104-624: Human accelerated regions ( HARs ), first described in August 2006, are a set of 49 segments of the human genome that are conserved throughout vertebrate evolution but are strikingly different in humans . They are named according to their degree of difference between humans and chimpanzees (HAR1 showing the largest degree of human-chimpanzee differences). Found by scanning through genomic databases of multiple species, some of these highly mutated areas may contribute to human-specific traits. Others may represent loss of functional mutations, possibly due to
208-481: A Creative Commons public domain license . The Personal Genome Project (started in 2005) is among the few to make both genome sequences and corresponding medical phenotypes publicly available. The sequencing of individual genomes further unveiled levels of genetic complexity that had not been appreciated before. Personal genomics helped reveal the significant level of diversity in the human genome attributed not only to SNPs but structural variations as well. However,
312-531: A cause and effect relationship between aneuploidy and cancer has not been established. Whereas a genome sequence lists the order of every DNA base in a genome, a genome map identifies the landmarks. A genome map is less detailed than a genome sequence and aids in navigating around the genome. An example of a variation map is the HapMap being developed by the International HapMap Project . The HapMap
416-484: A 1993 Nobel to Philip Sharp and Richard Roberts . Catalytic RNA molecules ( ribozymes ) were discovered in the early 1980s, leading to a 1989 Nobel award to Thomas Cech and Sidney Altman . In 1990, it was found in Petunia that introduced genes can silence similar genes of the plant's own, now known to be a result of RNA interference . At about the same time, 22 nt long RNAs, now called microRNAs , were found to have
520-425: A certain amount of time, the message degrades into its component nucleotides with the assistance of ribonucleases . Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anticodon region for codon recognition that binds to
624-456: A chromosome; ultra-rare means that they are only found in individuals or their family members and thus have arisen very recently. Single-nucleotide polymorphisms (SNPs) do not occur homogeneously across the human genome. In fact, there is enormous diversity in SNP frequency between genes, reflecting different selective pressures on each gene as well as different mutation and recombination rates across
728-483: A human female genome, filling all the gaps in the X chromosome (2020) and the 22 autosomes (May 2021). The previously unsequenced parts contain immune response genes that help to adapt to and survive infections, as well as genes that are important for predicting drug response . The completed human genome sequence will also provide better understanding of human formation as an individual organism and how humans vary both between each other and other species. Although
832-528: 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. Although the sequence of the human genome has been completely determined by DNA sequencing in 2022 (including methylome ), it is not yet fully understood. Most, but not all, genes have been identified by a combination of high throughput experimental and bioinformatics approaches, yet much work still needs to be done to further elucidate
936-480: A major role in sculpting the human genome. Some of these sequences represent endogenous retroviruses , DNA copies of viral sequences that have become permanently integrated into the genome and are now passed on to succeeding generations. There are also a significant number of retroviruses in human DNA , at least 3 of which have been proven to possess an important function (i.e., HIV -like functional HERV-K; envelope genes of non-functional viruses HERV-W and HERV-FRD play
1040-783: A microsatellite hexanucleotide repeat of the sequence (TTAGGG) n . Tandem repeats of longer sequences (arrays of repeated sequences 10–60 nucleotides long) are termed minisatellites . Transposable genetic elements , DNA sequences that can replicate and insert copies of themselves at other locations within a host genome, are an abundant component in the human genome. The most abundant transposon lineage, Alu , has about 50,000 active copies, and can be inserted into intragenic and intergenic regions. One other lineage, LINE-1, has about 100 active copies per genome (the number varies between people). Together with non-functional relics of old transposons, they account for over half of total human DNA. Sometimes called "jumping genes", transposons have played
1144-682: A negative charge each, making RNA a charged molecule (polyanion). The bases form hydrogen bonds between cytosine and guanine, between adenine and uracil and between guanine and uracil. However, other interactions are possible, such as a group of adenine bases binding to each other in a bulge, or the GNRA tetraloop that has a guanine–adenine base-pair. The chemical structure of RNA is very similar to that of DNA , but differs in three primary ways: Like DNA, most biologically active RNAs, including mRNA , tRNA , rRNA , snRNAs , and other non-coding RNAs , contain self-complementary sequences that allow parts of
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#17328756116241248-644: A nucleoprotein called a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a single mRNA at any time. Nearly all the RNA found in a typical eukaryotic cell is rRNA. Transfer-messenger RNA (tmRNA) is found in many bacteria and plastids . It tags proteins encoded by mRNAs that lack stop codons for degradation and prevents the ribosome from stalling. The earliest known regulators of gene expression were proteins known as repressors and activators – regulators with specific short binding sites within enhancer regions near
1352-547: A nucleus, also contain nucleic acids. The role of RNA in protein synthesis was suspected already in 1939. Severo Ochoa won the 1959 Nobel Prize in Medicine (shared with Arthur Kornberg ) after he discovered an enzyme that can synthesize RNA in the laboratory. However, the enzyme discovered by Ochoa ( polynucleotide phosphorylase ) was later shown to be responsible for RNA degradation, not RNA synthesis. In 1956 Alex Rich and David Davies hybridized two separate strands of RNA to form
1456-544: A number of RNA-dependent RNA polymerases that use RNA as their template for synthesis of a new strand of RNA. For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their genetic material. Also, RNA-dependent RNA polymerase is part of the RNA interference pathway in many organisms. Many RNAs are involved in modifying other RNAs. Introns are spliced out of pre-mRNA by spliceosomes , which contain several small nuclear RNAs (snRNA), or
1560-457: A pathogen and determine which molecular parts to extract, inactivate, and use in a vaccine. Small molecules with conventional therapeutic properties can target RNA and DNA structures, thereby treating novel diseases. However, research is scarce on small molecules targeting RNA and approved drugs for human illness. Ribavirin, branaplam, and ataluren are currently available medications that stabilize double-stranded RNA structures and control splicing in
1664-410: A role in placenta formation by inducing cell-cell fusion). Mobile elements within the human genome can be classified into LTR retrotransposons (8.3% of total genome), SINEs (13.1% of total genome) including Alu elements , LINEs (20.4% of total genome), SVAs (SINE- VNTR -Alu) and Class II DNA transposons (2.9% of total genome). There is no consensus on what constitutes a "functional" element in
1768-468: A role in the development of C. elegans . Studies on RNA interference earned a Nobel Prize for Andrew Fire and Craig Mello in 2006, and another Nobel for studies on the transcription of RNA to Roger Kornberg in the same year. The discovery of gene regulatory RNAs has led to attempts to develop drugs made of RNA, such as siRNA , to silence genes. Adding to the Nobel prizes for research on RNA, in 2009 it
1872-417: A role in the activation of the innate immune system against viral infections. In the late 1970s, it was shown that there is a single stranded covalently closed, i.e. circular form of RNA expressed throughout the animal and plant kingdom (see circRNA ). circRNAs are thought to arise via a "back-splice" reaction where the spliceosome joins a upstream 3' acceptor to a downstream 5' donor splice site. So far
1976-480: A single individual, later revealed to have been Venter himself. Thus the Celera human genome sequence released in 2000 was largely that of one man. Subsequent replacement of the early composite-derived data and determination of the diploid sequence, representing both sets of chromosomes , rather than a haploid sequence originally reported, allowed the release of the first personal genome. In April 2008, that of James Watson
2080-455: A specific sequence on the messenger RNA chain through hydrogen bonding. Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. The rRNA is the component of the ribosome that hosts translation. Eukaryotic ribosomes contain four different rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus , and one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form
2184-431: A specific spatial tertiary structure . The scaffold for this structure is provided by secondary structural elements that are hydrogen bonds within the molecule. This leads to several recognizable "domains" of secondary structure like hairpin loops , bulges, and internal loops . In order to create, i.e., design, RNA for any given secondary structure, two or three bases would not be enough, but four bases are enough. This
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#17328756116242288-399: A uniform density. Thus follows the popular statement that "we are all, regardless of race , genetically 99.9% the same", although this would be somewhat qualified by most geneticists. For example, a much larger fraction of the genome is now thought to be involved in copy number variation . A large-scale collaborative effort to catalog SNP variations in the human genome is being undertaken by
2392-809: A variety of disorders. Protein-coding mRNAs have emerged as new therapeutic candidates, with RNA replacement being particularly beneficial for brief but torrential protein expression. In vitro transcribed mRNAs (IVT-mRNA) have been used to deliver proteins for bone regeneration, pluripotency, and heart function in animal models. SiRNAs, short RNA molecules, play a crucial role in innate defense against viruses and chromatin structure. They can be artificially introduced to silence specific genes, making them valuable for gene function studies, therapeutic target validation, and drug development. mRNA vaccines have emerged as an important new class of vaccines, using mRNA to manufacture proteins which provoke an immune response. Their first successful large-scale application came in
2496-402: Is protein synthesis , a universal function in which RNA molecules direct the synthesis of proteins on ribosomes . This process uses transfer RNA ( tRNA ) molecules to deliver amino acids to the ribosome , where ribosomal RNA ( rRNA ) then links amino acids together to form coded proteins. It has become widely accepted in science that early in the history of life on Earth , prior to
2600-478: Is a haplotype map of the human genome, "which will describe the common patterns of human DNA sequence variation." It catalogs the patterns of small-scale variations in the genome that involve single DNA letters, or bases. Researchers published the first sequence-based map of large-scale structural variation across the human genome in the journal Nature in May 2008. Large-scale structural variations are differences in
2704-423: Is a ribozyme . Each nucleotide in RNA contains a ribose sugar, with carbons numbered 1' through 5'. A base is attached to the 1' position, in general, adenine (A), cytosine (C), guanine (G), or uracil (U). Adenine and guanine are purines , and cytosine and uracil are pyrimidines . A phosphate group is attached to the 3' position of one ribose and the 5' position of the next. The phosphate groups have
2808-569: Is assembled as a chain of nucleotides . Cellular organisms use messenger RNA ( mRNA ) to convey genetic information (using the nitrogenous bases of guanine , uracil , adenine , and cytosine , denoted by the letters G, U, A, and C) that directs synthesis of specific proteins. Many viruses encode their genetic information using an RNA genome . Some RNA molecules play an active role within cells by catalyzing biological reactions, controlling gene expression , or sensing and communicating responses to cellular signals. One of these active processes
2912-495: Is called enhancer RNAs . It is not clear at present whether they are a unique category of RNAs of various lengths or constitute a distinct subset of lncRNAs. In any case, they are transcribed from enhancers , which are known regulatory sites in the DNA near genes they regulate. They up-regulate the transcription of the gene(s) under control of the enhancer from which they are transcribed. At first, regulatory RNA
3016-583: Is deliterious to the organism and is under negative selective pressure is called garbage DNA. The first human genome sequences were published in nearly complete draft form in February 2001 by the Human Genome Project and Celera Corporation . Completion of the Human Genome Project's sequencing effort was announced in 2004 with the publication of a draft genome sequence, leaving just 341 gaps in
3120-419: Is likely why nature has "chosen" a four base alphabet: fewer than four would not allow the creation of all structures, while more than four bases are not necessary to do so. Since RNA is charged, metal ions such as Mg are needed to stabilise many secondary and tertiary structures . The naturally occurring enantiomer of RNA is D -RNA composed of D -ribonucleotides. All chirality centers are located in
3224-447: Is no consensus in the literature on the amount of functional DNA since, depending on how "function" is understood, ranges have been estimated from up to 90% of the human genome is likely nonfunctional DNA (junk DNA) to up to 80% of the genome is likely functional. It is also possible that junk DNA may acquire a function in the future and therefore may play a role in evolution, but this is likely to occur only very rarely. Finally DNA that
Human accelerated regions - Misplaced Pages Continue
3328-443: Is not present in fish or frogs that have been studied. There are 18 base pair mutations different between humans and chimpanzees, far more than expected by its history of conservation. HAR2 includes HACNS1 a gene enhancer "that may have contributed to the evolution of the uniquely opposable human thumb , and possibly also modifications in the ankle or foot that allow humans to walk on two legs". Evidence to date shows that of
3432-413: Is processed to mature mRNA. This removes its introns —non-coding sections of the pre-mRNA. The mRNA is then exported from the nucleus to the cytoplasm , where it is bound to ribosomes and translated into its corresponding protein form with the help of tRNA . In prokaryotic cells, which do not have nucleus and cytoplasm compartments, mRNA can bind to ribosomes while it is being transcribed from DNA. After
3536-501: Is unclear whether any significant phenotypic effect results from typical variation in repeats or heterochromatin. Most gross genomic mutations in gamete germ cells probably result in inviable embryos; however, a number of human diseases are related to large-scale genomic abnormalities. Down syndrome , Turner Syndrome , and a number of other diseases result from nondisjunction of entire chromosomes. Cancer cells frequently have aneuploidy of chromosomes and chromosome arms, although
3640-550: Is used as template for building the ends of eukaryotic chromosomes . Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells, but with the replacement of thymine by uracil and the adding of one oxygen atom. dsRNA forms the genetic material of some viruses ( double-stranded RNA viruses ). Double-stranded RNA, such as viral RNA or siRNA , can trigger RNA interference in eukaryotes , as well as interferon response in vertebrates . In eukaryotes, double-stranded RNA (dsRNA) plays
3744-547: The D -ribose. By the use of L -ribose or rather L -ribonucleotides, L -RNA can be synthesized. L -RNA is much more stable against degradation by RNase . Like other structured biopolymers such as proteins, one can define topology of a folded RNA molecule. This is often done based on arrangement of intra-chain contacts within a folded RNA, termed as circuit topology . RNA is transcribed with only four bases (adenine, cytosine, guanine and uracil), but these bases and attached sugars can be modified in numerous ways as
3848-969: The DNA within each of the 24 distinct chromosomes in the cell nucleus. A small DNA molecule is 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
3952-552: The International HapMap Project . The genomic loci and length of certain types of small repetitive sequences are highly variable from person to person, which is the basis of DNA fingerprinting and DNA paternity testing technologies. The heterochromatic portions of the human genome, which total several hundred million base pairs, are also thought to be quite variable within the human population (they are so repetitive and so long that they cannot be accurately sequenced with current technology). These regions contain few genes, and it
4056-493: The RNA World theory. There are indications that the enterobacterial sRNAs are involved in various cellular processes and seem to have significant role in stress responses such as membrane stress, starvation stress, phosphosugar stress and DNA damage. Also, it has been suggested that sRNAs have been evolved to have important role in stress responses because of their kinetic properties that allow for rapid response and stabilisation of
4160-453: The amino acid sequence in the protein that is produced. However, many RNAs do not code for protein (about 97% of the transcriptional output is non-protein-coding in eukaryotes ). These so-called non-coding RNAs ("ncRNA") can be encoded by their own genes (RNA genes), but can also derive from mRNA introns . The most prominent examples of non-coding RNAs are transfer RNA (tRNA) and ribosomal RNA (rRNA), both of which are involved in
4264-575: The galactic center of the Milky Way Galaxy . RNA, initially deemed unsuitable for therapeutics due to its short half-life, has been made useful through advances in stabilization. Therapeutic applications arise as RNA folds into complex conformations and binds proteins, nucleic acids, and small molecules to form catalytic centers. RNA-based vaccines are thought to be easier to produce than traditional vaccines derived from killed or altered pathogens, because it can take months or years to grow and study
Human accelerated regions - Misplaced Pages Continue
4368-414: The genetic code . There are more than 100 other naturally occurring modified nucleosides. The greatest structural diversity of modifications can be found in tRNA , while pseudouridine and nucleosides with 2'-O-methylribose often present in rRNA are the most common. The specific roles of many of these modifications in RNA are not fully understood. However, it is notable that, in ribosomal RNA, many of
4472-486: The 'completion' of the human genome project was announced in 2001, there remained hundreds of gaps, with about 5–10% of the total sequence remaining undetermined. The missing genetic information was mostly in repetitive heterochromatic regions and near the centromeres and telomeres , but also some gene-encoding euchromatic regions. There remained 160 euchromatic gaps in 2015 when the sequences spanning another 50 formerly unsequenced regions were determined. Only in 2020
4576-480: The 110,000 gene enhancer sequences identified in the human genome , HACNS1 has undergone the most change during the evolution of humans following the split with the ancestors of chimpanzees . The substitutions in HAR2 may have resulted in loss of binding sites for a repressor, possibly due to biased gene conversion. Human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as
4680-469: The 2006 Nobel Prize in Physiology or Medicine for discovering microRNAs (miRNAs), specific short RNA molecules that can base-pair with mRNAs. Post-transcriptional expression levels of many genes can be controlled by RNA interference , in which miRNAs , specific short RNA molecules, pair with mRNA regions and target them for degradation. This antisense -based process involves steps that first process
4784-423: The 3’ to 5’ direction, synthesizing a complementary RNA molecule with elongation occurring in the 5’ to 3’ direction. The DNA sequence also dictates where termination of RNA synthesis will occur. Primary transcript RNAs are often modified by enzymes after transcription. For example, a poly(A) tail and a 5' cap are added to eukaryotic pre-mRNA and introns are removed by the spliceosome . There are also
4888-558: The B-form most commonly observed in DNA. The A-form geometry results in a very deep and narrow major groove and a shallow and wide minor groove. A second consequence of the presence of the 2'-hydroxyl group is that in conformationally flexible regions of an RNA molecule (that is, not involved in formation of a double helix), it can chemically attack the adjacent phosphodiester bond to cleave the backbone. The functional form of single-stranded RNA molecules, just like proteins, frequently requires
4992-768: The RNA so that it can base-pair with a region of its target mRNAs. Once the base pairing occurs, other proteins direct the mRNA to be destroyed by nucleases . Next to be linked to regulation were Xist and other long noncoding RNAs associated with X chromosome inactivation . Their roles, at first mysterious, were shown by Jeannie T. Lee and others to be the silencing of blocks of chromatin via recruitment of Polycomb complex so that messenger RNA could not be transcribed from them. Additional lncRNAs, currently defined as RNAs of more than 200 base pairs that do not appear to have coding potential, have been found associated with regulation of stem cell pluripotency and cell division . The third major group of regulatory RNAs
5096-410: The RNA to fold and pair with itself to form double helices. Analysis of these RNAs has revealed that they are highly structured. Unlike DNA, their structures do not consist of long double helices, but rather collections of short helices packed together into structures akin to proteins. In this fashion, RNAs can achieve chemical catalysis (like enzymes). For instance, determination of the structure of
5200-503: The RNAs mature. Pseudouridine (Ψ), in which the linkage between uracil and ribose is changed from a C–N bond to a C–C bond, and ribothymidine (T) are found in various places (the most notable ones being in the TΨC loop of tRNA ). Another notable modified base is hypoxanthine , a deaminated adenine base whose nucleoside is called inosine (I). Inosine plays a key role in the wobble hypothesis of
5304-403: The Y chromosome is quite small. Most human cells are diploid so they contain twice as much DNA (~6.2 billion base pairs). In 2023, a draft human pangenome reference was published. It is based on 47 genomes from persons of varied ethnicity. Plans are underway for an improved reference capturing still more biodiversity from a still wider sample. While there are significant differences among
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#17328756116245408-435: The accumulation of inactivating mutations. The number of pseudogenes in the human genome is on the order of 13,000, and in some chromosomes is nearly the same as the number of functional protein-coding genes. Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution . For example, the olfactory receptor gene family is one of the best-documented examples of pseudogenes in
5512-469: The action of biased gene conversion rather than adaptive evolution . Several of the HARs encompass genes known to produce proteins important in neurodevelopment. HAR1 is a 106-base pair stretch found on the long arm of chromosome 20 overlapping with part of the RNA genes HAR1F and HAR1R. HAR1F is active in the developing human brain. The HAR1 sequence is found (and conserved) in chickens and chimpanzees but
5616-435: The advent of genomic sequencing, the identification of these sequences could be inferred by evolutionary conservation. The evolutionary branch between the primates and mouse , for example, occurred 70–90 million years ago. So computer comparisons of gene sequences that identify conserved non-coding sequences will be an indication of their importance in duties such as gene regulation. Other genomes have been sequenced with
5720-773: The application of such knowledge to the treatment of disease and in the medical field is only in its very beginnings. Exome sequencing has become increasingly popular as a tool to aid in diagnosis of genetic disease because the exome contributes only 1% of the genomic sequence but accounts for roughly 85% of mutations that contribute significantly to disease. In humans, gene knockouts naturally occur as heterozygous or homozygous loss-of-function gene knockouts. These knockouts are often difficult to distinguish, especially within heterogeneous genetic backgrounds. They are also difficult to find as they occur in low frequencies. Populations with high rates of consanguinity , such as countries with high rates of first-cousin marriages, display
5824-418: The average size of an intron is about 6 kb (6,000 bp). This means that the average size of a protein-coding gene is about 62 kb and these genes take up about 40% of the genome. Exon sequences consist of coding DNA and untranslated regions (UTRs) at either end of the mature mRNA. The total amount of coding DNA is about 1-2% of the genome. Many people divide the genome into coding and non-coding DNA based on
5928-514: The biological functions of their protein and RNA products. In 2000, scientists reported the sequencing of 88% of human genome, but as of 2020, at least 8% was still missing. In 2021, scientists reported sequencing a complete, female genome (i.e., without the Y chromosome). The human Y chromosome , consisting of 62,460,029 base pairs from a different cell line and found in all males, was sequenced completely in January 2022. The current version of
6032-445: The case of the 5S rRNA of the members of the genus Halococcus ( Archaea ), which have an insertion, thus increasing its size. Messenger RNA (mRNA) carries information about a protein sequence to the ribosomes , the protein synthesis factories in the cell. It is coded so that every three nucleotides (a codon ) corresponds to one amino acid. In eukaryotic cells, once precursor mRNA (pre-mRNA) has been transcribed from DNA, it
6136-402: The cell nucleus and is usually catalyzed by an enzyme— RNA polymerase —using DNA as a template, a process known as transcription . Initiation of transcription begins with the binding of the enzyme to a promoter sequence in the DNA (usually found "upstream" of a gene). The DNA double helix is unwound by the helicase activity of the enzyme. The enzyme then progresses along the template strand in
6240-410: The diagnosis and treatment of diseases, and to new insights in many fields of biology, including human evolution . By 2018, the total number of genes had been raised to at least 46,831, plus another 2300 micro-RNA genes. A 2018 population survey found another 300 million bases of human genome that was not in the reference sequence. Prior to the acquisition of the full genome sequence, estimates of
6344-517: The dinucleotide repeat (AC) n ) are termed microsatellite sequences. Among the microsatellite sequences, trinucleotide repeats are of particular importance, as sometimes occur within coding regions of genes for proteins and may lead to genetic disorders. For example, Huntington's disease results from an expansion of the trinucleotide repeat (CAG) n within the Huntingtin gene on human chromosome 4. Telomeres (the ends of linear chromosomes) end with
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#17328756116246448-444: The earliest forms of life (self-replicating molecules) could have relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA world . In May 2022, scientists discovered that RNA can form spontaneously on prebiotic basalt lava glass , presumed to have been abundant on the early Earth . In March 2015, DNA and RNA nucleobases , including uracil , cytosine and thymine , were reportedly formed in
6552-414: The evolution of DNA and possibly of protein-based enzymes as well, an " RNA world " existed in which RNA served as both living organisms' storage method for genetic information —a role fulfilled today by DNA, except in the case of RNA viruses —and potentially performed catalytic functions in cells—a function performed today by protein enzymes, with the notable and important exception of the ribosome, which
6656-537: The exact number in the human genome is yet to be determined. Many RNAs are thought to be non-functional. Many ncRNAs are critical elements in gene regulation and expression. Noncoding RNA also contributes to epigenetics, transcription, RNA splicing, and the translational machinery. The role of RNA in genetic regulation and disease offers a new potential level of unexplored genomic complexity. Pseudogenes are inactive copies of protein-coding genes, often generated by gene duplication , that have become nonfunctional through
6760-456: The first crystal of RNA whose structure could be determined by X-ray crystallography. The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965, winning Holley the 1968 Nobel Prize in Medicine (shared with Har Gobind Khorana and Marshall Nirenberg ). In the early 1970s, retroviruses and reverse transcriptase were discovered, showing for the first time that enzymes could copy RNA into DNA (the opposite of
6864-430: The first family sequenced as part of Illumina's Personal Genome Sequencing program. Since then hundreds of personal genome sequences have been released, including those of Desmond Tutu , and of a Paleo-Eskimo . In 2012, the whole genome sequences of two family trios among 1092 genomes was made public. In November 2013, a Spanish family made four personal exome datasets (about 1% of the genome) publicly available under
6968-423: The function of circRNAs is largely unknown, although for few examples a microRNA sponging activity has been demonstrated. Research on RNA has led to many important biological discoveries and numerous Nobel Prizes . Nucleic acids were discovered in 1868 by Friedrich Miescher , who called the material 'nuclein' since it was found in the nucleus . It was later discovered that prokaryotic cells, which do not have
7072-459: The gene that has been knocked out. RNA Ribonucleic acid ( RNA ) is a polymeric molecule that is essential for most biological functions, either by performing the function itself ( non-coding RNA ) or by forming a template for the production of proteins ( messenger RNA ). RNA and deoxyribonucleic acid (DNA) are nucleic acids . The nucleic acids constitute one of the four major macromolecules essential for all known forms of life . RNA
7176-551: The genes to be regulated. Later studies have shown that RNAs also regulate genes. There are several kinds of RNA-dependent processes in eukaryotes regulating the expression of genes at various points, such as RNAi repressing genes post-transcriptionally , long non-coding RNAs shutting down blocks of chromatin epigenetically , and enhancer RNAs inducing increased gene expression. Bacteria and archaea have also been shown to use regulatory RNA systems such as bacterial small RNAs and CRISPR . Fire and Mello were awarded
7280-427: The genome among people that range from a few thousand to a few million DNA bases; some are gains or losses of stretches of genome sequence and others appear as re-arrangements of stretches of sequence. These variations include differences in the number of copies individuals have of a particular gene, deletions, translocations and inversions. Structural variation refers to genetic variants that affect larger segments of
7384-446: The genome since geneticists, evolutionary biologists, and molecular biologists employ different definitions and methods. Due to the ambiguity in the terminology, different schools of thought have emerged. In evolutionary definitions, "functional" DNA, whether it is coding or non-coding, contributes to the fitness of the organism, and therefore is maintained by negative evolutionary pressure whereas "non-functional" DNA has no benefit to
7488-511: The genome, however extrapolations from the ENCODE project give that 20 or more of the genome is gene regulatory sequence. Some types of non-coding DNA are genetic "switches" that do not encode proteins, but do regulate when and where genes are expressed (called enhancers ). Regulatory sequences have been known since the late 1960s. The first identification of regulatory sequences in the human genome relied on recombinant DNA technology. Later with
7592-533: The genome. However, studies on SNPs are biased towards coding regions, the data generated from them are unlikely to reflect the overall distribution of SNPs throughout the genome. Therefore, the SNP Consortium protocol was designed to identify SNPs with no bias towards coding regions and the Consortium's 100,000 SNPs generally reflect sequence diversity across the human chromosomes. The SNP Consortium aims to expand
7696-409: The genomes of human individuals (on the order of 0.1% due to single-nucleotide variants and 0.6% when considering indels ), these are considerably smaller than the differences between humans and their closest living relatives, the bonobos and chimpanzees (~1.1% fixed single-nucleotide variants and 4% when including indels). The total length of the human reference genome does not represent
7800-427: The highest frequencies of homozygous gene knockouts. Such populations include Pakistan, Iceland, and Amish populations. These populations with a high level of parental-relatedness have been subjects of human knock out research which has helped to determine the function of specific genes in humans. By distinguishing specific knockouts, researchers are able to use phenotypic analyses of these individuals to help characterize
7904-499: The highest mutation rate, presumably due to deamination. A personal genome sequence is a (nearly) complete sequence of the chemical base pairs that make up the DNA of a single person. Because medical treatments have different effects on different people due to genetic variations such as single-nucleotide polymorphisms (SNPs), the analysis of personal genomes may lead to personalized medical treatment based on individual genotypes. The first personal genome sequence to be determined
8008-692: The human genome, as opposed to point mutations . Often, structural variants (SVs) are defined as variants of 50 base pairs (bp) or greater, such as deletions, duplications, insertions, inversions and other rearrangements. About 90% of structural variants are noncoding deletions but most individuals have more than a thousand such deletions; the size of deletions ranges from dozens of base pairs to tens of thousands of bp. On average, individuals carry ~3 rare structural variants that alter coding regions, e.g. delete exons . About 2% of individuals carry ultra-rare megabase-scale structural variants, especially rearrangements. That is, millions of base pairs may be inverted within
8112-643: The human genome. More than 60 percent of the genes in this family are non-functional pseudogenes in humans. By comparison, only 20 percent of genes in the mouse olfactory receptor gene family are pseudogenes. Research suggests that this is a species-specific characteristic, as the most closely related primates all have proportionally fewer pseudogenes. This genetic discovery helps to explain the less acute sense of smell in humans relative to other mammals. The human genome has many different regulatory sequences which are crucial to controlling gene expression . Conservative estimates indicate that these sequences make up 8% of
8216-441: The human genome. These sequences ultimately lead to the production of all human proteins , although several biological processes (e.g. DNA rearrangements and alternative pre-mRNA splicing ) can lead to the production of many more unique proteins than the number of protein-coding genes. The human reference genome contains somewhere between 19,000 and 20,000 protein-coding genes. These genes contain an average of 10 introns and
8320-542: The human reference genome: The Genome Reference Consortium is responsible for updating the HRG. Version 38 was released in December 2013. Most studies of human genetic variation have focused on single-nucleotide polymorphisms (SNPs), which are substitutions in individual bases along a chromosome. Most analyses estimate that SNPs occur 1 in 1000 base pairs, on average, in the euchromatic human genome, although they do not occur at
8424-468: The idea that coding DNA is the most important functional component of the genome. About 98-99% of the human genome is non-coding DNA. Noncoding RNA molecules play many essential roles in cells, especially in the many reactions of protein synthesis and RNA processing . Noncoding genes include those for tRNAs , ribosomal RNAs, microRNAs , snRNAs and long non-coding RNAs (lncRNAs). The number of reported non-coding genes continues to rise slowly but
8528-461: The introns can be ribozymes that are spliced by themselves. RNA can also be altered by having its nucleotides modified to nucleotides other than A , C , G and U . In eukaryotes, modifications of RNA nucleotides are in general directed by small nucleolar RNAs (snoRNA; 60–300 nt), found in the nucleolus and cajal bodies . snoRNAs associate with enzymes and guide them to a spot on an RNA by basepairing to that RNA. These enzymes then perform
8632-582: The investigated cell type. Repetitive DNA sequences comprise approximately 50% of the human genome. About 8% of the human genome consists of tandem DNA arrays or tandem repeats, low complexity repeat sequences that have multiple adjacent copies (e.g. "CAGCAGCAG..."). The tandem sequences may be of variable lengths, from two nucleotides to tens of nucleotides. These sequences are highly variable, even among closely related individuals, and so are used for genealogical DNA testing and forensic DNA analysis . Repeated sequences of fewer than ten nucleotides (e.g.
8736-472: The laboratory under outer space conditions, using starter chemicals such as pyrimidine , an organic compound commonly found in meteorites . Pyrimidine , like polycyclic aromatic hydrocarbons (PAHs), is one of the most carbon-rich compounds found in the universe and may have been formed in red giants or in interstellar dust and gas clouds. In July 2022, astronomers reported massive amounts of prebiotic molecules , including possible RNA precursors, in
8840-401: The nucleotide modification. rRNAs and tRNAs are extensively modified, but snRNAs and mRNAs can also be the target of base modification. RNA can also be methylated. Like DNA, RNA can carry genetic information. RNA viruses have genomes composed of RNA that encodes a number of proteins. The viral genome is replicated by some of those proteins, while other proteins protect the genome as
8944-423: The number of SNPs identified across the genome to 300 000 by the end of the first quarter of 2001. Changes in non-coding sequence and synonymous changes in coding sequence are generally more common than non-synonymous changes, reflecting greater selective pressure reducing diversity at positions dictating amino acid identity. Transitional changes are more common than transversions, with CpG dinucleotides showing
9048-462: The number of human genes ranged from 50,000 to 140,000 (with occasional vagueness about whether these estimates included non-protein coding genes). As genome sequence quality and the methods for identifying protein-coding genes improved, the count of recognized protein-coding genes dropped to 19,000–20,000. In 2022, the Telomere-to-Telomere (T2T) consortium reported the complete sequence of
9152-610: The organism and therefore is under neutral selective pressure. This type of DNA has been described as junk DNA . In genetic definitions, "functional" DNA is related to how DNA segments manifest by phenotype and "nonfunctional" is related to loss-of-function effects on the organism. In biochemical definitions, "functional" DNA relates to DNA sequences that specify molecular products (e.g. noncoding RNAs) and biochemical activities with mechanistic roles in gene or genome regulation (i.e. DNA sequences that impact cellular level activity such as cell type, condition, and molecular processes). There
9256-693: The physiological state. Bacterial small RNAs generally act via antisense pairing with mRNA to down-regulate its translation, either by affecting stability or affecting cis-binding ability. Riboswitches have also been discovered. They are cis-acting regulatory RNA sequences acting allosterically . They change shape when they bind metabolites so that they gain or lose the ability to bind chromatin to regulate expression of genes. Archaea also have systems of regulatory RNA. The CRISPR system, recently being used to edit DNA in situ , acts via regulatory RNAs in archaea and bacteria to provide protection against virus invaders. Synthesis of RNA typically occurs in
9360-405: The post-transcriptional modifications occur in highly functional regions, such as the peptidyl transferase center and the subunit interface, implying that they are important for normal function. Messenger RNA (mRNA) is the type of RNA that carries information from DNA to the ribosome , the sites of protein synthesis ( translation ) in the cell cytoplasm. The coding sequence of the mRNA determines
9464-928: The process of translation. There are also non-coding RNAs involved in gene regulation, RNA processing and other roles. Certain RNAs are able to catalyse chemical reactions such as cutting and ligating other RNA molecules, and the catalysis of peptide bond formation in the ribosome ; these are known as ribozymes . According to the length of RNA chain, RNA includes small RNA and long RNA. Usually, small RNAs are shorter than 200 nt in length, and long RNAs are greater than 200 nt long. Long RNAs, also called large RNAs, mainly include long non-coding RNA (lncRNA) and mRNA . Small RNAs mainly include 5.8S ribosomal RNA (rRNA), 5S rRNA , transfer RNA (tRNA), microRNA (miRNA), small interfering RNA (siRNA), small nucleolar RNA (snoRNAs), Piwi-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA) and small rDNA-derived RNA (srRNA). There are certain exceptions as in
9568-508: The ribosome—an RNA-protein complex that catalyzes the assembly of proteins—revealed that its active site is composed entirely of RNA. An important structural component of RNA that distinguishes it from DNA is the presence of a hydroxyl group at the 2' position of the ribose sugar . The presence of this functional group causes the helix to mostly take the A-form geometry , although in single strand dinucleotide contexts, RNA can rarely also adopt
9672-468: The same intention of aiding conservation-guided methods, for exampled the pufferfish genome. However, regulatory sequences disappear and re-evolve during evolution at a high rate. As of 2012, the efforts have shifted toward finding interactions between DNA and regulatory proteins by the technique ChIP-Seq , or gaps where the DNA is not packaged by histones ( DNase hypersensitive sites ), both of which tell where there are active regulatory sequences in
9776-448: The sequence of any specific individual, nor does it represent the sequence of all of the DNA found within a cell. The human reference genome only includes one copy of each of the paired, homologous autosomes plus one copy of each of the two sex chromosomes (X and Y). The total amount of DNA in this reference genome is 3.1 billion base pairs (3.1 Gb). Protein-coding sequences represent the most widely studied and best understood component of
9880-511: The sequence, representing highly repetitive and other DNA that could not be sequenced with the technology available at the time. The human genome was the first of all vertebrates to be sequenced to such near-completion, and as of 2018, the diploid genomes of over a million individual humans had been determined using next-generation sequencing . These data are used worldwide in biomedical science , anthropology , forensics and other branches of science. Such genomic studies have led to advances in
9984-419: The standard reference genome is called GRCh38.p14 (July 2023). It consists of 22 autosomes plus one copy of the X chromosome and one copy of the Y chromosome. It contains approximately 3.1 billion base pairs (3.1 Gb or 3.1 x 10 bp). This represents the size of a composite genome based on data from multiple individuals but it is a good indication of the typical amount of DNA in a haploid set of chromosomes because
10088-423: The usual route for transmission of genetic information). For this work, David Baltimore , Renato Dulbecco and Howard Temin were awarded a Nobel Prize in 1975. In 1976, Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of bacteriophage MS2 . In 1977, introns and RNA splicing were discovered in both mammalian viruses and in cellular genes, resulting in
10192-467: The virus particle moves to a new host cell. Viroids are another group of pathogens, but they consist only of RNA, do not encode any protein and are replicated by a host plant cell's polymerase. Reverse transcribing viruses replicate their genomes by reverse transcribing DNA copies from their RNA; these DNA copies are then transcribed to new RNA. Retrotransposons also spread by copying DNA and RNA from one another, and telomerase contains an RNA that
10296-502: Was also completed. In 2009, Stephen Quake published his own genome sequence derived from a sequencer of his own design, the Heliscope. A Stanford team led by Euan Ashley published a framework for the medical interpretation of human genomes implemented on Quake's genome and made whole genome-informed medical decisions for the first time. That team further extended the approach to the West family,
10400-556: Was awarded for the elucidation of the atomic structure of the ribosome to Venki Ramakrishnan , Thomas A. Steitz , and Ada Yonath . In 2023 the Nobel Prize in Physiology or Medicine was awarded to Katalin Karikó and Drew Weissman for their discoveries concerning modified nucleosides that enabled the development of effective mRNA vaccines against COVID-19. In 1968, Carl Woese hypothesized that RNA might be catalytic and suggested that
10504-413: Was published. It is based on 47 genomes from persons of varied ethnicity. Plans are underway for an improved reference capturing still more biodiversity from a still wider sample. With the exception of identical twins, all humans show significant variation in genomic DNA sequences. The human reference genome (HRG) is used as a standard sequence reference. There are several important points concerning
10608-493: Was that of Craig Venter in 2007. Personal genomes had not been sequenced in the public Human Genome Project to protect the identity of volunteers who provided DNA samples. That sequence was derived from the DNA of several volunteers from a diverse population. However, early in the Venter-led Celera Genomics genome sequencing effort the decision was made to switch from sequencing a composite sample to using DNA from
10712-408: Was the first truly complete telomere-to-telomere sequence of a human chromosome determined, namely of the X chromosome . The first complete telomere-to-telomere sequence of a human autosomal chromosome, chromosome 8 , followed a year later. The complete human genome (without Y chromosome) was published in 2021, while with Y chromosome in January 2022. In 2023, a draft human pangenome reference
10816-405: Was thought to be a eukaryotic phenomenon, a part of the explanation for why so much more transcription in higher organisms was seen than had been predicted. But as soon as researchers began to look for possible RNA regulators in bacteria, they turned up there as well, termed as small RNA (sRNA). Currently, the ubiquitous nature of systems of RNA regulation of genes has been discussed as support for
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