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152-401: 1N0W , 3EU7 675 12190 ENSG00000139618 ENSMUSG00000041147 P51587 P97929 NM_000059 NM_001081001 NM_009765 NP_000050 NP_001074470 NP_033895 BRCA2 and BRCA2 ( / ˌ b r æ k ə ˈ t uː / ) are human genes and their protein products, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and
304-433: A DNA repair process, and that when it occurs during meiosis it is an adaptation for repairing the genomic DNA that is passed on to progeny. Experimental findings indicate that a substantial benefit of meiosis is recombinational repair of DNA damage in the germline , as indicated by the following examples. Hydrogen peroxide is an agent that causes oxidative stress leading to oxidative DNA damage. Treatment of
456-420: A beta-barrel . OB3 has a pronounced groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for strong ssDNA binding . The Tower domain adopts a secondary structure consisting of a pair of long, antiparallel alpha-helices (the stem) that support a three-helix bundle (3HB) at their end. The 3HB contains
608-588: A helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive beta-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure . In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds . This domain binds
760-464: A helix-turn-helix motif and is similar to the DNA binding domains of the bacterial site-specific recombinases , and of eukaryotic Myb and homeodomain transcription factors . The Tower domain has an important role in the tumour suppressor function of BRCA2, and is essential for appropriate binding of BRCA2 to DNA. Studies shown that conformation of this tower domain is allosterically controlled by
912-584: 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
1064-619: 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. Meiosis Meiosis ( / m aɪ ˈ oʊ s ɪ s / ; from Ancient Greek μείωσις ( meíōsis ) 'lessening', (since it
1216-493: A barrel shaped spindle. In human oocytes spindle microtubule nucleation begins on the chromosomes, forming an aster that eventually expands to surround the chromosomes. Chromosomes then slide along the microtubules towards the equator of the spindle, at which point the chromosome kinetochores form end-on attachments to microtubules. Homologous pairs move together along the metaphase plate: As kinetochore microtubules from both spindle poles attach to their respective kinetochores,
1368-465: A common intestinal parasite, was previously considered to have descended from a lineage that predated the emergence of meiosis and sex. However, G. intestinalis has now been found to possess a core set of meiotic genes, including five meiosis specific genes. Also evidence for meiotic recombination , indicative of sexual reproduction , was found in G. intestinalis . Another example of organisms previously thought to be asexual are parasitic protozoa of
1520-445: 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
1672-433: A diploid cell called the zygote . The organism's diploid germ-line stem cells undergo meiosis to make haploid gametes (the spermatozoa in males and ova in females), which fertilize to form the zygote. The diploid zygote undergoes repeated cellular division by mitosis to grow into the organism. In the haplontic life cycle (with post-zygotic meiosis), the organism is haploid, by the proliferation and differentiation of
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#17328452993801824-406: A diploid cell, which contains two copies of each chromosome, termed homologs . First, the cell undergoes DNA replication , so each homolog now consists of two identical sister chromatids. Then each set of homologs pair with each other and exchange genetic information by homologous recombination often leading to physical connections ( crossovers ) between the homologs. In the first meiotic division,
1976-449: 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
2128-488: 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
2280-434: 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
2432-565: 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
2584-410: 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
2736-404: 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
2888-565: 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
3040-439: 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
3192-448: 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
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#17328452993803344-471: A moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below. In the plant Arabidopsis thaliana , loss of
3496-407: A new combination of maternal and paternal genetic information, resulting in offspring that are genetically distinct from either parent. Furthermore, an individual gamete can include an assortment of maternal, paternal, and recombinant chromatids. This genetic diversity resulting from sexual reproduction contributes to the variation in traits upon which natural selection can act. Meiosis uses many of
3648-400: A new diploid organism. The haplodiplontic life cycle can be considered a fusion of the diplontic and haplontic life cycles. Meiosis occurs in all animals and plants. The result, the production of gametes with half the number of chromosomes as the parent cell, is the same, but the detailed process is different. In animals, meiosis produces gametes directly. In land plants and some algae, there
3800-572: 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
3952-402: A pair of sister chromatids) to opposite poles. Nonkinetochore microtubules lengthen, pushing the centrosomes farther apart. The cell elongates in preparation for division down the center. Unlike in mitosis, only the cohesin from the chromosome arms is degraded while the cohesin surrounding the centromere remains protected by a protein named Shugoshin (Japanese for "guardian spirit"), what prevents
4104-420: A period of rest known as interkinesis or interphase II. No DNA replication occurs during this stage. Meiosis II is the second meiotic division, and usually involves equational segregation, or separation of sister chromatids. Mechanically, the process is similar to mitosis, though its genetic results are fundamentally different. The result is the production of four haploid cells (n chromosomes; 23 in humans) from
4256-485: A phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in these mutant rats is due to a failure of homologous chromosome synapsis during meiosis. DMC1 (DNA meiotic recombinase 1) is a meiosis specific homolog of RAD51 that mediates strand exchange during homologous recombinational repair. DMC1 promotes the formation of DNA strand invasion products (joint molecules) between homologous DNA molecules. Human DMC1 interacts directly with each of
4408-400: 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
4560-423: A prolonged G 2 -like stage known as meiotic prophase . During this time, homologous chromosomes pair with each other and undergo genetic recombination , a programmed process in which DNA may be cut and then repaired, which allows them to exchange some of their genetic information . A subset of recombination events results in crossovers , which create physical links known as chiasmata (singular: chiasma, for
4712-419: 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
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4864-446: A result, there is an increase in mutations due to error-prone translesion synthesis past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor. People who have two mutated copies of the BRCA2 gene have one type of Fanconi anemia . This condition is caused by extremely reduced levels of the BRCA2 protein in cells, which allows
5016-498: A series of repeat sequences in the BRCA2 protein (called BRC repeats) that stimulate joint molecule formation by DMC1. BRC repeats conform to a motif consisting of a sequence of about 35 highly conserved amino acids that are present at least once in all BRCA2-like proteins. The BRCA2 BRC repeats stimulate joint molecule formation by promoting the interaction of single-stranded DNA (ssDNA) with DMC1. The ssDNA complexed with DMC1 can pair with homologous ssDNA from another chromosome during
5168-523: A significant correlation is found between hypomethylation and a >3-fold over-expression of BRCA2. This indicates that hypomethylation of the BRCA2 promoter and 5'-UTR regions leads to over-expression of BRCA2 mRNA. One report indicated some epigenetic control of BRCA2 expression by the microRNAs miR-146a and miR-148a. In eukaryotes , BRCA2 protein has an important role in homologous recombinational repair. In mice and humans, BRCA2 primarily mediates orderly assembly of RAD51 on single-stranded (ss) DNA,
5320-412: 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
5472-399: A single haploid cell called the gamete . Two organisms of opposing sex contribute their haploid gametes to form a diploid zygote. The zygote undergoes meiosis immediately, creating four haploid cells. These cells undergo mitosis to create the organism. Many fungi and many protozoa utilize the haplontic life cycle. In the haplodiplontic life cycle (with sporic or intermediate meiosis),
5624-523: A small protein "DSS1", which interacts with helical, OB1 and OB2 domains of BRCA2. A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; over the next year, Myriad, in collaboration with other investigators, isolated and sequenced
5776-400: A special type of cell division that creates sperm and eggs ( meiosis ). Double strand breaks are also generated during repair of DNA cross links. By repairing DNA, these proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic and other cancers. BRCA2 has been shown to possess a crucial role in protection from
5928-472: 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
6080-448: A total of four daughter cells, each with a haploid set of chromosomes. Meiosis is now complete and ends up with four new daughter cells. Meiosis appears to be a fundamental characteristic of eukaryotic organisms and to have been present early in eukaryotic evolution. Eukaryotes that were once thought to lack meiotic sex have recently been shown to likely have, or once have had, this capability. As one example, Giardia intestinalis ,
6232-409: 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
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6384-479: Is crossed over , creating new combinations of code on each chromosome. Later on, during fertilisation , the haploid cells produced by meiosis from a male and a female will fuse to create a zygote , a cell with two copies of each chromosome again. Errors in meiosis resulting in aneuploidy (an abnormal number of chromosomes) are the leading known cause of miscarriage and the most frequent genetic cause of developmental disabilities . In meiosis, DNA replication
6536-416: Is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes , the sperm or egg cells . It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome ( haploid ). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome
6688-400: Is an alternation of generations such that meiosis in the diploid sporophyte generation produces haploid spores instead of gametes. When they germinate, these spores undergo repeated cell division by mitosis, developing into a multicellular haploid gametophyte generation, which then produces gametes directly (i.e. without further meiosis). In both animals and plants, the final stage is for
6840-456: 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,
6992-423: Is cleaved, allowing the sister chromatids to segregate. The sister chromatids by convention are now called sister chromosomes as they move toward opposing poles. The process ends with telophase II , which is similar to telophase I, and is marked by decondensation and lengthening of the chromosomes and the disassembly of the spindle. Nuclear envelopes re-form and cleavage or cell plate formation eventually produces
7144-482: Is damaged by a BRCA mutation , damaged DNA is not repaired properly, and this increases the risk for breast cancer . BRCA1 and BRCA2 have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins". The predominant allele has a normal tumor suppressive function whereas high penetrance mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer. The BRCA2 gene
7296-520: Is divided into meiosis I and meiosis II which are further divided into Karyokinesis I, Cytokinesis I, Karyokinesis II, and Cytokinesis II, respectively. The preparatory steps that lead up to meiosis are identical in pattern and name to interphase of the mitotic cell cycle. Interphase is divided into three phases: Interphase is followed by meiosis I and then meiosis II. Meiosis I separates replicated homologous chromosomes, each still made up of two sister chromatids, into two daughter cells, thus reducing
7448-443: Is epigenetically repressed by hypermethylation of the promoter. In this case, promoter hypermethylation is significantly associated with low mRNA expression and low protein expression but not with loss of heterozygosity of the gene. In sporadic ovarian cancer, an opposite effect is found. BRCA2 promoter and 5'-UTR regions have relatively few or no methylated CpG dinucleotides in the tumor DNA compared with that of non-tumor DNA, and
7600-575: Is followed by two rounds of cell division to produce four daughter cells, each with half the number of chromosomes as the original parent cell. The two meiotic divisions are known as meiosis I and meiosis II . Before meiosis begins, during S phase of the cell cycle , the DNA of each chromosome is replicated so that it consists of two identical sister chromatids , which remain held together through sister chromatid cohesion. This S-phase can be referred to as "premeiotic S-phase" or "meiotic S-phase". Immediately following DNA replication, meiotic cells enter
7752-578: Is likely mediated by oxidative stress leading to increased DNA damage. Meiosis occurs in eukaryotic life cycles involving sexual reproduction , consisting of the cyclical process of growth and development by mitotic cell division, production of gametes by meiosis and fertilization. At certain stages of the life cycle, germ cells produce gametes. Somatic cells make up the body of the organism and are not involved in gamete production. Cycling meiosis and fertilization events results in alternation between haploid and diploid states. The organism phase of
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#17328452993807904-510: Is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3). The human reference BRCA2 gene contains 27 exons, and the cDNA has 10,254 base pairs coding for a protein of 3418 amino acids. Although the structures of the BRCA1 and BRCA2 genes are very different, at least some functions are interrelated. The proteins made by both genes are essential for repairing damaged DNA (see Figure of recombinational repair steps). BRCA2 binds
8056-400: 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
8208-477: Is required in the mouse for neurogenesis and suppression of medulloblastoma . ‘’BRCA2’’ loss profoundly affects neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arise from DNA damage. Epigenetic alterations in expression of BRCA2 (causing over-expression or under-expression) are very frequent in sporadic cancers (see Table below) while mutations in BRCA2 are rarely found. In non-small cell lung cancer, BRCA2
8360-403: 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
8512-399: 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
8664-436: Is that it suggests there are some options in addition to prophylactic surgery. In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian , uterine tube , prostate and pancreatic cancer . In some studies, mutations in the central part of the gene have been associated with a higher risk of ovarian cancer and a lower risk of prostate cancer than mutations in other parts of
8816-449: Is the stage at which all autosomal chromosomes have synapsed. In this stage homologous recombination, including chromosomal crossover (crossing over), is completed through the repair of the double strand breaks formed in leptotene. Most breaks are repaired without forming crossovers resulting in gene conversion . However, a subset of breaks (at least one per chromosome) form crossovers between non-sister (homologous) chromosomes resulting in
8968-408: The BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome. As
9120-493: The BRCA2 homolog AtBRCA2 causes severe defects in both male meiosis and in the development of the female gametocyte . AtBRCA2 protein is required for proper localization of the synaptonemal complex protein AtZYP1 and the recombinases AtRAD51 and AtDMC1. Furthermore, AtBRCA2 is required for proper meiotic synapsis. Thus AtBRCA2 is likely important for meiotic recombination. It appears that AtBRCA2 acts during meiosis to control
9272-543: The MRE11 -dependent nucleolytic degradation of the reversed forks that are forming during DNA replication fork stalling (caused by obstacles such as mutations, intercalating agents etc.). Like BRCA1, BRCA2 probably regulates the activity of other genes and plays a critical role in embryo development. Certain variations of the BRCA2 gene increase risks for breast cancer as part of a hereditary breast–ovarian cancer syndrome . Researchers have identified hundreds of mutations in
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#17328452993809424-511: 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
9576-401: 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
9728-419: 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
9880-440: The diakinesis stage, from Greek words meaning "moving through". This is the first point in meiosis where the four parts of the tetrads are actually visible. Sites of crossing over entangle together, effectively overlapping, making chiasmata clearly visible. Other than this observation, the rest of the stage closely resembles prometaphase of mitosis; the nucleoli disappear, the nuclear membrane disintegrates into vesicles, and
10032-474: The meiotic spindle begins to form. Unlike mitotic cells, human and mouse oocytes do not have centrosomes to produce the meiotic spindle. In mice, approximately 80 MicroTubule Organizing Centers (MTOCs) form a sphere in the ooplasm and begin to nucleate microtubules that reach out towards chromosomes, attaching to the chromosomes at the kinetochore . Over time, the MTOCs merge until two poles have formed, generating
10184-549: 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
10336-475: 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
10488-750: 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
10640-508: The phenotype of the individual. Most biological traits occur under 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
10792-449: 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,
10944-429: The synonym breast cancer type 2 susceptibility protein , is responsible for repairing DNA. BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks. If BRCA1 or BRCA2 itself
11096-424: The 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome. The BRCA OB1 domain assumes an OB fold , which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel . OB1 has a shallow groove formed by one face of
11248-566: The BRCA1 and BRCA2 patents will affect the field of genetic testing in general. In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However,
11400-515: The BRCA2 gene and identified relevant mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and the other institutions in 1995. Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs. This business model led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $ 500M in annual revenue in 2012; it also led to controversy over high prices and
11552-608: The Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection. The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013, but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling. |} Gene In biology ,
11704-449: The DNA of the germline . The repair process used appears to involve homologous recombinational repair Prophase I arrested oocytes have a high capability for efficient repair of DNA damage , particularly exogenously induced double-strand breaks. DNA repair capability appears to be a key quality control mechanism in the female germ line and a critical determinant of fertility . Genetic recombination can be viewed as fundamentally
11856-404: 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
12008-450: 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
12160-766: 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
12312-498: The Greek letter Chi , Χ) between the homologous chromosomes. In most organisms, these links can help direct each pair of homologous chromosomes to segregate away from each other during meiosis I, resulting in two haploid cells that have half the number of chromosomes as the parent cell. During meiosis II, the cohesion between sister chromatids is released and they segregate from one another, as during mitosis . In some cases, all four of
12464-506: 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 —
12616-409: The ability to reproduce by parthenogenesis . Meiosis does not occur in archaea or bacteria , which generally reproduce asexually via binary fission . However, a "sexual" process known as horizontal gene transfer involves the transfer of DNA from one bacterium or archaeon to another and recombination of these DNA molecules of different parental origin. Meiosis was discovered and described for
12768-712: The accumulation of damaged DNA. Patients with Fanconi anemia are prone to several types of leukemia (a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia ). Women having inherited a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery . There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1 - and BRCA2 -associated hereditary cancers occur are related to tissue specificity of
12920-433: 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
13072-1036: The assembly or stability of the RAD51 nucleoprotein filament . RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (see homologous recombination models ). Some studies of cancers report over-expressed BRCA2 whereas other studies report under-expression of BRCA2 . At least two reports found over-expression in some sporadic breast tumors and under-expression in other sporadic breast tumors. (see Table). Many cancers have epigenetic deficiencies in various DNA repair genes (see Frequencies of epimutations in DNA repair genes in cancers ). These repair deficiencies likely cause increased unrepaired DNA damages. The over-expression of BRCA2 seen in many cancers may reflect compensatory BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. Egawa et al. suggest that increased expression of BRCA2 can be explained by
13224-438: The cancer pathogen, the agent that causes chronic inflammation, or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to carcinogens and an infectious process. An innate genomic deficit impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2 . A major advantage of this model
13376-535: The chromosome number by half. During meiosis II, sister chromatids decouple and the resultant daughter chromosomes are segregated into four daughter cells. For diploid organisms, the daughter cells resulting from meiosis are haploid and contain only one copy of each chromosome. In some species, cells enter a resting phase known as interkinesis between meiosis I and meiosis II. Meiosis I and II are each divided into prophase , metaphase , anaphase , and telophase stages, similar in purpose to their analogous subphases in
13528-596: The chromosomes at the first meiotic division. The paired and replicated chromosomes are called bivalents (two chromosomes) or tetrads (four chromatids ), with one chromosome coming from each parent. Prophase I is divided into a series of substages which are named according to the appearance of chromosomes. The first stage of prophase I is the leptotene stage, also known as leptonema , from Greek words meaning "thin threads". In this stage of prophase I, individual chromosomes—each consisting of two replicated sister chromatids—become "individualized" to form visible strands within
13680-402: 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
13832-405: The curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding . The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein. The BRCA OB3 domain assumes an OB fold , which consists of a highly curved five-stranded beta-sheet that closes on itself to form
13984-474: The diagnostic test led from Myriad's beginnings as a startup in 1994 to its being a publicly traded company with 1200 employees and about $ 500M in annual revenue in 2012; it also led to controversy over high test prices and the unavailability of second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit. All germline BRCA2 mutations identified to date have been inherited, suggesting
14136-524: 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
14288-410: 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
14440-469: The exchange of genetic information. The exchange of information between the homologous chromatids results in a recombination of information; each chromosome has the complete set of information it had before, and there are no gaps formed as a result of the process. Because the chromosomes cannot be distinguished in the synaptonemal complex, the actual act of crossing over is not perceivable through an ordinary light microscope, and chiasmata are not visible until
14592-514: 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
14744-618: The first time in sea urchin eggs in 1876 by the German biologist Oscar Hertwig . It was described again in 1883, at the level of chromosomes , by the Belgian zoologist Edouard Van Beneden , in Ascaris roundworm eggs. The significance of meiosis for reproduction and inheritance, however, was described only in 1890 by German biologist August Weismann , who noted that two cell divisions were necessary to transform one diploid cell into four haploid cells if
14896-595: The form that is active for homologous pairing and strand invasion. BRCA2 also redirects RAD51 from double-stranded DNA and prevents dissociation from ssDNA. In addition, the four paralogs of RAD51 , consisting of RAD51B ( RAD51L1 ), RAD51C (RAD51L2), RAD51D ( RAD51L3 ), XRCC2 form a complex called the BCDX2 complex (see Figure: Recombinational repair of DNA). This complex participates in RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating
15048-413: 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
15200-630: 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
15352-504: The gene. Several other types of cancer have also been seen in certain families with BRCA2 mutations. In general, strongly inherited gene mutations (including mutations in BRCA2 ) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors. The BRCA2 gene was discovered in 1994. In 1996, Kenneth Offit and his research group at Memorial Sloan Kettering Cancer Center successfully identified
15504-421: 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
15656-421: 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
15808-610: The genomic instability frequently seen in cancers, which induces BRCA2 mRNA expression due to an increased need for BRCA2 for DNA repair. Under-expression of BRCA2 would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis ) would lead to increased mutations and cancer. BRCA2 has been shown to interact with BRCA2 contains a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment. The BRCA2 helical domain adopts
15960-443: The genus Leishmania , which cause human disease. However, these organisms were shown to have a sexual cycle consistent with a meiotic process. Although amoeba were once generally regarded as asexual, evidence has been presented that most lineages are anciently sexual and that the majority of asexual groups probably arose recently and independently. Dacks and Rogers proposed, based on a phylogenetic analysis, that facultative sex
16112-518: The homologous chromosomes become much more closely (~100 nm) and stably paired (a process called synapsis) mediated by the installation of the transverse and central elements of the synaptonemal complex . Synapsis is thought to occur in a zipper-like fashion starting from a recombination nodule. The paired chromosomes are called bivalent or tetrad chromosomes. The pachytene stage ( / ˈ p æ k ɪ t iː n / PAK -i-teen ), also known as pachynema , from Greek words meaning "thick threads".
16264-414: The homologous chromosomes, forming inter-axis bridges, and resulting in the pairing/co-alignment of homologues (to a distance of ~400 nm in mice). Leptotene is followed by the zygotene stage, also known as zygonema , from Greek words meaning "paired threads", which in some organisms is also called the bouquet stage because of the way the telomeres cluster at one end of the nucleus. In this stage
16416-460: The homologs are segregated to separate daughter cells by the spindle apparatus . The cells then proceed to a second division without an intervening round of DNA replication. The sister chromatids are segregated to separate daughter cells to produce a total of four haploid cells. Female animals employ a slight variation on this pattern and produce one large ovum and three small polar bodies. Because of recombination, an individual chromatid can consist of
16568-402: The idiosyncratic rendering "maiosis": We propose to apply the terms Maiosis or Maiotic phase to cover the whole series of nuclear changes included in the two divisions that were designated as Heterotype and Homotype by Flemming . The spelling was changed to "meiosis" by Koernicke (1905) and by Pantel and De Sinety (1906) to follow the usual conventions for transliterating Greek . Meiosis
16720-449: The inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit. The patents begin to expire in 2014. Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe. Legal decisions surrounding
16872-477: The intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring , 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
17024-417: The life cycle can occur either during the diploid state ( diplontic life cycle), during the haploid state ( haplontic life cycle), or both ( haplodiplontic life cycle), in which there are two distinct organism phases, one with haploid cells and the other with diploid cells. In the diplontic life cycle (with pre-gametic meiosis), as in humans, the organism is multicellular and diploid, grown by mitosis from
17176-458: The living organism alternates between haploid and diploid states. Consequently, this cycle is also known as the alternation of generations . The diploid organism's germ-line cells undergo meiosis to produce spores. The spores proliferate by mitosis, growing into a haploid organism. The haploid organism's gamete then combines with another haploid organism's gamete, creating the zygote. The zygote undergoes repeated mitosis and differentiation to produce
17328-556: The meiotic products form gametes such as sperm , spores or pollen . In female animals, three of the four meiotic products are typically eliminated by extrusion into polar bodies , and only one cell develops to produce an ovum . Because the number of chromosomes is halved during meiosis, gametes can fuse (i.e. fertilization ) to form a diploid zygote that contains two copies of each chromosome, one from each parent. Thus, alternating cycles of meiosis and fertilization enable sexual reproduction , with successive generations maintaining
17480-577: The metaphase plate during metaphase I and orientation of sister chromatids in metaphase II, this is the subsequent separation of homologs and sister chromatids during anaphase I and II, it allows a random and independent distribution of chromosomes to each daughter cell (and ultimately to gametes); and (2) Crossing Over . The physical exchange of homologous chromosomal regions by homologous recombination during prophase I results in new combinations of genetic information within chromosomes. However, such physical exchange does not always occur during meiosis. In
17632-704: The metaphase plate, with respect to the orientation of the other bivalents along the same equatorial line. The protein complex cohesin holds sister chromatids together from the time of their replication until anaphase. In mitosis, the force of kinetochore microtubules pulling in opposite directions creates tension. The cell senses this tension and does not progress with anaphase until all the chromosomes are properly bi-oriented. In meiosis, establishing tension ordinarily requires at least one crossover per chromosome pair in addition to cohesin between sister chromatids (see Chromosome segregation ). Kinetochore microtubules shorten, pulling homologous chromosomes (which each consist of
17784-431: The mitotic cell cycle. Therefore, meiosis includes the stages of meiosis I (prophase I, metaphase I, anaphase I, telophase I) and meiosis II (prophase II, metaphase II, anaphase II, telophase II). During meiosis, specific genes are more highly transcribed . In addition to strong meiotic stage-specific expression of mRNA , there are also pervasive translational controls (e.g. selective usage of preformed mRNA), regulating
17936-622: The most common mutation on the gene associated with breast and ovarian cancer among individuals of Ashkenazi Jewish ancestry. The gene was first cloned by scientists at Myriad Genetics , Endo Recherche, Inc., HSC Research & Development Limited Partnership, and the University of Pennsylvania . Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics . Myriad's business model of exclusively offering
18088-417: The next stage. During the diplotene stage, also known as diplonema , from Greek words meaning "two threads", the synaptonemal complex disassembles and homologous chromosomes separate from one another a little. However, the homologous chromosomes of each bivalent remain tightly bound at chiasmata, the regions where crossing-over occurred. The chiasmata remain on the chromosomes until they are severed at
18240-452: The nucleus. The chromosomes each form a linear array of loops mediated by cohesin , and the lateral elements of the synaptonemal complex assemble forming an "axial element" from which the loops emanate. Recombination is initiated in this stage by the enzyme SPO11 which creates programmed double strand breaks (around 300 per meiosis in mice). This process generates single stranded DNA filaments coated by RAD51 and DMC1 which invade
18392-413: 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
18544-474: The number of chromosomes had to be maintained. In 1911, the American geneticist Thomas Hunt Morgan detected crossovers in meiosis in the fruit fly Drosophila melanogaster , which helped to establish that genetic traits are transmitted on chromosomes. The term "meiosis" is derived from the Greek word μείωσις , meaning 'lessening'. It was introduced to biology by J.B. Farmer and J.E.S. Moore in 1905, using
18696-575: The official name (originally breast cancer 2 ; currently BRCA2, DNA repair associated ) are maintained by the HUGO Gene Nomenclature Committee . One alternative symbol, FANCD1 , recognizes its association with the FANC protein complex. Orthologs , styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene (specifically, a caretaker gene ), found in all humans; its protein , also called by
18848-417: The oocytes of the silkworm Bombyx mori , meiosis is completely achiasmate (lacking crossovers). Although synaptonemal complexes are present during the pachytene stage of meiosis in B. mori , crossing-over homologous recombination is absent between the paired chromosomes . Female mammals and birds are born possessing all the oocytes needed for future ovulations, and these oocytes are arrested at
19000-417: The paired homologous chromosomes align along an equatorial plane that bisects the spindle, due to continuous counterbalancing forces exerted on the bivalents by the microtubules emanating from the two kinetochores of homologous chromosomes. This attachment is referred to as a bipolar attachment. The physical basis of the independent assortment of chromosomes is the random orientation of each bivalent along with
19152-431: 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
19304-399: The pinching of the cell membrane in animal cells or the formation of the cell wall in plant cells, occurs, completing the creation of two daughter cells. However, cytokinesis does not fully complete resulting in "cytoplasmic bridges" which enable the cytoplasm to be shared between daughter cells until the end of meiosis II. Sister chromatids remain attached during telophase I. Cells may enter
19456-730: The ploidy is reduced from diploid to haploid, meiosis I is referred to as a reductional division . Meiosis II is an equational division analogous to mitosis, in which the sister chromatids are segregated, creating four haploid daughter cells (1n, 1c). Prophase I is by far the longest phase of meiosis (lasting 13 out of 14 days in mice ). During prophase I, homologous maternal and paternal chromosomes pair, synapse , and exchange genetic information (by homologous recombination ), forming at least one crossover per chromosome. These crossovers become visible as chiasmata (plural; singular chiasma ). This process facilitates stable pairing between homologous chromosomes and hence enables accurate segregation of
19608-399: The possibility of a large "founder" effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits
19760-447: The prophase I stage of meiosis. In humans, as an example, oocytes are formed between three and four months of gestation within the fetus and are therefore present at birth. During this prophase I arrested stage ( dictyate ), which may last for decades, four copies of the genome are present in the oocytes. The arrest of ooctyes at the four genome copy stage was proposed to provide the informational redundancy needed to repair damage in
19912-401: The same mechanisms as mitosis , the type of cell division used by eukaryotes to divide one cell into two identical daughter cells. In some plants, fungi, and protists meiosis results in the formation of spores : haploid cells that can divide vegetatively without undergoing fertilization. Some eukaryotes, like bdelloid rotifers , do not have the ability to carry out meiosis and have acquired
20064-561: The same number of chromosomes, occurs in all organisms that utilize meiosis. Meiosis occurs in all sexually-reproducing single-celled and multicellular organisms (which are all eukaryotes ), including animals , plants and fungi . It is an essential process for oogenesis and spermatogenesis . Although the process of meiosis is related to the more general cell division process of mitosis , it differs in two important respects: usually occurs between identical sister chromatids and does not result in genetic changes Meiosis begins with
20216-465: The same number of chromosomes. For example, diploid human cells contain 23 pairs of chromosomes including 1 pair of sex chromosomes (46 total), half of maternal origin and half of paternal origin. Meiosis produces haploid gametes (ova or sperm) that contain one set of 23 chromosomes. When two gametes (an egg and a sperm) fuse, the resulting zygote is once again diploid, with the mother and father each contributing 23 chromosomes. This same pattern, but not
20368-405: The second meiotic division. In metaphase II , the centromeres contain two kinetochores that attach to spindle fibers from the centrosomes at opposite poles. The new equatorial metaphase plate is rotated by 90 degrees when compared to meiosis I, perpendicular to the previous plate. This is followed by anaphase II , in which the remaining centromeric cohesin, not protected by Shugoshin anymore,
20520-648: The single strand DNA and directly interacts with the recombinase RAD51 to stimulate and maintain strand invasion, a vital step of homologous recombination . The localization of RAD51 to the DNA double-strand break requires the formation of the BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2) can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. These breaks can be caused by natural and medical radiation or other environmental exposures, but also occur when chromosomes exchange genetic material during
20672-405: The single-strand invasion steps mediated by AtRAD51 and AtDMC1 occurring during meiotic homologous recombinational repair of DNA damages. Homologs of BRCA2 are also essential for meiosis in the fungus Ustilago maydis , the worm Caenorhabditis elegans , and the fruitfly Drosophila melanogaster . Mice that produce truncated versions of BRCA2 are viable but sterile. BRCA2 mutant rats have
20824-452: The sister chromatids from separating. This allows the sister chromatids to remain together while homologs are segregated. The first meiotic division effectively ends when the chromosomes arrive at the poles. Each daughter cell now has half the number of chromosomes but each chromosome consists of a pair of chromatids. The microtubules that make up the spindle network disappear, and a new nuclear membrane surrounds each haploid set. Cytokinesis,
20976-467: 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
21128-524: The study of their clinical expression. A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families. This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had
21280-461: 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
21432-454: The synopsis stage of meiosis to form a joint molecule, a central step in homologous recombination . Thus the BRC repeat sequences of BRCA2 appear to play a key role in recombinational repair of DNA damages during meiotic recombination. Overall, it appears that homologous recombination during meiosis functions to repair DNA damages, and that BRCA2 plays a key role in performing this function. BRCA2
21584-805: 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
21736-436: 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,
21888-412: 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)
22040-446: The transition to anaphase I to allow homologous chromosomes to move to opposite poles of the cell. In human fetal oogenesis , all developing oocytes develop to this stage and are arrested in prophase I before birth. This suspended state is referred to as the dictyotene stage or dictyate. It lasts until meiosis is resumed to prepare the oocyte for ovulation, which happens at puberty or even later. Chromosomes condense further during
22192-428: The two haploid cells (with n chromosomes, each consisting of two sister chromatids) produced in meiosis I. The four main steps of meiosis II are: prophase II, metaphase II, anaphase II, and telophase II. In prophase II , we see the disappearance of the nucleoli and the nuclear envelope again as well as the shortening and thickening of the chromatids. Centrosomes move to the polar regions and arrange spindle fibers for
22344-413: The ultimate meiotic stage-specific protein expression of genes during meiosis. Thus, both transcriptional and translational controls determine the broad restructuring of meiotic cells needed to carry out meiosis. Meiosis I segregates homologous chromosomes , which are joined as tetrads (2n, 4c), producing two haploid cells (n chromosomes, 23 in humans) which each contain chromatid pairs (1n, 2c). Because
22496-469: 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 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
22648-401: The yeast Schizosaccharomyces pombe with hydrogen peroxide increased the frequency of mating and the formation of meiotic spores by 4 to 18-fold. Volvox carteri , a haploid multicellular, facultatively sexual green algae, can be induced by heat shock to reproduce by meiotic sex. This induction can be inhibited by antioxidants indicating that the induction of meiotic sex by heat shock
22800-446: 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
22952-404: Was likely present in the common ancestor of eukaryotes. The new combinations of DNA created during meiosis are a significant source of genetic variation alongside mutation, resulting in new combinations of alleles , which may be beneficial. Meiosis generates gamete genetic diversity in two ways: (1) Law of Independent Assortment . The independent orientation of homologous chromosome pairs along
23104-430: 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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