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134-438: 2D4Q , 2E2X , 3P7Z , 3PEG , 3PG7 4763 18015 ENSG00000196712 ENSMUSG00000020716 P21359 Q04690 NM_000267 NM_001042492 NM_001128147 NM_010897 NP_000258 NP_001035957 NP_001121619 NP_035027 Neurofibromin ( NF-1 ) is a protein that is encoded in humans, in the NF1 gene . NF1 is located on chromosome 17. Neurofibromin,

268-682: A GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras -bound GTP . NF1 has a high mutation rate and mutations can alter cellular growth control, and neural development , resulting in neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome). Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots , plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas , life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma , attention deficits , learning deficits and other cognitive disabilities . NF1

402-428: A cortex , composed of neuron-bodies constituting gray matter, while internally there is more white matter that form tracts and commissures . Apart from cortical gray matter there is also subcortical gray matter making up a large number of different nuclei . From and to the spinal cord are projections of the peripheral nervous system in the form of spinal nerves (sometimes segmental nerves ). The nerves connect

536-519: A pleckstrin homology-like (PH) domain. Sec14 domains are defined by a lipid binding pocket that resembles a cage and is covered by a helical lid portion that is believed to regulate ligand access. The PH-like region displays a protrusion that connects two beta-strands from the PH core that extend to interact with the helical lid found in the Sec14 domain. The function of the interaction between these two regions

670-584: A promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. The recognition typically occurs as a consensus sequence like the TATA box . A gene can have more than one promoter, resulting in messenger RNAs ( mRNA ) that differ in how far they extend in the 5' end. Highly transcribed genes have "strong" promoter sequences that form strong associations with transcription factors, thereby initiating transcription at

804-411: A splicing regulatory element . Intronic mutations that fall outside of splice sites also fall under splicing mutations, and approximately 5% of splicing mutations are of this nature. Point mutations that effect splicing are commonly seen and these are often substitutions in the regulatory sequence. Exonic mutations can lead to deletion of an entire exon, or a fragment of an exon if the mutation creates

938-870: A tumor suppressor gene . The development of several other NF1 mouse models has also allowed the implementation of preclinical research to test the therapeutic potential of targeted pharmacologic agents, such as sorafenib (VEGFR, PDGFR and RAF kinases inhibitor) and everolimus (mTORC inhibitor) for the treatment of NF1 plexiform neurofibromas, sirolimus (rapamycin) (mTORC inhibitor) for MPNSTs, or lovastatin (HMG-CoA reductase inhibitor), and alectinib (ALK inhibitor) for NF1 cognitive and learning disabilities. In 2013, two conditional knockout mouse models, called Dhh-Cre;Nf1 (which develops neurofibromas similar to those found in NF1 patients) and Mx1-Cre;Nf1 (which develops myeloproliferative neoplasms similar to those found in NF1 juvenile myelomonocytic leukemia/JMML) were used to study

1072-533: A " start codon ", and three " stop codons " indicate the beginning and end of the protein coding region . There are 64 possible codons (four possible nucleotides at each of three positions, hence 4  possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms. Central nervous system The rest of this article exclusively discusses

1206-445: A continuous messenger RNA , referred to as a polycistronic mRNA . The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region , and represses transcription of

1340-495: A double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'→3' direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile . The expression of genes encoded in DNA begins by transcribing the gene into RNA , a second type of nucleic acid that is very similar to DNA, but whose monomers contain

1474-488: A few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer . Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas

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1608-498: A few months later in 2019, FDA to grant a Breakthrough Therapy Designation to the inhibitor. The Drosophila melanogaster ortholog gene of human NF1 (dNF1) has been identified and cloned in 1997. The gene is slightly more compact than its human counterpart but still remains one of the largest genes of the fly genome. It encodes a protein 55% identical and 69% similar to human neurofibromin over its entire 2,802 amino acid length. It comprises an IRA-related central segment containing

1742-434: A gene - surprisingly, there is no definition that is entirely satisfactory. A gene is a DNA sequence that codes for a diffusible product. This product may be protein (as is the case in the majority of genes) or may be RNA (as is the case of genes that code for tRNA and rRNA). The crucial feature is that the product diffuses away from its site of synthesis to act elsewhere. The important parts of such definitions are: (1) that

1876-565: A gene corresponds to a transcription unit; (2) that genes produce both mRNA and noncoding RNAs; and (3) regulatory sequences control gene expression but are not part of the gene itself. However, there's one other important part of the definition and it is emphasized in Kostas Kampourakis' book Making Sense of Genes . Therefore in this book I will consider genes as DNA sequences encoding information for functional products, be it proteins or RNA molecules. With 'encoding information', I mean that

2010-410: A gene may be split across chromosomes but those transcripts are concatenated back together into a functional sequence by trans-splicing . It is also possible for overlapping genes to share some of their DNA sequence, either on opposite strands or the same strand (in a different reading frame, or even the same reading frame). In all organisms, two steps are required to read the information encoded in

2144-404: A gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA ( mRNA ). Second, that mRNA is translated to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression , and the resulting molecule

2278-565: A gene: that of bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project . The theories developed in the early 20th century to integrate Mendelian genetics with Darwinian evolution are called

2412-439: A gene; however, members of a population may have different alleles at the locus, each with a slightly different gene sequence. The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome . DNA packaged and condensed in this way is called chromatin . The manner in which DNA

2546-478: A high incidence of de novo mutations , meaning that the mutations are not inherited maternally or paternally . Although the mutation rate is high, there are no mutation "hot spot" regions. Mutations tend to be distributed within the gene, although exons 3, 5, and 27 are common sites for mutations. The Human Gene Mutation Database contains 1,347 NF1 mutations, but none are in the "regulatory" category. There have not been any mutations conclusively identified within

2680-448: A high rate. Others genes have "weak" promoters that form weak associations with transcription factors and initiate transcription less frequently. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters. Additionally, genes can have regulatory regions many kilobases upstream or downstream of the gene that alter expression. These act by binding to transcription factors which then cause

2814-400: A highly-specific ALK inhibitor corrected all these defects in flies and this therapeutic approach was later successfully validated in a preclinical mouse model of NF1 by treating mice with Alectinib , suggesting it represents a promising therapeutic target. Gene In biology , the word gene has two meanings. The Mendelian gene is a basic unit of heredity . The molecular gene is

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2948-401: A motor structure, the cerebellum also displays connections to areas of the cerebral cortex involved in language and cognition . These connections have been shown by the use of medical imaging techniques, such as functional MRI and Positron emission tomography . The body of the cerebellum holds more neurons than any other structure of the brain, including that of the larger cerebrum , but

3082-572: A new expanded definition that includes noncoding genes. However, some modern writers still do not acknowledge noncoding genes although this so-called "new" definition has been recognised for more than half a century. Although some definitions can be more broadly applicable than others, the fundamental complexity of biology means that no definition of a gene can capture all aspects perfectly. Not all genomes are DNA (e.g. RNA viruses ), bacterial operons are multiple protein-coding regions transcribed into single large mRNAs, alternative splicing enables

3216-465: A new splice site. Intronic mutations can result in the insertion of a cryptic exon, or result in exon skipping if the mutation is in the conserved 3' or 5' end. NF1 encodes neurofibromin (NF1), which is a 320- kDa protein that contains 2,818 amino acids. Neurofibromin is a GTPase-activating protein (GAP) that negatively regulates Ras pathway activity by accelerating hydrolysis of Ras-bound guanosine triphosphate (GTP). Neurofibromin localizes in

3350-437: A pathway for therapeutic agents which cannot otherwise cross the meninges barrier. The CNS consists of two major structures: the brain and spinal cord . The brain is encased in the skull, and protected by the cranium. The spinal cord is continuous with the brain and lies caudally to the brain. It is protected by the vertebrae . The spinal cord reaches from the base of the skull, and continues through or starting below

3484-400: A process known as RNA splicing . Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites , where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The poly(A) tail protects mature mRNA from degradation and has other functions, affecting translation, localization, and transport of the transcript from

3618-419: A protein-coding gene consists of many elements of which the actual protein coding sequence is often only a small part. These include introns and untranslated regions of the mature mRNA. Noncoding genes can also contain introns that are removed during processing to produce the mature functional RNA. All genes are associated with regulatory sequences that are required for their expression. First, genes require

3752-481: A sequence of nucleotides in DNA that is transcribed to produce a functional RNA . There are two types of molecular genes: protein-coding genes and non-coding genes. During gene expression (the synthesis of RNA or protein from a gene), DNA is first copied into RNA . RNA can be directly functional or be the intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring ,

3886-403: A single axon, completely surrounding it. Sometimes, they may myelinate many axons, especially when in areas of short axons. Oligodendrocytes usually myelinate several axons. They do this by sending out thin projections of their cell membrane , which envelop and enclose the axon. During early development of the vertebrate embryo, a longitudinal groove on the neural plate gradually deepens and

4020-412: A single genomic region to encode multiple district products and trans-splicing concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors, and other regulatory regions , these are instead thought of as "associated" with the gene and affect its function. An even broader operational definition is sometimes used to encompass

4154-534: A specialized form of macrophage , involved in the immune system of the brain as well as the clearance of various metabolites from the brain tissue . Astrocytes may be involved with both clearance of metabolites as well as transport of fuel and various beneficial substances to neurons from the capillaries of the brain. Upon CNS injury astrocytes will proliferate, causing gliosis , a form of neuronal scar tissue, lacking in functional neurons. The brain ( cerebrum as well as midbrain and hindbrain ) consists of

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4288-472: A strict definition of the word "gene" with which nearly every expert can agree. First, in order for a nucleotide sequence to be considered a true gene, an open reading frame (ORF) must be present. The ORF can be thought of as the "gene itself"; it begins with a starting mark common for every gene and ends with one of three possible finish line signals. One of the key enzymes in this process, the RNA polymerase, zips along

4422-526: A team of specialists to manage symptoms or complications. However, in April, 2020, the FDA approved selumetinib (brand name Koselugo) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). A lot about of our knowledge on the biology of NF1 came from model organisms including the fruit fly Drosophila melanogaster ,

4556-409: A true gene, by this definition, one has to prove that the transcript has a biological function. Early speculations on the size of a typical gene were based on high-resolution genetic mapping and on the size of proteins and RNA molecules. A length of 1500 base pairs seemed reasonable at the time (1965). This was based on the idea that the gene was the DNA that was directly responsible for production of

4690-439: Is also more extensively understood than other structures of the brain, as it includes fewer types of different neurons. It handles and processes sensory stimuli, motor information, as well as balance information from the vestibular organ . The two structures of the diencephalon worth noting are the thalamus and the hypothalamus. The thalamus acts as a linkage between incoming pathways from the peripheral nervous system as well as

4824-471: Is at its highest level in adult neurons , Schwann cells , astrocytes , leukocytes , and oligodendrocytes. The catalytic RasGAP activity of neurofibromin is located in a central portion of the protein, that is called the GAP-related domain (GRD). The GRD is closely homologous to RasGAP and represents about 10% (229 amino acids) of the neurofibromin sequence. The GRD is made up of a central portion called

4958-456: Is called a gene product . The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code . Sets of three nucleotides, known as codons , each correspond to a specific amino acid. The principle that three sequential bases of DNA code for each amino acid was demonstrated in 1961 using frameshift mutations in the rIIB gene of bacteriophage T4 (see Crick, Brenner et al. experiment ). Additionally,

5092-400: Is nearly the same for all known organisms. The total complement of genes in an organism or cell is known as its genome , which may be stored on one or more chromosomes . A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The region of the chromosome at which a particular gene is located is called its locus . Each locus contains one allele of

5226-462: Is presently unclear, but the structure implies a regulatory interaction that influences the helical-lid conformation in order to control ligand access to the lipid binding pocket. Through its NF1-GRD domain, neurofibromin increases the rate of GTP hydrolysis of Ras, and acts as a tumor suppressor by reducing Ras activity. When the Ras-Nf1 complex assembles, active Ras binds in a groove that is present in

5360-451: Is situated above and rostral to the pons. It includes nuclei linking distinct parts of the motor system, including the cerebellum, the basal ganglia and both cerebral hemispheres , among others. Additionally, parts of the visual and auditory systems are located in the midbrain, including control of automatic eye movements. The brainstem at large provides entry and exit to the brain for a number of pathways for motor and autonomic control of

5494-403: Is still part of the definition of a gene in most textbooks. For example, The primary function of the genome is to produce RNA molecules. Selected portions of the DNA nucleotide sequence are copied into a corresponding RNA nucleotide sequence, which either encodes a protein (if it is an mRNA) or forms a 'structural' RNA, such as a transfer RNA (tRNA) or ribosomal RNA (rRNA) molecule. Each region of

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5628-399: Is stored on the histones, as well as chemical modifications of the histone itself, regulate whether a particular region of DNA is accessible for gene expression . In addition to genes, eukaryotic chromosomes contain sequences involved in ensuring that the DNA is copied without degradation of end regions and sorted into daughter cells during cell division: replication origins , telomeres , and

5762-431: Is the basis of the inheritance of phenotypic traits from one generation to the next. These genes make up different DNA sequences, together called a genotype , that is specific to every given individual, within the gene pool of the population of a given species . The genotype, along with environmental and developmental factors, ultimately determines the phenotype of the individual. Most biological traits occur under

5896-1065: Is the most common single gene disorder in humans, occurring in about 1 in 2500–3000 births worldwide. NF1 is an autosomal dominant disorder , but approximately half of NF1 cases arise from de novo mutations. NF1 has high phenotypic variability, with members of the same family with the same mutation displaying different symptoms and symptom intensities. Café-au-lait spots are the most common sign of NF1, but other symptoms include lisch nodules of iris, cutaneous neurofibromas (CNF), plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas , life-threatening malignant peripheral nerve sheath tumors (MPNST), attention deficits , learning deficits and other cognitive disabilities . In addition to neurofibromatosis type I , mutations in NF1 can also lead to juvenile myelomonocytic leukemias (JMML), gastrointestinal stromal tumors (GIST), Watson syndrome , astrocytic neoplasms , phaeochromocytomas and breast cancer . No effective therapy NF1 yet exists. Instead, people with neurofibromatosis are followed by

6030-501: The Evi-2A and Evi-2B genes in mice that encode proteins related to leukemia in mice. OMG is a membrane glycoprotein that is expressed in the human central nervous system during myelination of nerve cells . Early studies of the NF1 promoter found that there is great homology between the human and mouse NF1 promoters. The major transcription start site has been confirmed, as well as two minor transcription start sites in both

6164-511: The aging process. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division . Prokaryotes ( bacteria and archaea ) typically store their genomes on a single, large, circular chromosome . Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes. Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids , which usually encode only

6298-463: The body fluid found outside the cells of all bilateral animals . In vertebrates, the CNS is contained within the dorsal body cavity , while the brain is housed in the cranial cavity within the skull . The spinal cord is housed in the spinal canal within the vertebrae . Within the CNS, the interneuronal space is filled with a large amount of supporting non-nervous cells called neuroglia or glia from

6432-401: The central dogma of molecular biology , which states that proteins are translated from RNA , which is transcribed from DNA . This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses . The modern study of genetics at the level of DNA is known as molecular genetics . In 1972, Walter Fiers and his team were the first to determine the sequence of

6566-419: The centromere . Replication origins are the sequence regions where DNA replication is initiated to make two copies of the chromosome. Telomeres are long stretches of repetitive sequences that cap the ends of the linear chromosomes and prevent degradation of coding and regulatory regions during DNA replication . The length of the telomeres decreases each time the genome is replicated and has been implicated in

6700-421: The cytoplasm ; however, some studies have found neurofibromin or fragments of it in the nucleus . Neurofibromin does contain a nuclear localization signal that is encoded by exon 43, but whether or not neurofibromin plays a role in the nucleus is currently unknown. Neurofibromin is ubiquitously expressed, but expression levels vary depending on the tissue type and developmental stage of the organism. Expression

6834-433: The face and neck . The next structure rostral to the medulla is the pons, which lies on the ventral anterior side of the brainstem. Nuclei in the pons include pontine nuclei which work with the cerebellum and transmit information between the cerebellum and the cerebral cortex . In the dorsal posterior pons lie nuclei that are involved in the functions of breathing, sleep, and taste. The midbrain, or mesencephalon,

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6968-453: The foramen magnum , and terminates roughly level with the first or second lumbar vertebra , occupying the upper sections of the vertebral canal . Microscopically, there are differences between the neurons and tissue of the CNS and the peripheral nervous system (PNS). The CNS is composed of white and gray matter . This can also be seen macroscopically on brain tissue. The white matter consists of axons and oligodendrocytes , while

7102-434: The medulla , the pons and the midbrain . The medulla can be referred to as an extension of the spinal cord, which both have similar organization and functional properties. The tracts passing from the spinal cord to the brain pass through here. Regulatory functions of the medulla nuclei include control of blood pressure and breathing . Other nuclei are involved in balance , taste , hearing , and control of muscles of

7236-549: The modern synthesis , a term introduced by Julian Huxley . This view of evolution was emphasized by George C. Williams ' gene-centric view of evolution . He proposed that the Mendelian gene is a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency." Related ideas emphasizing the centrality of Mendelian genes and the importance of natural selection in evolution were popularized by Richard Dawkins . The development of

7370-459: The neocortex , and its cavity becomes the first and second ventricles (lateral ventricles). Diencephalon elaborations include the subthalamus , hypothalamus , thalamus and epithalamus , and its cavity forms the third ventricle . The tectum , pretectum , cerebral peduncle and other structures develop out of the mesencephalon, and its cavity grows into the mesencephalic duct (cerebral aqueduct). The metencephalon becomes, among other things,

7504-475: The neutral theory of evolution in the late 1960s led to the recognition that random genetic drift is a major player in evolution and that neutral theory should be the null hypothesis of molecular evolution. This led to the construction of phylogenetic trees and the development of the molecular clock , which is the basis of all dating techniques using DNA sequences. These techniques are not confined to molecular gene sequences but can be used on all DNA segments in

7638-418: The olfactory nerves and the optic nerves are often considered structures of the CNS. This is because they do not synapse first on peripheral ganglia, but directly on CNS neurons. The olfactory epithelium is significant in that it consists of CNS tissue expressed in direct contact to the environment, allowing for administration of certain pharmaceuticals and drugs. At the anterior end of the spinal cord lies

7772-750: The operon ; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon ). The products of operon genes typically have related functions and are involved in the same regulatory network . Though many genes have simple structures, as with much of biology, others can be quite complex or represent unusual edge-cases. Eukaryotic genes often have introns that are much larger than their exons, and those introns can even have other genes nested inside them . Associated enhancers may be many kilobase away, or even on entirely different chromosomes operating via physical contact between two chromosomes. A single gene can encode multiple different functional products by alternative splicing , and conversely

7906-467: The pons and the cerebellum , the myelencephalon forms the medulla oblongata , and their cavities develop into the fourth ventricle . Rhinencephalon , amygdala , hippocampus , neocortex , basal ganglia , lateral ventricles Epithalamus , thalamus , hypothalamus , subthalamus , pituitary gland , pineal gland , third ventricle Tectum , cerebral peduncle , pretectum , mesencephalic duct Pons , cerebellum Planarians , members of

8040-449: The population . These alleles encode slightly different versions of a gene, which may cause different phenotypical traits. Genes evolve due to natural selection or survival of the fittest and genetic drift of the alleles. There are many different ways to use the term "gene" based on different aspects of their inheritance, selection, biological function, or molecular structure but most of these definitions fall into two categories,

8174-424: The proximal promoter ; however, some are in the 5' UTR as well and there is a lot of interindividual variability in the cytosine methylation in these regions. A study in 1993 compared the mouse NF1 cDNA to the human transcript and found that both the untranslated regions and coding regions were highly conserved. It was verified that there are two NF1 polyadenylated transcripts that differ in size because of

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8308-472: The rescue study of The et al. 1997), synaptic growth , neuromuscular junction function, circadian clock and rhythmic behaviors , mitochondrial function, and learning (also found in The) including associative learning and long-term memory . Large scale genetic and functional screens have also led to the identification of dominant modifier genes responsible for the dNF1-associated defects. The et al. 1997 found

8442-427: The tectum ). The neocortex of monotremes (the duck-billed platypus and several species of spiny anteaters ) and of marsupials (such as kangaroos , koalas , opossums , wombats , and Tasmanian devils ) lack the convolutions – gyri and sulci – found in the neocortex of most placental mammals ( eutherians ). Within placental mammals, the size and complexity of the neocortex increased over time. The area of

8576-402: The transcription start site and 5,334-bp upstream of the translation initiation codon , with the length of the 5' UTR being 484-bp long. There are three genes that are present within intron 27b of NF1 . These genes are EVI2B , EVI2A and OMG , which are encoded on the opposite strand and are transcribed in the opposite direction of NF1. EVI2A and EVI2B are human homologs of

8710-449: The 116 genes involved in the nervous system of planarians, which includes genes related to the CNS, also exist in humans. In arthropods , the ventral nerve cord , the subesophageal ganglia and the supraesophageal ganglia are usually seen as making up the CNS. Arthropoda, unlike vertebrates, have inhibitory motor neurons due to their small size. The CNS of chordates differs from that of other animals in being placed dorsally in

8844-413: The 3' UTR and are thought to be negative regulators of transcript stability. This supports the idea that post-transcriptional mechanisms may influence the levels of NF1 transcript. NF1 has one of the highest mutation rates amongst known human genes, however mutation detection is difficult because of its large size, the presence of pseudogenes , and the variety of possible mutations. The NF1 locus has

8978-558: The ApoB holoenzyme . NF1 mRNA editing was believed to involve the ApoB holoenzyme due to the high homology between the two editing sites, however studies have shown that this is not the case. The editing site in NF1 is longer than the sequence required for ApoB mediated mRNA editing, and the region contains two guanidines which are not present in the ApoB editing site. Mutations in NF1 are primarily associated with neurofibromatosis type 1 (NF1, also known as von Recklinghausen syndrome). NF1

9112-404: The DNA helix that produces a functional RNA molecule constitutes a gene. We define a gene as a DNA sequence that is transcribed. This definition includes genes that do not encode proteins (not all transcripts are messenger RNA). The definition normally excludes regions of the genome that control transcription but are not themselves transcribed. We will encounter some exceptions to our definition of

9246-450: The DNA sequence is used as a template for the production of an RNA molecule or a protein that performs some function. The emphasis on function is essential because there are stretches of DNA that produce non-functional transcripts and they do not qualify as genes. These include obvious examples such as transcribed pseudogenes as well as less obvious examples such as junk RNA produced as noise due to transcription errors. In order to qualify as

9380-766: The DNA to loop so that the regulatory sequence (and bound transcription factor) become close to the RNA polymerase binding site. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase. The mature messenger RNA produced from protein-coding genes contains untranslated regions at both ends which contain binding sites for ribosomes , RNA-binding proteins , miRNA , as well as terminator , and start and stop codons . In addition, most eukaryotic open reading frames contain untranslated introns , which are removed and exons , which are connected together in

9514-463: The Greek for "glue". In vertebrates, the CNS also includes the retina and the optic nerve ( cranial nerve II), as well as the olfactory nerves and olfactory epithelium . As parts of the CNS, they connect directly to brain neurons without intermediate ganglia . The olfactory epithelium is the only central nervous tissue outside the meninges in direct contact with the environment, which opens up

9648-506: The Mendelian gene or the molecular gene. The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. This is the gene described in The Selfish Gene . More thorough discussions of this version of a gene can be found in the articles Genetics and Gene-centered view of evolution . The molecular gene definition is more commonly used across biochemistry, molecular biology, and most of genetics —

9782-456: The PNS that synapse through intermediaries or ganglia directly on the CNS. These 12 nerves exist in the head and neck region and are called cranial nerves . Cranial nerves bring information to the CNS to and from the face, as well as to certain muscles (such as the trapezius muscle , which is innervated by accessory nerves as well as certain cervical spinal nerves ). Two pairs of cranial nerves;

9916-472: The Sp1 sites may affect promoter activity. Proximal NF1 promoter/5' UTR methylation has been analyzed in tissues from NF1 patients, with the idea that reduced transcription as a result of methylation could be a "second hit" mechanism equivalent to a somatic mutation . There are some sites that have been detected to be methylated at a higher frequency in tumor tissues than normal tissues. These sites are mostly within

10050-433: The adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose ; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end . The two strands of

10184-486: The aforementioned reticular system the thalamus is involved in wakefulness and consciousness, such as though the SCN . The hypothalamus engages in functions of a number of primitive emotions or feelings such as hunger , thirst and maternal bonding . This is regulated partly through control of secretion of hormones from the pituitary gland . Additionally the hypothalamus plays a role in motivation and many other behaviors of

10318-461: The amygdala plays a role in perception and communication of emotion, while the basal ganglia play a major role in the coordination of voluntary movement. The PNS consists of neurons, axons, and Schwann cells . Oligodendrocytes and Schwann cells have similar functions in the CNS and PNS, respectively. Both act to add myelin sheaths to the axons, which acts as a form of insulation allowing for better and faster proliferation of electrical signals along

10452-415: The body, above the gut and notochord / spine . The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: the telencephalon of reptiles is only an appendix to the large olfactory bulb , while in mammals it makes up most of the volume of the CNS. In the human brain,

10586-413: The brain. The brain makes up the largest portion of the CNS. It is often the main structure referred to when speaking of the nervous system in general. The brain is the major functional unit of the CNS. While the spinal cord has certain processing ability such as that of spinal locomotion and can process reflexes , the brain is the major processing unit of the nervous system. The brainstem consists of

10720-607: The catalytic GAP-related domain (GRD), which are both highly similar to their human counterparts. Also, other conserved regions exist both up- and downstream of this domain. dNF1, like its human counterpart, is mainly expressed in the developing and adult nervous system and primarily controls the MAPK RAS/ERK signaling pathway . Through the use of several mutant null alleles of dNF1 that have been generated, its role has been progressively elucidated. dNF1 functions to regulate organism growth and whole-body size (first elucidated by

10854-539: The cell cycle, cell differentiation or migration. Neurofibromin is also known to interact with CASK through syndecan , a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B to the synapse. This suggests that neurofibromin has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. Neurofibromin is also believed to be involved in

10988-429: The central nervous system can cause severe illness and, when malignant , can have very high mortality rates. Symptoms depend on the size, growth rate, location and malignancy of tumors and can include alterations in motor control, hearing loss, headaches and changes in cognitive ability and autonomic functioning. Specialty professional organizations recommend that neurological imaging of the brain be done only to answer

11122-433: The cognitive capabilities of the brain. Connecting each of the hemispheres is the corpus callosum as well as several additional commissures. One of the most important parts of the cerebral hemispheres is the cortex , made up of gray matter covering the surface of the brain. Functionally, the cerebral cortex is involved in planning and carrying out of everyday tasks. The hippocampus is involved in storage of memories,

11256-436: The combined influence of polygenes (a set of different genes) and gene–environment interactions . Some genetic traits are instantly visible, such as eye color or the number of limbs, others are not, such as blood type , the risk for specific diseases, or the thousands of basic biochemical processes that constitute life . A gene can acquire mutations in its sequence , leading to different variants, known as alleles , in

11390-402: The complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products. This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions. The existence of discrete inheritable units

11524-605: The conversion of cytidine into uridine at nucleotide 3916. This deamination changes an arginine codon (CGA) to an in-frame translation stop codon (UGA). If the edited transcript is translated, it produces a protein that cannot function as a tumor suppressor because the N-terminal of the GRD is truncated. The editing site in NF1 mRNA was shown to have high homology to the ApoB editing site, where double stranded mRNA undergoes editing by

11658-524: The distinction between a heterozygote and homozygote , and the phenomenon of discontinuous inheritance. Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance , which suggested that each parent contributed fluids to the fertilization process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis , from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used

11792-410: The early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4 (1955–1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA. Collectively, this body of research established

11926-466: The effects of the specific MEK inhibitor PD032590 on tumor progression. The inhibitor demonstrated a remarkable response in tumor regression and in hematologic improvement. Based on these results, phase I and later phase II clinical trials were then conducted in children with inoperable NF1-related plexiform neurofibromas, using Selumetinib , an oral selective MEK inhibitor used previously in several advanced adult neoplasms. The children enrolled in

12060-432: The face and neck through cranial nerves, Autonomic control of the organs is mediated by the tenth cranial nerve . A large portion of the brainstem is involved in such autonomic control of the body. Such functions may engage the heart , blood vessels , and pupils , among others. The brainstem also holds the reticular formation , a group of nuclei involved in both arousal and alertness . The cerebellum lies behind

12194-514: The fact that both protein-coding genes and noncoding genes have been known for more than 50 years, there are still a number of textbooks, websites, and scientific publications that define a gene as a DNA sequence that specifies a protein. In other words, the definition is restricted to protein-coding genes. Here is an example from a recent article in American Scientist. ... to truly assess the potential significance of de novo genes, we relied on

12328-592: The first NF1 genetically engineered knockout mice were published: homozygosity for the Nf1 mutation ( Nf1 ) induced severe developmental cardiac abnormalities that led to embryonic lethality at early stages of the development, pointing out that NF1 plays a fundamental role in normal development. On the contrary, Nf1 heterozygous animals ( Nf1 ) were viable but predisposed to form different types of tumors . In some of these tumor cells, genetic events of loss of heterozygosity (LOH) were observed, supporting that NF1 functions as

12462-413: The functional product. The discovery of introns in the 1970s meant that many eukaryotic genes were much larger than the size of the functional product would imply. Typical mammalian protein-coding genes, for example, are about 62,000 base pairs in length (transcribed region) and since there are about 20,000 of them they occupy about 35–40% of the mammalian genome (including the human genome). In spite of

12596-630: The gene that is described in terms of DNA sequence. There are many different definitions of this gene — some of which are misleading or incorrect. Very early work in the field that became molecular genetics suggested the concept that one gene makes one protein (originally 'one gene - one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s and by the 1960s, textbooks were using molecular gene definitions that included those that specified functional RNA molecules such as ribosomal RNA and tRNA (noncoding genes) as well as protein-coding genes. This idea of two kinds of genes

12730-421: The genome. The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar ( 2-deoxyribose ), a phosphate group, and one of the four bases adenine , cytosine , guanine , and thymine . Two chains of DNA twist around each other to form a DNA double helix with

12864-421: The genomes of complex multicellular organisms , including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as " junk DNA ". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome , about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer. The structure of

12998-414: The gray matter consists of neurons and unmyelinated fibers. Both tissues include a number of glial cells (although the white matter contains more), which are often referred to as supporting cells of the CNS. Different forms of glial cells have different functions, some acting almost as scaffolding for neuroblasts to climb during neurogenesis such as bergmann glia , while others such as microglia are

13132-429: The human and mouse gene. The major transcription start is 484-bp upstream of the translation initiation site. The open reading frame is 8,520-bp long and begins at the translation initiation site. NF1 exon 1 is 544-bp long, contains the 5' UTR and encodes the first 20 amino acids of neurofibromin. The NF1 promoter lies within a CpG island that is 472-bp long, consisting of 43 CpG dinucleotides , and extends into

13266-431: The individual. The cerebrum of cerebral hemispheres make up the largest visual portion of the human brain. Various structures combine to form the cerebral hemispheres, among others: the cortex, basal ganglia, amygdala and hippocampus. The hemispheres together control a large portion of the functions of the human brain such as emotion, memory, perception and motor functions. Apart from this the cerebral hemispheres stand for

13400-472: The length of the 3' UTR , which is consistent with what has been found in the mouse gene. A study conducted in 2000 examined whether the involvement of the 3' UTR in post-transcriptional gene regulation had an effect on the variation of NF1 transcript quantity both spatially and temporally. Five regions of the 3' UTR that appear to bind proteins were found, one of which is HuR , a tumor antigen . HuR binds to AU-rich elements which are scattered throughout

13534-401: The minimal central catalytic domain (GAPc) as well as an extra domain (GAPex) that is formed through the coiling of about 50 residues from the N - and C - terminus. The Ras-binding region is found in the surface of GAPc and consists of a shallow pocket that is lined by conserved amino acid residues. In addition to the GRD, neurofibromin also contains a Sec14 homology-like region as well as

13668-1079: The neocortex of mice is only about 1/100 that of monkeys, and that of monkeys is only about 1/10 that of humans. In addition, rats lack convolutions in their neocortex (possibly also because rats are small mammals), whereas cats have a moderate degree of convolutions, and humans have quite extensive convolutions. Extreme convolution of the neocortex is found in dolphins , possibly related to their complex echolocation . There are many CNS diseases and conditions, including infections such as encephalitis and poliomyelitis , early-onset neurological disorders including ADHD and autism , seizure disorders such as epilepsy , headache disorders such as migraine , late-onset neurodegenerative diseases such as Alzheimer's disease , Parkinson's disease , and essential tremor , autoimmune and inflammatory diseases such as multiple sclerosis and acute disseminated encephalomyelitis , genetic disorders such as Krabbe's disease and Huntington's disease , as well as amyotrophic lateral sclerosis and adrenoleukodystrophy . Lastly, cancers of

13802-439: The nerves synapse at different regions of the spinal cord, either from the periphery to sensory relay neurons that relay the information to the CNS or from the CNS to motor neurons, which relay the information out. The spinal cord relays information up to the brain through spinal tracts through the final common pathway to the thalamus and ultimately to the cortex. Apart from the spinal cord, there are also peripheral nerves of

13936-466: The nerves. Axons in the CNS are often very short, barely a few millimeters, and do not need the same degree of isolation as peripheral nerves. Some peripheral nerves can be over 1 meter in length, such as the nerves to the big toe. To ensure signals move at sufficient speed, myelination is needed. The way in which the Schwann cells and oligodendrocytes myelinate nerves differ. A Schwann cell usually myelinates

14070-513: The neurofibromin catalytic domain. This binding occurs through Ras switch regions I and II, and an arginine finger present in neurofibromin. The interaction between Ras and neurofibromin causes GAP-stimulated hydrolysis of GTP to GDP. This process depends on the stabilization of residues in the Ras switch I and switch II regions, which drives Ras into the confirmation required for enzymatic function. This interaction between Ras and neurofibromin also requires

14204-413: The nucleus. Splicing, followed by CPA, generate the final mature mRNA , which encodes the protein or RNA product. Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails. Many prokaryotic genes are organized into operons , with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as

14338-423: The only vertebrates to possess the evolutionarily recent, outermost part of the cerebral cortex (main part of the telencephalon excluding olfactory bulb) known as the neocortex . This part of the brain is, in mammals, involved in higher thinking and further processing of all senses in the sensory cortices (processing for smell was previously only done by its bulb while those for non-smell senses were only done by

14472-423: The optical nerve (though it does not receive input from the olfactory nerve) to the cerebral hemispheres. Previously it was considered only a "relay station", but it is engaged in the sorting of information that will reach cerebral hemispheres ( neocortex ). Apart from its function of sorting information from the periphery, the thalamus also connects the cerebellum and basal ganglia with the cerebrum. In common with

14606-431: The phosphate–sugar backbone spiralling around the outside, and the bases pointing inward with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds , whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary , with their sequence of bases matching such that

14740-399: The phylum Platyhelminthes (flatworms), have the simplest, clearly defined delineation of a nervous system into a CNS and a PNS . Their primitive brains, consisting of two fused anterior ganglia, and longitudinal nerve cords form the CNS. Like vertebrates, have a distinct CNS and PNS. The nerves projecting laterally from the CNS form their PNS. A molecular study found that more than 95% of

14874-400: The pons. The cerebellum is composed of several dividing fissures and lobes. Its function includes the control of posture and the coordination of movements of parts of the body, including the eyes and head, as well as the limbs. Further, it is involved in motion that has been learned and perfected through practice, and it will adapt to new learned movements. Despite its previous classification as

15008-416: The process of neurogenesis , forming the rudiment of the CNS. The neural tube gives rise to both brain and spinal cord . The anterior (or 'rostral') portion of the neural tube initially differentiates into three brain vesicles (pockets): the prosencephalon at the front, the mesencephalon , and, between the mesencephalon and the spinal cord, the rhombencephalon . (By six weeks in the human embryo)

15142-436: The promoter or untranslated regions. This may be because such mutations are rare, or they do not result in a recognizable phenotype . There have been mutations identified that affect splicing , in fact 286 of the known mutations are identified as splicing mutations. About 78% of splicing mutations directly affect splice sites , which can cause aberrant splicing to occur. Aberrant splicing may also occur due to mutations within

15276-416: The prosencephalon then divides further into the telencephalon and diencephalon ; and the rhombencephalon divides into the metencephalon and myelencephalon . The spinal cord is derived from the posterior or 'caudal' portion of the neural tube. As a vertebrate grows, these vesicles differentiate further still. The telencephalon differentiates into, among other things, the striatum , the hippocampus and

15410-453: The reading frame. These five isoforms are expressed in distinct tissues and are each detected by specific antibodies . It has been suggested that the quantitative differences in expression between the different isoforms may be related to the phenotypic variability of neurofibromatosis type 1 patients. In the NF1 mRNA , there is a site within the first half of the GRD where mRNA editing occurs. Deamination occurs at this site, resulting in

15544-454: The ridges on either side of the groove (the neural folds ) become elevated, and ultimately meet, transforming the groove into a closed tube called the neural tube . The formation of the neural tube is called neurulation . At this stage, the walls of the neural tube contain proliferating neural stem cells in a region called the ventricular zone . The neural stem cells, principally radial glial cells , multiply and generate neurons through

15678-464: The size defect to be rescuable by transgenic modification by either a working NF1 or a protein kinase – but this works only during development and not in adulthood. Interestingly, whole-body size deficits, learning defects and aberrant RAS/ERK signaling are also key features of the NF1 condition in humans, and are all due to a deregulation of the anaplastic lymphoma kinase ALK -NF1- RAS/ERK signaling pathway in flies. Pharmacological treatment using

15812-460: The spinal cord to skin, joints, muscles etc. and allow for the transmission of efferent motor as well as afferent sensory signals and stimuli. This allows for voluntary and involuntary motions of muscles, as well as the perception of senses. All in all 31 spinal nerves project from the brain stem, some forming plexa as they branch out, such as the brachial plexa , sacral plexa etc. Each spinal nerve will carry both sensory and motor signals, but

15946-416: The start of exon 1. This CpG Island begins 731-bp upstream of the promoter and no core promoter element, such as a TATA or CCATT box, has been found within it. Although no core promoter element has been found, consensus binding sequences have been identified in the 5' UTR for several transcription factors such as Sp1 and AP2. A methylation map of five regions of the promoter in both mouse and human

16080-467: The strand of DNA like a train on a monorail, transcribing it into its messenger RNA form. This point brings us to our second important criterion: A true gene is one that is both transcribed and translated. That is, a true gene is first used as a template to make transient messenger RNA, which is then translated into a protein. This restricted definition is so common that it has spawned many recent articles that criticize this "standard definition" and call for

16214-541: The study benefited from the treatment without suffering from excessive toxic effects, and treatment induced partial responses in 72% of them. These unprecedented and promising results from the phase II SPRINT trial, led, first in 2018, both the Food and Drug Administration (FDA) and the European Medicines Agency to grant selumetinib an Orphan Drug Status for the treatment of neurofibromatosis type 1 , and then,

16348-461: The sugar ribose rather than deoxyribose . RNA also contains the base uracil in place of thymine . RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three- nucleotide sequences called codons , which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids . The genetic code

16482-404: The synaptic ATP-PKA-cAMP pathway, through modulation of adenylyl cyclase . It is also known to bind the caveolin 1 , a protein which regulates p21ras, PKC and growth response factors. There are currently five known isoforms of neurofibromin (II, 3, 4, 9a, and 10a-2) and these isoforms are generated through the inclusion of alternative splicing exons (9a, 10a-2, 23a, and 48a) that do not alter

16616-413: The telencephalon covers most of the diencephalon and the entire mesencephalon . Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts . Mammals – which appear in the fossil record after the first fishes, amphibians, and reptiles – are

16750-805: The term gemmule to describe hypothetical particles that would mix during reproduction. Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries , Carl Correns , and Erich von Tschermak , who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis , in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. De Vries called these units "pangenes" ( Pangens in German), after Darwin's 1868 pangenesis theory. Twenty years later, in 1909, Wilhelm Johannsen introduced

16884-436: The term gene , he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured Wilhelm Johannsen 's distinction between genotype (the genetic material of an organism) and phenotype (the observable traits of that organism). Mendel was also the first to demonstrate independent assortment , the distinction between dominant and recessive traits,

17018-412: The term "gene" (inspired by the ancient Greek : γόνος, gonos , meaning offspring and procreation) and, in 1906, William Bateson , that of " genetics " while Eduard Strasburger , among others, still used the term "pangene" for the fundamental physical and functional unit of heredity. Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA)

17152-426: The transition state of GDP hydrolysis to be stabilized, which is performed through the insertion of the positively charged arginine finger into the Ras active site. This neutralizes the negative charges that are present on GTP during phosphoryl transfer. By hydrolyzing GTP to GDP, neurofibromin inactivates Ras and therefore negatively regulates the Ras pathway, which controls the expression of genes involved in apoptosis,

17286-412: The vertebrate central nervous system, which is radically distinct from all other animals. In vertebrates , the brain and spinal cord are both enclosed in the meninges . The meninges provide a barrier to chemicals dissolved in the blood, protecting the brain from most neurotoxins commonly found in food. Within the meninges the brain and spinal cord are bathed in cerebral spinal fluid which replaces

17420-446: The zebrafish Danio rerio and the mouse Mus musculus , which all contain an NF1 ortholog in their genome (no NF1 ortholog exists in the nematode Caenorhabditis elegans .) Research based on these preclinical models has already proven its efficacy as multiple clinical assays have been initiated subsequently regarding neurofibromatosis type 1 -related plexiform neurofibromas, gliomas, MPNST and neurocognitive disorders. In 1994,

17554-493: Was cloned in 1990 and its product neurofibromin was identified in 1992. Neurofibromin, a GTPase-activating protein , primarily regulates the protein Ras . NF1 is located on the long arm of chromosome 17 , position q11.2 NF1 spans over 350- kb of genomic DNA and contains 62 exons. 58 of these exons are constitutive and 4 exhibit alternative splicing ( 9a, 10a-2, 23a, and 28a). The genomic sequence starts 4,951- bp upstream of

17688-446: Was first suggested by Gregor Mendel (1822–1884). From 1857 to 1864, in Brno , Austrian Empire (today's Czech Republic), he studied inheritance patterns in 8000 common edible pea plants , tracking distinct traits from parent to offspring. He described these mathematically as 2  combinations where n is the number of differing characteristics in the original peas. Although he did not use

17822-461: Was published in 1999. This map showed that three of the regions (at approximately – 1000, – 3000, and – 4000) were frequently methylated, but the cytosines near the transcription start site were unmethylated. Methylation has been shown to functionally impact Sp1 sites as well as a CREB binding site. It has been shown that the CREB site must be intact for normal promoter activity to occur and methylation at

17956-430: Was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography , which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication. In

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