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Bioinformatics is an interdisciplinary field of science that develops methods and software tools for understanding biological data, especially when the data sets are large and complex. Bioinformatics uses biology, chemistry, physics, computer science, computer programming, information engineering, mathematics and statistics to analyze and interpret biological data. The subsequent process of analyzing and interpreting data is referred to as computational biology.
Genetics is the study of genes, genetic variation, and heredity in organisms. It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar working in the 19th century in Brno, was the first to study genetics scientifically. Mendel studied "trait inheritance", patterns in the way traits are handed down from parents to offspring over time. He observed that organisms inherit traits by way of discrete "units of inheritance". This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.
The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria. These are usually treated separately as the nuclear genome and the mitochondrial genome. Human genomes include both protein-coding DNA sequences and various types of DNA that does not encode proteins. The latter is a diverse category that includes DNA coding for non-translated RNA, such as that for ribosomal RNA, transfer RNA, ribozymes, small nuclear RNAs, and several types of regulatory RNAs. It also includes promoters and their associated gene-regulatory elements, DNA playing structural and replicatory roles, such as scaffolding regions, telomeres, centromeres, and origins of replication, plus large numbers of transposable elements, inserted viral DNA, non-functional pseudogenes and simple, highly repetitive sequences. Introns make up a large percentage of non-coding DNA. Some of this non-coding DNA is non-functional junk DNA, such as pseudogenes, but there is no firm consensus on the total amount of junk DNA.
Genomics is an interdisciplinary field of molecular biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dimensional structural configuration. In contrast to genetics, which refers to the study of individual genes and their roles in inheritance, genomics aims at the collective characterization and quantification of all of an organism's genes, their interrelations and influence on the organism. Genes may direct the production of proteins with the assistance of enzymes and messenger molecules. In turn, proteins make up body structures such as organs and tissues as well as control chemical reactions and carry signals between cells. Genomics also involves the sequencing and analysis of genomes through uses of high throughput DNA sequencing and bioinformatics to assemble and analyze the function and structure of entire genomes. Advances in genomics have triggered a revolution in discovery-based research and systems biology to facilitate understanding of even the most complex biological systems such as the brain.
A DNA sequencer is a scientific instrument used to automate the DNA sequencing process. Given a sample of DNA, a DNA sequencer is used to determine the order of the four bases: G (guanine), C (cytosine), A (adenine) and T (thymine). This is then reported as a text string, called a read. Some DNA sequencers can be also considered optical instruments as they analyze light signals originating from fluorochromes attached to nucleotides.
In bioinformatics, sequence analysis is the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. It can be performed on the entire genome, transcriptome or proteome of an organism, and can also involve only selected segments or regions, like tandem repeats and transposable elements. Methodologies used include sequence alignment, searches against biological databases, and others.
Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.
In bioinformatics, sequence assembly refers to aligning and merging fragments from a longer DNA sequence in order to reconstruct the original sequence. This is needed as DNA sequencing technology might not be able to 'read' whole genomes in one go, but rather reads small pieces of between 20 and 30,000 bases, depending on the technology used. Typically, the short fragments (reads) result from shotgun sequencing genomic DNA, or gene transcript (ESTs).
Comparative genomics is a branch of biological research that examines genome sequences across a spectrum of species, spanning from humans and mice to a diverse array of organisms from bacteria to chimpanzees. This large-scale holistic approach compares two or more genomes to discover the similarities and differences between the genomes and to study the biology of the individual genomes. Comparison of whole genome sequences provides a highly detailed view of how organisms are related to each other at the gene level. By comparing whole genome sequences, researchers gain insights into genetic relationships between organisms and study evolutionary changes. The major principle of comparative genomics is that common features of two organisms will often be encoded within the DNA that is evolutionarily conserved between them. Therefore, Comparative genomics provides a powerful tool for studying evolutionary changes among organisms, helping to identify genes that are conserved or common among species, as well as genes that give unique characteristics of each organism. Moreover, these studies can be performed at different levels of the genomes to obtain multiple perspectives about the organisms.
DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. The advent of rapid DNA sequencing methods has greatly accelerated biological and medical research and discovery.
Sanger sequencing is a method of DNA sequencing that involves electrophoresis and is based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Frederick Sanger and colleagues in 1977, it became the most widely used sequencing method for approximately 40 years. It was first commercialized by Applied Biosystems in 1986. More recently, higher volume Sanger sequencing has been replaced by next generation sequencing methods, especially for large-scale, automated genome analyses. However, the Sanger method remains in wide use for smaller-scale projects and for validation of deep sequencing results. It still has the advantage over short-read sequencing technologies in that it can produce DNA sequence reads of > 500 nucleotides and maintains a very low error rate with accuracies around 99.99%. Sanger sequencing is still actively being used in efforts for public health initiatives such as sequencing the spike protein from SARS-CoV-2 as well as for the surveillance of norovirus outbreaks through the Center for Disease Control and Prevention's (CDC) CaliciNet surveillance network.
Gene mapping or genome mapping describes the methods used to identify the location of a gene on a chromosome and the distances between genes. Gene mapping can also describe the distances between different sites within a gene.
Coalescent theory is a model of how alleles sampled from a population may have originated from a common ancestor. In the simplest case, coalescent theory assumes no recombination, no natural selection, and no gene flow or population structure, meaning that each variant is equally likely to have been passed from one generation to the next. The model looks backward in time, merging alleles into a single ancestral copy according to a random process in coalescence events. Under this model, the expected time between successive coalescence events increases almost exponentially back in time. Variance in the model comes from both the random passing of alleles from one generation to the next, and the random occurrence of mutations in these alleles.
The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a physical and a functional standpoint. It started in 1990 and was completed in 2003. It remains the world's largest collaborative biological project. Planning for the project started after it was adopted in 1984 by the US government, and it officially launched in 1990. It was declared complete on April 14, 2003, and included about 92% of the genome. Level "complete genome" was achieved in May 2021, with only 0.3% of the bases covered by potential issues. The final gapless assembly was finished in January 2022.
A Phred quality score is a measure of the quality of the identification of the nucleobases generated by automated DNA sequencing. It was originally developed for the computer program Phred to help in the automation of DNA sequencing in the Human Genome Project. Phred quality scores are assigned to each nucleotide base call in automated sequencer traces. The FASTQ format encodes phred scores as ASCII characters alongside the read sequences. Phred quality scores have become widely accepted to characterize the quality of DNA sequences, and can be used to compare the efficacy of different sequencing methods. Perhaps the most important use of Phred quality scores is the automatic determination of accurate, quality-based consensus sequences.
Bisulfitesequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the most studied. In animals it predominantly involves the addition of a methyl group to the carbon-5 position of cytosine residues of the dinucleotide CpG, and is implicated in repression of transcriptional activity.
Population genomics is the large-scale comparison of DNA sequences of populations. Population genomics is a neologism that is associated with population genetics. Population genomics studies genome-wide effects to improve our understanding of microevolution so that we may learn the phylogenetic history and demography of a population.
Phred is a computer program for base calling, that is to say, identifying a nucleobase sequence from fluorescence "trace" data generated by an automated DNA sequencer that uses electrophoresis and 4-fluorescent dye method. When originally developed, Phred produced significantly fewer errors in the data sets examined than other methods, averaging 40–50% fewer errors. Phred quality scores have become widely accepted to characterize the quality of DNA sequences, and can be used to compare the efficacy of different sequencing methods.
Ladeana Hillier is a biomedical engineer and computational biologist. She was one of the earliest scientists involved in the Human Genome Project and is noted for her work in various branches of DNA sequencing, as well as for having co-developed Phred, a widely used DNA trace analyzer.
Michael Christopher Wendl is a mathematician and biomedical engineer who has worked on DNA sequencing theory, covering and matching problems in probability, theoretical fluid mechanics, and co-wrote Phred. He was a scientist on the Human Genome Project and has done bioinformatics and biostatistics work in cancer. Wendl is of ethnic German heritage and is the son of the aerospace engineer Michael J. Wendl.
References
- ↑ Ewing, B., Hillier, L., Wendl, M.C., and Green, P. (1998) Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 8(3), 175–185. PMID 9521921 full article
- ↑ Koboldt, D. C. and Miller, R. D. (2011) Identification of Polymorphic Markers for Genetic Mapping, chapter 2 in "Genomics: Essential Methods", John Wiley and Sons.
- ↑ Highsmith, W. E. (2006) Electrophoretic Methods for Mutation Detection and DNA Sequencing, chapter 9 in "Molecular Diagnostics for the Clinical Laboratorian", Humana Press
- ↑ Lander, E.S. and Green, P. (1987) Construction of multilocus genetic-linkage maps in humans. PNAS 84(8), 2363–2367.
- ↑ Ewing, B. and Green, P. (2000) Analysis of expressed sequence tags indicates 35,000 human genes. Nature Genetics 25(2), 232–234.
- ↑ Green, P. et al. (1993) Ancient conserved regions in new gene-sequences and the protein databases. Science 259(5102), 1711–1716.
- ↑ National Academy of Sciences (2004) Biography of Phil Green. PNAS 101(39), 13991–13993.
