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96-538: 3CMY 5077 18505 ENSG00000135903 ENSMUSG00000004872 P23760 P24610 NM_181459 NM_181460 NM_181461 NM_001159520 NM_008781 NP_852124 NP_852125 NP_852126 NP_852122.1 NP_001152992 NP_032807 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors . The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in

192-584: 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

288-487: 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. Somite The word somite

384-691: A 128 amino acid region that binds to DNA sequences related to the TCACGC/G motif. The HD motif usually consists of 60 amino acids and binds to sequences containing a TAAT core motif. The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites. In the C-terminus of PAX3, there is a proline, serine and threonine (PST)-rich region measuring 78 amino acids that functions to stimulate transcriptional activity. There are also transcriptional repression domains in

480-1007: A PAX7 molecule enables binding to a palindromic HD binding site (TAATCAATTA). Interaction of PAX3 with other transcription factors (such as SOX10) or chromatin factors (such as PAX3/7BP) enables synergistic activation of PAX3 target genes. In contrast, binding of PAX3 to co-repressors, such as calmyrin, inhibits activation of PAX3 target genes. These co-repressors may function by altering chromatin structure at target genes, inhibiting PAX3 recognition of its DNA binding site or directly altering PAX3 transcriptional activity. Finally, PAX3 protein expression and function can be modulated by post-translational modifications. PAX3 can be phosphorylated at serines 201, 205 and 209 by kinases such as GSK3b, which in some settings will increase PAX3 protein stability. In addition, PAX3 can also undergo ubiquitination and acetylation at lysines 437 and 475, which regulates protein stability and function. Table 1. Representative PAX3 transcriptional target genes. During development, one of

576-445: 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

672-495: 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

768-488: 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

864-434: 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

960-565: 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

1056-410: 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

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1152-404: 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

1248-565: 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

1344-439: 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

1440-448: 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

1536-572: 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

1632-400: 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

1728-419: 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

1824-414: A rostral to caudal direction. During early development, Pax3 expression also occurs at the lateral and posterior margins of the neural plate, which is the region from which the neural crest arises. Pax3 is later expressed by various cell types and structures arising from the neural crest, such as melanoblasts, Schwann cell precursors, and dorsal root ganglia. In addition, Pax3-expressing cells derived from

1920-412: 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

2016-472: 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

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2112-447: A subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region. Alternative splicing and processing generates multiple PAX3 isoforms that have been detected at the mRNA level. PAX3e is the longest isoform and consists of 10 exons that encode a 505 amino acid protein. In other mammalian species, including mouse,

2208-691: A transcriptional coactivator involved in Notch signaling. The PAX3-MAML3 fusion juxtaposes the N-terminal PAX3 DNA binding domain with the C-terminal MAML3 transactivation domain to create another potent activator of target genes with PAX3 binding sites. Of note, PAX3 is rearranged without MAML3 involvement in a smaller subset of BSNS cases, and some of these variant cases contain a PAX3-NCOA1 or PAX3-FOXO1 fusion. Though PAX3-FOXO1 and PAX3-NCOA1 fusions can be formed in both ARMS and BSNS, there are differences in

2304-409: 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

2400-431: Is activated. To form other skeletal muscles, Pax3-expressing cells detach from the dermomyotome and migrate to more distant sites, such as the limbs and diaphragm. A subset of these Pax3-expressing dermomyotome-derived cells also serves as an ongoing progenitor pool for skeletal muscle growth during fetal development. During later developmental stages, myogenic precursors expressing Pax3 and/or Pax7 form satellite cells within

2496-456: 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,

2592-436: Is expressed in cancers associated with neural tube-derived lineages, (e.g., glioblastoma), neural crest-derived lineages (e.g., melanoma) and myogenic lineages (e.g., embryonal rhabdomyosarcoma). However, PAX3 is also expressed in other cancer types without a clear relationship to a PAX3-expressing developmental lineages, such as breast carcinoma and osteosarcoma. In these wild-type PAX3-expressing cancers, PAX3 function impacts on

2688-528: Is frequently distinguished by musculoskeletal abnormalities affecting the upper limbs. Most WS1 cases are caused by heterozygous PAX3 mutations while WS3 is caused by either partial or total deletion of PAX3 and contiguous genes or by smaller PAX3 mutations in the heterozygous or homozygous state. These PAX3 mutations in WS1 and WS3 include missense, nonsense and splicing mutations; small insertions; and small or gross deletions. Though these changes are usually not recurrent,

2784-400: 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

2880-404: Is sometimes also used in place of the word metamere . In this definition, the somite is a homologously -paired structure in an animal body plan , such as is visible in annelids and arthropods . The mesoderm forms at the same time as the other two germ layers , the ectoderm and endoderm . The mesoderm at either side of the neural tube is called paraxial mesoderm . It is distinct from

2976-403: 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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3072-399: 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

3168-458: Is that part of a somite that forms the muscles of the animal. Each myotome divides into an epaxial part ( epimere ), at the back, and a hypaxial part ( hypomere ) at the front. The myoblasts from the hypaxial division form the muscles of the thoracic and anterior abdominal walls. The epaxial muscle mass loses its segmental character to form the extensor muscles of the neck and trunk of mammals. In fishes, salamanders, caecilians, and reptiles,

3264-410: 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 , is the basis of

3360-511: 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

3456-401: 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

3552-419: 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

3648-445: The chick embryo, somites are formed every 90 minutes. In the mouse the interval is 2 hours. For some species, the number of somites may be used to determine the stage of embryonic development more reliably than the number of hours post-fertilization because rate of development can be affected by temperature or other environmental factors. The somites appear on both sides of the neural tube simultaneously. Experimental manipulation of

3744-549: 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

3840-475: 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

3936-750: 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

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4032-449: 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,

4128-648: The 5’ promoter, first intron and 3’ untranslated region. A substantial number of PAX3 binding sites are located at larger distances upstream and downstream of target genes. Among the PAX3 target genes, there is one group associated with muscle development and a second group associated with neural and melanocyte development. The proteins encoded by these target genes regulate various functional activities in these lineages, including differentiation, proliferation, migration, adhesion, and apoptosis. PAX3 interacts with other nuclear proteins, which modulate PAX3 transcriptional activity. Dimerization of PAX3 with another PAX3 molecule or

4224-404: 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

4320-450: 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

4416-766: 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

4512-603: The HD and N-terminal region (including the first half of the PD) that repress the C-terminal transcriptional activation domain. PAX3 functions as a transcriptional activator for most target genes, but also may repress a smaller subset of target genes. These expression changes are effected through binding of PAX3 to specific recognition sites, which are situated in various genomic locations. Some binding sites are located in or near target genes, such as

4608-506: 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 —

4704-653: The PAX3 and FOXO1 genes to generate a PAX3-FOXO1 fusion gene that expresses a PAX3-FOXO1 fusion transcript encoding a PAX3-FOXO1 fusion protein. PAX3 and FOXO1 encode transcription factors, and the translocation results in a fusion transcription factor containing the N-terminal PAX3 DNA-binding domain and the C-terminal FOXO1 transactivation domain. A smaller subset of ARMS cases is associated with less common fusions of PAX7 to FOXO1 or rare fusions of PAX3 to other transcription factors, such as NCOA1. Compared to

4800-456: The PAX3 gene occur in the human disease Waardenburg syndrome , which consists of four autosomal dominant genetic disorders (WS1, WS2, WS3 and WS4). Of the four subtypes, WS1 and WS3 are usually caused by PAX3 mutations. All four subtypes are characterized by hearing loss, eye abnormalities and pigmentation disorders. In addition, WS1 is frequently associated with a midfacial alteration called dystopia canthorum, while WS3 (Klein-Waardenburg syndrome)

4896-571: The PAX3 mRNA involves the sequence CAG at the 5’ end of exon 3. This splice either includes or excludes these three bases, thus resulting in the presence or absence of a glutamine residue in the paired box motif. Limited sequencing studies of full-length human cDNAs identified this splicing event as a variant of the PAX3d isoform, and this spliced isoform has been separately termed the PAX3i isoform. The Q+ and Q− isoforms of PAX3 are generally co-expressed in cells. At

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4992-433: 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

5088-521: The anterior-posterior axis through specifying the pre-somitic mesoderm before somitogenesis occurs. After somites are made, their identity as a whole has already been determined, as is shown by the fact that transplantation of somites from one region to a completely different region results in the formation of structures usually observed in the original region. In contrast, the cells within each somite retain plasticity (the ability to form any kind of structure) until relatively late in somitic development. In

5184-407: The body musculature remains segmented as in the embryo, though it often becomes folded and overlapping, with epaxial and hypaxial masses divided into several distinct muscle groups. The sclerotome (or cutis plate ) forms the vertebrae and the rib cartilage and part of the occipital bone; the myotome forms the musculature of the back, the ribs and the limbs; the syndetome forms the tendons and

5280-427: The boundaries of somites. EPHB2 is also important for boundaries. Fibronectin and N-cadherin are key to the mesenchymal–epithelial transition process in the developing embryo. The process is probably regulated by paraxis and MESP2. In turn, MESP2 is regulated by Notch signaling. Paraxis is regulated by processes involving the cytoskeleton . The Hox genes specify somites as a whole based on their position along

5376-494: The caudal half of the somite. Notch activation turns on LFNG which in turn inhibits the Notch receptor. Notch activation also turns on the HES1 gene which inactivates LFNG, re-enabling the Notch receptor, and thus accounting for the oscillating clock model. MESP2 induces the EPHA4 gene, which causes repulsive interaction that separates somites by causing segmentation. EPHA4 is restricted to

5472-436: 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

5568-402: 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

5664-445: The control of proliferation, apoptosis, differentiation and motility. Therefore, wild-type PAX3 exerts a regulatory role in tumorigenesis and tumor progression, which may be related to its role in normal development. Gene In biology , the word gene has two meanings. The Mendelian gene is a basic unit of heredity . The molecular gene is a sequence of nucleotides in DNA that

5760-414: The dermatome forms the skin on the back. In addition, the somites specify the migration paths of neural crest cells and the axons of spinal nerves . From their initial location within the somite, the sclerotome cells migrate medially towards the notochord . These cells meet the sclerotome cells from the other side to form the vertebral body. The lower half of one sclerotome fuses with the upper half of

5856-435: The developing somites will not alter the rostral/caudal orientation of the somites, as the cell fates have been determined prior to somitogenesis. Somite formation can be induced by Noggin -secreting cells. The number of somites is species dependent and independent of embryo size (for example, if modified via surgery or genetic engineering). Chicken embryos have 50 somites; mice have 65, while snakes have 500. As cells within

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5952-428: The developing vertebrate embryo , somites split to form dermatomes, skeletal muscle (myotomes), tendons and cartilage (syndetomes) and bone (sclerotomes). Because the sclerotome differentiates before the dermatome and the myotome, the term dermomyotome refers to the combined dermatome and myotome before they separate out. The dermatome is the dorsal portion of the paraxial mesoderm somite which gives rise to

6048-524: 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

6144-410: 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

6240-514: 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

6336-570: The functional level, the Q+ isoform shows similar or less DNA binding and transcriptional activation than the Q− isoform. PAX3 encodes a transcription factor with an N-terminal DNA binding domain consisting of a paired box (PD) encoded by exons 2, 3, and 4, and an octapeptide and complete homeodomain (HD) encoded by exons 5 and 6. In addition, the PAX3 protein has a C-terminal transcriptional activation domain encoded by exons 7 and 8. The highly conserved PD consists of

6432-413: 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

6528-630: 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

6624-421: 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

6720-421: 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

6816-529: The heterozygous state, the splotch phenotype is characterized by white patches in the belly, tail and feet. These white spots are attributed to localized deficiencies in pigment-forming melanocytes resulting from neural crest cell defects. In the homozygous state, these Pax3 mutations cause embryonic lethality, which is associated with prominent neural tube closure defects and abnormalities of neural crest-derived structures, such as melanocytes, dorsal root ganglia and enteric ganglia. Heart malformations also result from

6912-415: 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

7008-604: The longest mRNAs correspond to the human PAX3c and PAX3d isoforms, which consist of the first 8 or 9 exons of the PAX3 gene, respectively. Shorter PAX3 isoforms include mRNAs that skip exon 8 (PAX3g and PAX3h) and mRNAs containing 4 or 5 exons (PAX3a and PAX3b). In limited studies comparing isoform expression, PAX3d is expressed at the highest levels. From a functional standpoint, PAX3c, PAX3d, and PAX3h stimulate activities such as cell growth whereas PAX3e and PAX3g inhibit these activities, and PAX3a and PAX3b show no activity or inhibit these endpoints. A common alternative splice affecting

7104-417: The loss of cardiac neural crest cells, which normally contribute to the cardiac outflow tract and innervation of the heart. Finally, limb musculature does not develop in the homozygotes and axial musculature demonstrates varying abnormalities. These myogenic effects are caused by increased cell death of myogenic precursors in the dermomyotome and diminished migration from the dermomyotome. Germline mutations of

7200-416: The major lineages expressing Pax3 is the skeletal muscle lineage. Pax3 expression is first seen in the pre-somitic paraxial mesoderm, and then ultimately becomes restricted to the dermomyotome , which forms from the dorsal region of the somites. To form skeletal muscle in central body segments, PAX3-expressing cells detach from the dermomyotome and then Pax3 expression is turned off as Myf5 and MyoD1 expression

7296-442: The mesoderm underneath the neural tube, which is called the chordamesoderm that becomes the notochord. The paraxial mesoderm is initially called the "segmental plate" in the chick embryo or the "unsegmented mesoderm" in other vertebrates. As the primitive streak regresses and neural folds gather (to eventually become the neural tube ), the paraxial mesoderm separates into blocks called somites. The pre-somitic mesoderm commits to

7392-453: The model, oscillating Notch and Wnt signals provide the clock. The wave is a gradient of the fibroblast growth factor protein that is rostral to caudal (nose to tail gradient). Somites form one after the other down the length of the embryo from the head to the tail, with each new somite forming on the caudal (tail) side of the previous one. The timing of the interval is not universal. Different species have different interval timing. In

7488-437: The mutations generally occur in exons 2 through 6 with exon 2 mutations being most common. As these exons encode the paired box and homeodomain, these mutations often affect DNA binding function. Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma that occurs in children and is usually characterized by a recurrent t(2;13)(q35;q14) chromosomal translocation. This 2;13 translocation breaks and rejoins portions of

7584-532: The neural crest contribute to the formation of other structures, such as the inner ear, mandible and maxilla. Pax3 controls the location of the nasion (a facial feature between the eyes and at the top of the nose), and is associated with the presence of a unibrow . Germline mutations of the Pax3 gene cause the splotch phenotype in mice. At the molecular level, this phenotype is caused by point mutations or deletions that alter or abolish Pax3 transcriptional function. In

7680-461: The neural tube, Pax3 is expressed in the dorsal portion of the neural tube. As the neural tube enlarges, Pax3 expression is localized to proliferative cells in the inner ventricular zone and then this expression is turned off as these cells migrate to more superficial regions. Pax3 is expressed along the length of the neural tube and throughout much of the developing brain, and this expression is subsequently turned off during later developmental stages in

7776-413: 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

7872-499: The paraxial mesoderm begin to come together, they are termed somitomeres , indicating a lack of complete separation between segments. The outer cells undergo a mesenchymal–epithelial transition to form an epithelium around each somite. The inner cells remain as mesenchyme . The Notch system, as part of the clock and wavefront model, forms the boundaries of the somites. DLL1 and DLL3 are Notch ligands , mutations of which cause various defects. Notch regulates HES1 , which sets up

7968-472: The pattern of activated downstream target genes suggesting that the cell environment has an important role in modulating the output of these fusion transcription factors. In addition to tumors with PAX3-related fusion genes, there are several other tumor categories that express the wild-type PAX3 gene. The presence of PAX3 expression in some tumors can be explained by their derivation from developmental lineages normally expressing wild-type PAX3. For example, PAX3

8064-431: 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

8160-412: The skeletal muscle, which contribute to postnatal muscle growth and muscle regeneration. These adult satellite cells remain quiescent until injury occurs, and then are stimulated to divide and regenerate the injured muscle. Pax3 is also involved in the development of the nervous system. Expression of Pax3 is first detected in the dorsal region of the neural groove and, as this neural groove deepens to form

8256-423: The skin ( dermis ). In the human embryo, it arises in the third week of embryogenesis . It is formed when a dermomyotome (the remaining part of the somite left when the sclerotome migrates), splits to form the dermatome and the myotome. The dermatomes contribute to the skin, fat and connective tissue of the neck and of the trunk, though most of the skin is derived from lateral plate mesoderm . The myotome

8352-430: The somitic fate before mesoderm becomes capable of forming somites. The cells within each somite are specified based on their location within the somite. Additionally, they retain the ability to become any kind of somite-derived structure until relatively late in the process of somitogenesis . The development of the somites depends on a clock mechanism as described by the clock and wavefront model . In one description of

8448-467: 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

8544-461: 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

8640-805: 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

8736-436: 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,

8832-412: 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)

8928-454: The vicinity of a subset of these target genes. These dysregulated target genes contribute to tumorigenesis by altering signaling pathways that affect proliferation, cell death, myogenic differentiation, and migration. A t(2;4)(q35;q31.1) chromosomal translocation that fuses the PAX3 and MAML3 genes occurs in biphenotypic sinonasal sarcoma (BSNS), a low-grade adult malignancy associated with both myogenic and neural differentiation. MAML3 encodes

9024-473: The wild-type PAX3 protein, the PAX3-FOXO1 fusion protein more potently activates PAX3 target genes. In ARMS cells, PAX3-FOXO1 usually functions as a transcriptional activator and excessively increases expression of downstream target genes. In addition, PAX3-FOXO1 binds along with MYOD1, MYOG and MYCN as well as chromatin structural proteins, such as CHD4 and BRD4, to contribute to the formation of super enhancers in

9120-446: 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

9216-430: 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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