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Before sequences can be analyzed they have to be obtained. DNA sequencing is still a non-trivial problem as the raw data may be noisy or afflicted by weak signals. Algorithms have been developed for base calling for the various experimental approaches to DNA sequencing. Most DNA sequencing techniques produce short fragments of sequence that need to be assembled to obtain complete gene or genome sequences. The so-called shotgun sequencing technique which was used, for example, by The Institute for Genomic Research TIGR to sequence the first bacterial genome, Haemophilus influenzae [19] generates the sequences of many thousands of small DNA fragments ranging from 35 to nucleotides long, depending on the sequencing technology.

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The ends of these fragments overlap and, when aligned properly by a genome assembly program, can be used to reconstruct the complete genome. Shotgun sequencing yields sequence data quickly, but the task of assembling the fragments can be quite complicated for larger genomes. For a genome as large as the human genome , it may take many days of CPU time on large-memory, multiprocessor computers to assemble the fragments, and the resulting assembly usually contains numerous gaps that must be filled in later.

Shotgun sequencing is the method of choice for virtually all genomes sequenced today [ when? In the context of genomics , annotation is the process of marking the genes and other biological features in a DNA sequence.


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This process needs to be automated because most genomes are too large to annotate by hand, not to mention the desire to annotate as many genomes as possible, as the rate of sequencing has ceased to pose a bottleneck. Annotation is made possible by the fact that genes have recognisable start and stop regions, although the exact sequence found in these regions can vary between genes.

The first description of a comprehensive genome annotation system was published in [19] by the team at The Institute for Genomic Research that performed the first complete sequencing and analysis of the genome of a free-living organism, the bacterium Haemophilus influenzae.

Most current genome annotation systems work similarly, but the programs available for analysis of genomic DNA, such as the GeneMark program trained and used to find protein-coding genes in Haemophilus influenzae , are constantly changing and improving.

Following the goals that the Human Genome Project left to achieve after its closure in , a new project developed by the National Human Genome Research Institute in the U. S appeared.

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The so-called ENCODE project is a collaborative data collection of the functional elements of the human genome that uses next-generation DNA-sequencing technologies and genomic tiling arrays, technologies able to automatically generate large amounts of data at a dramatically reduced per-base cost but with the same accuracy base call error and fidelity assembly error. Evolutionary biology is the study of the origin and descent of species , as well as their change over time. Informatics has assisted evolutionary biologists by enabling researchers to:. Future work endeavours to reconstruct the now more complex tree of life.

The area of research within computer science that uses genetic algorithms is sometimes confused with computational evolutionary biology, but the two areas are not necessarily related. The core of comparative genome analysis is the establishment of the correspondence between genes orthology analysis or other genomic features in different organisms. It is these intergenomic maps that make it possible to trace the evolutionary processes responsible for the divergence of two genomes.

A multitude of evolutionary events acting at various organizational levels shape genome evolution. At the lowest level, point mutations affect individual nucleotides. At a higher level, large chromosomal segments undergo duplication, lateral transfer, inversion, transposition, deletion and insertion.

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The complexity of genome evolution poses many exciting challenges to developers of mathematical models and algorithms, who have recourse to a spectrum of algorithmic, statistical and mathematical techniques, ranging from exact, heuristics , fixed parameter and approximation algorithms for problems based on parsimony models to Markov chain Monte Carlo algorithms for Bayesian analysis of problems based on probabilistic models. Many of these studies are based on the detection of sequence homology to assign sequences to protein families.

Pan genomics is a concept introduced in by Tettelin and Medini which eventually took root in bioinformatics. Pan genome is the complete gene repertoire of a particular taxonomic group: although initially applied to closely related strains of a species, it can be applied to a larger context like genus, phylum etc. With the advent of next-generation sequencing we are obtaining enough sequence data to map the genes of complex diseases infertility , [24] breast cancer [25] or Alzheimer's disease.

Many studies are discussing both the promising ways to choose the genes to be used and the problems and pitfalls of using genes to predict disease presence or prognosis. In cancer , the genomes of affected cells are rearranged in complex or even unpredictable ways. Massive sequencing efforts are used to identify previously unknown point mutations in a variety of genes in cancer.

Bioinformaticians continue to produce specialized automated systems to manage the sheer volume of sequence data produced, and they create new algorithms and software to compare the sequencing results to the growing collection of human genome sequences and germline polymorphisms. New physical detection technologies are employed, such as oligonucleotide microarrays to identify chromosomal gains and losses called comparative genomic hybridization , and single-nucleotide polymorphism arrays to detect known point mutations.

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These detection methods simultaneously measure several hundred thousand sites throughout the genome, and when used in high-throughput to measure thousands of samples, generate terabytes of data per experiment. Again the massive amounts and new types of data generate new opportunities for bioinformaticians.

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The data is often found to contain considerable variability, or noise , and thus Hidden Markov model and change-point analysis methods are being developed to infer real copy number changes. Two important principles can be used in the analysis of cancer genomes bioinformatically pertaining to the identification of mutations in the exome. First, cancer is a disease of accumulated somatic mutations in genes. Second cancer contains driver mutations which need to be distinguished from passengers. With the breakthroughs that this next-generation sequencing technology is providing to the field of Bioinformatics, cancer genomics could drastically change.

These new methods and software allow bioinformaticians to sequence many cancer genomes quickly and affordably. This could create a more flexible process for classifying types of cancer by analysis of cancer driven mutations in the genome. Furthermore, tracking of patients while the disease progresses may be possible in the future with the sequence of cancer samples. Another type of data that requires novel informatics development is the analysis of lesions found to be recurrent among many tumors.

Protein microarrays and high throughput HT mass spectrometry MS can provide a snapshot of the proteins present in a biological sample. Bioinformatics is very much involved in making sense of protein microarray and HT MS data; the former approach faces similar problems as with microarrays targeted at mRNA, the latter involves the problem of matching large amounts of mass data against predicted masses from protein sequence databases, and the complicated statistical analysis of samples where multiple, but incomplete peptides from each protein are detected.

Cellular protein localization in a tissue context can be achieved through affinity proteomics displayed as spatial data based on immunohistochemistry and tissue microarrays.

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Gene regulation is the complex orchestration of events by which a signal, potentially an extracellular signal such as a hormone , eventually leads to an increase or decrease in the activity of one or more proteins. Bioinformatics techniques have been applied to explore various steps in this process. For example, gene expression can be regulated by nearby elements in the genome. Promoter analysis involves the identification and study of sequence motifs in the DNA surrounding the coding region of a gene.

These motifs influence the extent to which that region is transcribed into mRNA. Enhancer elements far away from the promoter can also regulate gene expression, through three-dimensional looping interactions. These interactions can be determined by bioinformatic analysis of chromosome conformation capture experiments.

Expression data can be used to infer gene regulation: one might compare microarray data from a wide variety of states of an organism to form hypotheses about the genes involved in each state. In a single-cell organism, one might compare stages of the cell cycle , along with various stress conditions heat shock, starvation, etc. One can then apply clustering algorithms to that expression data to determine which genes are co-expressed.

For example, the upstream regions promoters of co-expressed genes can be searched for over-represented regulatory elements. Examples of clustering algorithms applied in gene clustering are k-means clustering , self-organizing maps SOMs , hierarchical clustering , and consensus clustering methods. Several approaches have been developed to analyze the location of organelles, genes, proteins, and other components within cells. This is relevant as the location of these components affects the events within a cell and thus helps us to predict the behavior of biological systems.

A gene ontology category, cellular compartment , has been devised to capture subcellular localization in many biological databases. Microscopic pictures allow us to locate both organelles as well as molecules.

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It may also help us to distinguish between normal and abnormal cells, e. The localization of proteins helps us to evaluate the role of a protein. For instance, if a protein is found in the nucleus it may be involved in gene regulation or splicing. By contrast, if a protein is found in mitochondria , it may be involved in respiration or other metabolic processes. Protein localization is thus an important component of protein function prediction. There are well developed protein subcellular localization prediction resources available, including protein subcellular location databases, and prediction tools.

Analysis of these experiments can determine the three-dimensional structure and nuclear organization of chromatin. Bioinformatic challenges in this field include partitioning the genome into domains, such as Topologically Associating Domains TADs , that are organised together in three-dimensional space. Protein structure prediction is another important application of bioinformatics.

The amino acid sequence of a protein, the so-called primary structure , can be easily determined from the sequence on the gene that codes for it. In the vast majority of cases, this primary structure uniquely determines a structure in its native environment. Of course, there are exceptions, such as the bovine spongiform encephalopathy — a.


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Mad Cow Disease — prion. Knowledge of this structure is vital in understanding the function of the protein. Structural information is usually classified as one of secondary , tertiary and quaternary structure. A viable general solution to such predictions remains an open problem. Most efforts have so far been directed towards heuristics that work most of the time. One of the key ideas in bioinformatics is the notion of homology. In the genomic branch of bioinformatics, homology is used to predict the function of a gene: if the sequence of gene A , whose function is known, is homologous to the sequence of gene B, whose function is unknown, one could infer that B may share A's function.

In the structural branch of bioinformatics, homology is used to determine which parts of a protein are important in structure formation and interaction with other proteins. In a technique called homology modeling , this information is used to predict the structure of a protein once the structure of a homologous protein is known. This currently remains the only way to predict protein structures reliably.