomic sequences or modeling-based approaches based on sequence or structural homology to a protein of known structure or based on chemical and physical principles for a protein with no homology to any known structure. As opposed to traditional structural biology, the determination of a protein structure through a structural genomics effort often (but not always) comes before anything is known regarding the protein function. This raises new challenges in structural bioinformatics, i.e. determining protein function from its 3D structure.[69]

Epigenomics[edit]

Main article: Epigenomics

Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome.[70] Epigenetic modifications are reversible modifications on a cell’s DNA or histones that affect gene expression without altering the DNA sequence (Russell 2010 p. 475). Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis [70]. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays [71]

Metagenomics[edit]

Environmental Shotgun Sequencing (ESS) is a key technique in metagenomics. (A) Sampling from habitat; (B) filtering particles, typically by size; (C) Lysis and DNA extraction; (D) cloning and library construction; (E) sequencing the clones; (F) sequence assembly into contigs and scaffolds.
Main article: Metagenomics

Metagenomics is the study of metagenomes, genetic material recovered directly from environmental samples. The broad field may also be referred to as environmental genomics, ecogenomics or community genomics. While traditional microbiology and microbial genome sequencing rely upon cultivated clonal cultures, early environmental gene sequencing cloned specific genes (often the 16S rRNA gene) to produce a profile of diversity in a natural sample. Such work revealed that the vast majority of microbial biodiversity had been missed by cultivation-based methods.[72] Recent studies use "shotgun" Sanger sequencing or massively parallel pyrosequencing to get largely unbiased samples of all genes from all the members of the sampled communities.[73] Because of its power to reveal the previously hidden diversity of microscopic life, metagenomics offers a powerful lens for viewing the microbial world that has the potential to revolutionize understanding of the entire living world.[74][75]

Study systems[edit]

Viruses and bacteriophages[edit]

Bacteriophages have played and continue to play a key role in bacterial genetics and molecular biology. Historically, they were used to define gene structure and gene regulation. Also the first genome to be sequenced was a bacteriophage. However, bacteriophage research did not lead the genomics revolution, which is clearly dominated by bacterial genomics. Only very recently has the study of bacteriophage genomes become prominent, thereby enabling researchers to understand the mechanisms underlying phage evolution. Bacteriophage genome sequences can be obtained through direct sequencing of isolated bacteriophages, but can also be derived as part of microbial genomes. Analysis of bacterial genomes has shown that a substantial amount of microbial DNA consists of prophage sequences and prophage-like elements.[76] A detailed database mining of these sequences offers insights into the role of prophages in shaping the bacterial genome.[77][78]

Microbes[edit]

[79] [80]

Cyanobacteria[edit]

At present there are 24 cyanobacteria for which a total genome sequence is available. 15 of these cyanobacteria come from the marine environment. These are six Prochlorococcus strains, seven marine Synechococcus strains, Trichodesmium erythraeum IMS101 and Crocosphaera watsonii WH8501. Several studies have demonstrated how these sequences could be used very successfully to infer important ecological and physiological characteristics of marine cyanobacteria. However, there are many more genome projects currently in progress, amongst those there are further Prochlorococcus and marine Synechococcus isolates, Acaryochloris and Prochloron, the N2-fixing filamentous cyanobacteria Nodularia spumigena, Lyngbya aestuarii and Lyngbya majuscula, as well as bacteriophages infecting marine cyanobaceria. Thus, the growing body of genome information can also be tapped in a more general way to address global problems by applying a comparative approach. Some new and exciting examples of progress in this field are the identification of genes for regulatory RNAs, insights into the evolutionary origin of photosynthesis, or estimation of the contribution of horizontal gene transfer to the genomes that have been analyzed.[81]

Animals[edit]

Human genomics[edit]

Main article: Human genome

Applications of genomics[edit]

Genomics has provided applications in many fields, including medicine, biotechnology, anthropology and other social sciences.[37]

Genomic medicine[edit]

[82]

[83] [84] [85] [86]

Synthetic biology and bioengineering[edit]

[87]

Social aspects[edit]

'Astrological' genomics[edit]

[88]

Race and genomics[edit]

[89][90][91]

'Omics[edit]

See also[edit]

References[edit]

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