How to make humans

Compilation of free information about human parts, their function, assembly,  repair, and maintenance

DNA

Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions for the development and functioning of living organisms. All living things contain DNA genomes. A possible exception is a group of viruses that have RNA genomes, but viruses are not normally considered living organisms. The main role of DNA in the cell is the long-term storage of information. The genome is often compared to a set of blueprints, since it contains the instructions to construct other components of the cell, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the expression of genetic information.

The structure of part of a DNA double helix

The structure of part of a DNA double helix

In eukaryotes such as animals and plants, DNA is stored inside the cell nucleus, while in prokaryotes such as bacteria, the DNA is in the cell's cytoplasm. Unlike enzymes, DNA does not participate directly in most of the biochemical reactions it controls; rather, various enzymes act on DNA and copy its information into either more DNA, in DNA replication, or transcribe and translate it into protein. In chromosomes, chromatin proteins such as histones compact and organize DNA, which helps control its interactions with other proteins in the nucleus.

DNA is a long polymer of simple units called nucleotides, which are held together by a backbone made of sugars and phosphate groups. This backbone carries four types of molecules called bases, and it is the sequence of these four bases that encodes information. The major function of DNA is to encode the sequence of amino acid residues in proteins, using the genetic code. To read the genetic code, cells make a copy of a stretch of DNA in the nucleic acid RNA. Some RNA copies are used to direct protein biosynthesis, but others are used directly as parts of ribosomes or spliceosomes.

Base pairing

Each type of base on one strand forms a bond with just one type of base on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G. This arrangement of two nucleotides joined together across the double helix is called a base pair. In a double helix, the two strands are also held together by forces generated by the hydrophobic effect and pi stacking, but these forces are not affected by the sequence of the DNA.[14] As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical force or high temperature.[15] As a result of this complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[1]

The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, left). The GC base pair is therefore stronger than the AT base pair. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determine the strength of the association between the two strands of DNA. Long DNA helices with a high GC content have strongly interacting strands, while short helices with high AT content have weakly interacting strands.[16] Parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in bacterial promoters, tend to have sequences with a high AT content, making the strands easier to pull apart.[17] In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single shape, but some conformations are more stable than others.[18] The base pairing, or lack of it, can create various topologies at the DNA end. These can be exploited in biotechnology.

Sense and antisense

Further information: Sense (molecular biology)

A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA (mRNA) copy that is translated into protein. The sequence on the opposite strand is complementary to the sense sequence and is therefore called the "antisense" sequence. Since RNA polymerases work by making a complementary copy of their templates, it is this antisense strand that is the template for producing the sense mRNA. Both sense and antisense sequences can exist on different parts of the same strand of DNA. In both prokaryotes and eukaryotes, antisense sequences are transcribed, but the functions of these RNAs are not entirely clear.[19] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.[20]

A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction made above between sense and antisense strands by having overlapping genes.[21] In these cases, some DNA sequences do double duty, encoding one protein when read 5' to 3' along one strand, and a second protein when read in the opposite direction (still 5' to 3') along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[22] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[23] Another way of reducing genome size is seen in some viruses that contain linear or circular single-stranded DNA as their genetic material.[24][25]

Supercoiling

Further information: DNA supercoil

DNA can be twisted like a rope in a process called DNA supercoiling. Normally, with DNA in its "relaxed" state, a strand circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.[26] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.[27] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.[28]

Structure of a DNA quadruplex formed by telomere repeats.
Structure of a DNA quadruplex formed by telomere repeats.[36]

Quadruplex structures

At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as normal DNA polymerases working on the lagging strand cannot copy the extreme 3' ends of their DNA templates.[37] If a chromosome lacked telomeres it would become shorter each time it was replicated. These specialized chromosome caps also help protect the DNA ends from exonucleases and stop the DNA repair systems in the cell from treating them as damage to be corrected.[38] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[39]

These guanine-rich sequences may stabilize chromosome ends by forming very unusual quadruplex structures. Here, four guanine bases form a flat plate, through hydrogen bonding, and these flat four-base units then stack on top of each other, to form a stable quadruplex.[40] These structures are often stabilized by chelation of a metal ion in the centre of each four-base unit. The structure shown to the left is of a quadruplex formed by a DNA sequence containing four consecutive human telomere repeats. The single DNA strand forms a loop, with the sets of four bases stacking in a central quadruplex three plates deep. In the space at the centre of the stacked bases are three chelated potassium ions.[41] Other structures can also be formed and the central set of four bases can come from either one folded strand, or several different parallel strands.

In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a circle stabilized by telomere-binding proteins.[42] The very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.[40]

Chemical modifications

Regulatory base modifications

Further information: DNA methylation

The expression of genes is influenced by modifications of the bases in DNA. In humans, the most common base modification is cytosine methylation to produce 5-methylcytosine. This modification reduces gene expression and is important in X-chromosome inactivation.[43] The level of methylation varies between organisms, with Caenorhabditis elegans lacking cytosine methylation, while vertebrates show high levels, with up to 1% of their DNA being 5-methylcytosine.[44] Unfortunately, the spontaneous deamination of 5-methylcytosine produces thymine, and methylated cytosines are therefore mutation hotspots.[45] Other base modifications include adenine methylation in bacteria and the glycosylation of uracil to produce the "J-base" in kinetoplastids.[46][47]

DNA damage

Further information: Mutation
Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA.
Benzopyrene, the major mutagen in tobacco smoke, in an adduct to DNA.[48]

DNA can be damaged by many different sorts of mutagens. These include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and x-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light mostly damages DNA by producing thymine dimers, which are cross-links between adjacent pyrimidine bases in a DNA strand.[49] On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, as well as double-strand breaks.[50] It has been estimated that in each human cell, about 500 bases suffer oxidative damage per day.[51][52] Of these oxidative lesions, the most dangerous are double-strand breaks, as these lesions are difficult to repair and can produce point mutations, insertions and deletions from the DNA sequence, as well as chromosomal translocations.[53]

Many mutagens intercalate into the space between two adjacent base pairs. Intercalators are mostly polycyclic, aromatic, and planar molecules, and include ethidium, proflavin, daunomycin, doxorubicin and thalidomide. DNA intercalators are used in chemotherapy to inhibit DNA replication in rapidly-growing cancer cells.[54] In order for an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. These structural modifications inhibit transcription and replication processes, causing both toxicity and mutations. As a result, DNA intercalators are often carcinogens, with benzopyrene diol epoxide, acridines, aflatoxin and ethidium bromide being well-known examples.[55][56][57]

Overview of biological functions

The information carried by DNA is held in the sequence of pieces of DNA called genes. Genetic information in genes is transmitted through complementary base pairing. For example, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence in a process called transcription. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation. Alternatively, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here we focus on the interactions that happen in these processes between DNA and other molecules.

T7 RNA polymerase producing a mRNA (green) from a DNA template (red and blue). The protein is shown as a purple ribbon.
T7 RNA polymerase producing a mRNA (green) from a DNA template (red and blue). The protein is shown as a purple ribbon.[58]

Transcription and translation

Further information: Genetic code, Transcription (genetics), Protein biosynthesis

A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines a protein sequence. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids. Most amino acids, therefore, have more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA and TAG codons.

DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.
DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.

Replication

Further information: DNA replication

Cell division is essential for an organism to grow, but when a cell divides it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5' to 3' direction, different mechanisms are used to copy the antiparallel strands of the double helix.[59] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

Genes and genomes

Further information: Cell nucleus, Gene, Non-coding DNA

DNA is located in the cell nucleus of eukaryotes, as well as small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.[60] The DNA is usually in linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. In the human genome, there is approximately 3 billion base pairs of DNA arranged into 46 chromosomes.[61] The genetic information in a genome is held within genes. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such as promoters and enhancers, which control the expression of the open reading frame.

In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.[62] The reasons for the presence of so much non-coding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma."[63]

Some non-coding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.[38][64] An abundant form of non-coding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.[65] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.[66]

 

 

Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are coloured red, blue, green and yellow.[89]
Further information: Genetic recombination
Recombination involves the breakage and rejoining of two chromosomes (M and F) to produce two re-arranged chromosomes (C1 and C2).
Recombination involves the breakage and rejoining of two chromosomes (M and F) to produce two re-arranged chromosomes (C1 and C2).

A DNA helix does not usually interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".[90]/a> This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is when they recombine. Recombination is when two DNA helices break, swap a section and then rejoin. In eukaryotes this process usually occurs during meiosis, when the two sister chromatids are paired together in the center of the cell. Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of selection and can be important in the rapid evolution of new proteins.[91] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.[92]

The most common form of recombination is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as Cre recombinase.[93] In the first step, the recombinase creates a nick in one strand of a DNA double helix, allowing the nicked strand to pull apart from its complementary strand and anneal to one strand of the double helix on the opposite chromatid. A second nick allows the strand in the second chromatid to pull apart and anneal to the remaining strand in the first helix, forming a structure known as a cross-strand exchange or a Holliday junction. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.[94]

Evolution of DNA-based metabolism

DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.[84][95] RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.[96] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur since the number of unique bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[97]

Unfortunately, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible. This is because DNA will survive in the environment for less than one million years and slowly degrades into short fragments in solution.[98] Although claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250-million years old,[99] these claims are controversial and have been disputed.[100][101]

Uses in technology

Further information: Molecular biology and genetic engineering

Modern biology and biochemistry make intensive use of recombinant DNA technology. Recombinant DNA is a man-made DNA sequence assembled from other DNA sequences in a plasmid. These plasmids can be transformed into organisms. The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research,[102] or be grown in agriculture.[103][104]

Forensics

Further information: Genetic fingerprinting

Forensic scientists can use DNA in blood, semen, skin, saliva or hair at a crime scene to identify a perpetrator. This process is called genetic fingerprinting, or more accurately, DNA profiling. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a criminal.[105] However, identification can be complicated if the scene is contaminated with DNA from several people.[106] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[107] and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[108] People convicted of certain types of crimes may be required to provide a sample of DNA for a database. This has helped investigators solve old cases where only a DNA sample was obtained from the scene. DNA profiling can also be used to identify victims of mass casualty incidents.[109]

Bioinformatics

Further information: Bioinformatics

Bioinformatics involves the manipulation, searching, and data mining of DNA sequence data. The development of techniques to store and search DNA sequences have led to widely-applied advances in computer science, especially string searching algorithms, machine learning and database theory.[110] String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.[111] In other applications such as text editors, even simple algorithms for this problem usually suffice, but DNA sequences cause these algorithms to exhibit near-worst-case behaviour due to their small number of distinct characters. The related problem of sequence alignment aims to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.[112] Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without annotations, which label the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products in an organism even before they have been isolated experimentally.[113]

DNA and computation

Further information: DNA computing

DNA was first used in computing to solve a small version of the directed Hamiltonian path problem, an NP-complete problem.[114] DNA computing is advantageous over electronic computers in power use, space use, and efficiency, due to its ability to compute in a highly parallel fashion (see parallel computing). A number of other problems, including simulation of various abstract machines, the boolean satisfiability problem, and the bounded version of the travelling salesman problem, have since been analysed using DNA computing.[115] Due to its compactness, DNA also has a theoretical role in cryptography, where in particular it allows unbreakable one-time pads to be efficiently constructed and used.[116]

History and anthropology

Further information: Phylogenetics and Genetic genealogy

Because DNA collects mutations over time, which are then inherited, it contains historical information and by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.[117] This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology; for example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.[118][119]

DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes has matched relatives of the guilty individual.[120]

DNA has a start date also. This can be dated back using an array of other methods to isolate a window in the past where RNA and DNA become distict paths to persent times.

See also

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The content of this section is licensed under the GNU Free Documentation License (local copy). It uses material from the Wikipedia article "DNA" modified April 1, 2007 with previous authors listed in its history.

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