In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements. Mutations result from errors during DNA replication or other types of damage to DNA, which may undergo error-prone repair, or cause an error during other forms of repair, or else may cause an error during replication. Mutations may result from insertion or deletion of segments of DNA due to mobile genetic elements. Mutations may or may not produce discernible changes in the observable characteristics of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution and the development of the immune system, including junctional diversity; the genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double single stranded. In some of these viruses replication occurs and there are no mechanisms to check the genome for accuracy; this error-prone process results in mutations.
Mutation can result in many different types of change in sequences. Mutations in genes can either have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. Mutations can occur in nongenic regions. One study on genetic variations between different species of Drosophila suggests that, if a mutation changes a protein produced by a gene, the result is to be harmful, with an estimated 70 percent of amino acid polymorphisms that have damaging effects, the remainder being either neutral or marginally beneficial. Due to the damaging effects that mutations can have on genes, organisms have mechanisms such as DNA repair to prevent or correct mutations by reverting the mutated sequence back to its original state. Mutations can involve the duplication of large sections of DNA through genetic recombination; these duplications are a major source of raw material for evolving new genes, with tens to hundreds of genes duplicated in animal genomes every million years.
Most genes belong to larger gene families of shared ancestry. Novel genes are produced by several methods through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions. Here, protein domains act as modules, each with a particular and independent function, that can be mixed together to produce genes encoding new proteins with novel properties. For example, the human eye uses four genes to make structures that sense light: three for cone cell or color vision and one for rod cell or night vision. Another advantage of duplicating a gene is. Other types of mutation create new genes from noncoding DNA. Changes in chromosome number may involve larger mutations, where segments of the DNA within chromosomes break and rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2. In evolution, the most important role of such chromosomal rearrangements may be to accelerate the divergence of a population into new species by making populations less to interbreed, thereby preserving genetic differences between these populations.
Sequences of DNA that can move about the genome, such as transposons, make up a major fraction of the genetic material of plants and animals, may have been important in the evolution of genomes. For example, more than a million copies of the Alu sequence are present in the human genome, these sequences have now been recruited to perform functions such as regulating gene expression. Another effect of these mobile DNA sequences is that when they move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity. Nonlethal mutations increase the amount of genetic variation; the abundance of some genetic changes within the gene pool can be reduced by natural selection, while other "more favorable" mutations may accumulate and result in adaptive changes. For example, a butterfly may produce offspring with new mutations; the majority of these mutations will have no effect. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, over time the number of butterflies with this mutation may form a larger percentage of the population.
Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can increase in frequency over time due to genetic drift, it is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. DNA repair mechanisms are able to mend most changes before they become permanent mutations, many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells. Beneficial mutations can improve reproductive success. Mutationism is one of several alternatives to evolution by natural selection that have existed both before and after the publication of Charles Darwin's 1859 book, On the Origin of Species. In the theory, mutation was the source of novelty
Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists of collagen and proteoglycans. Although the word chondroblast is used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts. From least- to terminally-differentiated, the chondrocytic lineage is: Colony-forming unit-fibroblast Mesenchymal stem cell / marrow stromal cell Chondrocyte Hypertrophic chondrocyteMesenchymal stem cells are undifferentiated, meaning they can differentiate into a variety of generative cells known as osteochondrogenic cells; when referring to bone, or in this case cartilage, the undifferentiated mesenchymal stem cells lose their pluripotency and crowd together in a dense aggregate of chondrogenic cells at the location of chondrification. These chondrogenic cells differentiate into so-called chondroblasts, which synthesize the cartilage extracellular matrix, consisting of a ground substance and fibers.
The chondroblast is now a mature chondrocyte, inactive but can still secrete and degrade the matrix, depending on conditions. BMP4 and FGF2 have been experimentally shown to increase chondrocyte differentiation. Chondrocytes undergo terminal differentiation when they become hypertrophic, which happens during endochondral ossification; this last stage is characterized by major phenotypic changes in the cell. The chondrocyte in cartilage matrix has polygonal structure; the exception occurs at tissue boundaries, for example the articular surfaces of joints, in which chondrocytes may be flattened or discoid. Intra-cellular features are characteristic of a synthetically active cell; the cell density of full-thickness, adult, femoral condyle cartilage is maintained at 14.5 × 103 cells/ mm2 from age 20 to 30 years. Although chondrocyte senescence occurs with aging, mitotic figures are not seen in normal adult articular cartilage; the structure and synthetic activity of an adult chondrocyte are various according to its position.
Flattened cells are oriented parallel to the surface, along with the collagen fibers, in the superficial zone, the region of highest cell density. In the middle zone, chondrocytes are larger and more rounded and display a random distribution, in which the collagen fibers are more randomly arranged. In the deeper zones, chondrocytes form columns that are oriented perpendicular to the cartilage surface, along with the collagen fibers. Different behaviors may be exhibited by chondrocytes depending on their position within the different layers. In primary chondrocyte cultures, these zonal differences in synthetic properties may persist; the primary cilia are significant for spatial orientation of cells in developing growth plate and are sensory organelles in chondrocytes. Primary cilia work as centers for wingless type and hedgehog signaling and contain mechanosensitive receptors. Endochondral ossification Intramembranous ossification List of human cell types derived from the germ layers Dominici M, Hofmann T, Horwitz E. "Bone marrow mesenchymal cells: biological properties and clinical applications".
J Biol Regul Homeost Agents. 15: 28–37. PMID 11388742. Bianco P, Riminucci M, Gronthos S, Robey P. "Bone marrow stromal stem cells: nature and potential applications". Stem Cells. 19: 180–92. Doi:10.1634/stemcells.19-3-180. PMID 11359943. Histology image: 03317loa – Histology Learning System at Boston University Stem cell information
A karyotype is the number and appearance of chromosomes in the nucleus of a eukaryotic cell. The term is used for the complete set of chromosomes in a species or in an individual organism and for a test that detects this complement or measures the number. Karyotypes describe the chromosome count of an organism and what these chromosomes look like under a light microscope. Attention is paid to their length, the position of the centromeres, banding pattern, any differences between the sex chromosomes, any other physical characteristics; the preparation and study of karyotypes is part of cytogenetics. The study of whole sets of chromosomes is sometimes known as karyology; the chromosomes are depicted in a standard format known as a karyogram or idiogram: in pairs, ordered by size and position of centromere for chromosomes of the same size. The basic number of chromosomes in the somatic cells of an individual or a species is called the somatic number and is designated 2n. In the germ-line the chromosome number is n.p28 Thus, in humans 2n = 46.
So, in normal diploid organisms, autosomal chromosomes are present in two copies. There may, or may not, be sex chromosomes. Polyploid cells haploid cells have single copies; the study of karyotypes is important for cell biology and genetics, the results may be used in evolutionary biology and medicine. Karyotypes can be used for many purposes. Chromosomes were first observed in plant cells by Carl Wilhelm von Nägeli in 1842, their behavior in animal cells was described by Walther Flemming, the discoverer of mitosis, in 1882. The name was coined by another German anatomist, Heinrich von Waldeyer in 1888, it is New Latin from Ancient Greek κάρυον karyon, "kernel", "seed", or "nucleus", τύπος typos, "general form"). The next stage took place after the development of genetics in the early 20th century, when it was appreciated that chromosomes were the carrier of genes. Lev Delaunay in 1922 seems to have been the first person to define the karyotype as the phenotypic appearance of the somatic chromosomes, in contrast to their genic contents.
The subsequent history of the concept can be followed in the works of C. D. Darlington and Michael JD White. Investigation into the human karyotype took many years to settle the most basic question: how many chromosomes does a normal diploid human cell contain? In 1912, Hans von Winiwarter reported 47 chromosomes in spermatogonia and 48 in oogonia, concluding an XX/XO sex determination mechanism. Painter in 1922 was not certain whether the diploid of humans was 46 or 48, at first favoring 46, but revised his opinion from 46 to 48, he insisted on humans having an XX/XY system. Considering the techniques of the time, these results were remarkable. In textbooks, the number of human chromosomes remained at 48 for over thirty years. New techniques were needed to correct this error. Joe Hin Tjio working in Albert Levan's lab was responsible for finding the approach: Using cells in tissue culture Pretreating cells in a hypotonic solution, which swells them and spreads the chromosomes Arresting mitosis in metaphase by a solution of colchicine Squashing the preparation on the slide forcing the chromosomes into a single plane Cutting up a photomicrograph and arranging the result into an indisputable karyogram.
The work took place in 1955, was published in 1956. The karyotype of humans includes only 46 chromosomes; the great apes have 48 chromosomes. Human chromosome 2 is now known to be a result of an end-to-end fusion of two ancestral ape chromosomes; the study of karyotypes is made possible by staining. A suitable dye, such as Giemsa, is applied after cells have been arrested during cell division by a solution of colchicine in metaphase or prometaphase when most condensed. In order for the Giemsa stain to adhere all chromosomal proteins must be digested and removed. For humans, white blood cells are used most because they are induced to divide and grow in tissue culture. Sometimes observations may be made on non-dividing cells; the sex of an unborn fetus can be determined by observation of interphase cells. Six different characteristics of karyotypes are observed and compared: Differences in absolute sizes of chromosomes. Chromosomes can vary in absolute size by as much as twenty-fold between genera of the same family.
For example, the legumes Lotus tenuis and Vicia faba each have six pairs of chromosomes, yet V. faba chromosomes are many times larger. These differences reflect different amounts of DNA duplication. Differences in the position of centromeres; these differences came about through translocations. Differences in relative size of chromosomes; these differences arose from segmental interchange of unequal lengths. Differences in basic number of chromosomes; these differences could have resulted from successive unequal translocations which removed all the essential genetic material from a chromosome, permitting its loss without penalty to the organism or through fusion. Humans have one pair fewer chromosomes than the great apes. Human chromosome 2 appears to have resulted from the fusion of two ancestral chromosomes, many of the genes of those two original chromosomes have been translocated to other chromosomes. Differences in number and position of satellites. Satellites are small bodies attached to a chromosome by a thin thread.
Differences in degree and distribution of heterochromatic regions. Het
Dominance in genetics is a relationship between alleles of one gene, in which the effect on phenotype of one allele masks the contribution of a second allele at the same locus. The first allele is dominant and the second allele is recessive. For genes on an autosome, the alleles and their associated traits are autosomal dominant or autosomal recessive. Dominance is a key concept in Mendelian inheritance and classical genetics; the dominant allele codes for a functional protein whereas the recessive allele does not. A classic example of dominance is the inheritance of seed shape in peas. Peas associated with allele r. In this case, three combinations of alleles are possible: RR, Rr, rr; the RR individuals have round peas and the rr individuals have wrinkled peas. In Rr individuals the R allele masks the presence of the r allele, so these individuals have round peas. Thus, allele R is dominant to allele r, allele r is recessive to allele R; this use of upper case letters for dominant alleles and lower case ones for recessive alleles is a followed convention.
More where a gene exists in two allelic versions, three combinations of alleles are possible: AA, Aa, aa. If AA and aa individuals show different forms of some trait, Aa individuals show the same phenotype as AA individuals allele A is said to dominate, be dominant to or show dominance to allele a, a is said to be recessive to A. Dominance is not inherent to either its phenotype, it is a relationship between two alleles of their associated phenotypes. An allele may be dominant for a particular aspect of phenotype but not for other aspects influenced by the same gene. Dominance differs from epistasis, a relationship in which an allele of one gene affects the expression of another allele at a different gene; the concept of dominance was introduced by Gregor Johann Mendel. Though Mendel, "The Father of Genetics", first used the term in the 1860s, it was not known until the early twentieth century. Mendel observed that, for a variety of traits of garden peas having to do with the appearance of seeds, seed pods, plants, there were two discrete phenotypes, such as round versus wrinkled seeds, yellow versus green seeds, red versus white flowers or tall versus short plants.
When bred separately, the plants always produced generation after generation. However, when lines with different phenotypes were crossed and only one of the parental phenotypes showed up in the offspring. However, when these hybrid plants were crossed, the offspring plants showed the two original phenotypes, in a characteristic 3:1 ratio, the more common phenotype being that of the parental hybrid plants. Mendel reasoned that each parent in the first cross was a homozygote for different alleles, that each contributed one allele to the offspring, with the result that all of these hybrids were heterozygotes, that one of the two alleles in the hybrid cross dominated expression of the other: A masked a; the final cross between two heterozygotes would produce AA, Aa, aa offspring in a 1:2:1 genotype ratio with the first two classes showing the phenotype, the last showing the phenotype, thereby producing the 3:1 phenotype ratio. Mendel did not use the terms gene, phenotype, genotype and heterozygote, all of which were introduced later.
He did introduce the notation of capital and lowercase letters for dominant and recessive alleles still in use today. Most animals and some plants have paired chromosomes, are described as diploid, they have two versions of each chromosome, one contributed by the mother's ovum, the other by the father's sperm, known as gametes, described as haploid, created through meiosis. These gametes fuse during fertilization during sexual reproduction, into a new single cell zygote, which divides multiple times, resulting in a new organism with the same number of pairs of chromosomes in each cell as its parents; each chromosome of a matching pair is structurally similar to the other, has a similar DNA sequence. The DNA in each chromosome functions as a series of discrete genes that influence various traits. Thus, each gene has a corresponding homologue, which may exist in different versions called alleles; the alleles at the same locus on the two homologous chromosomes may be different. The blood type of a human is determined by a gene that creates an A, B, AB or O blood type and is located in the long arm of chromosome nine.
There are three different alleles that could be present at this locus, but only two can be present in any individual, one inherited from their mother and one from their father. If two alleles of a given gene are identical, the organism is called a homozygote and is said to be homozygous with respect to that gene; the genetic makeup of an organism, either at a single locus or over all its genes collectively, is called its genotype. The genotype of an organism directly and indirectly affects its molecular and other traits, which individually or collectively are called its phenotype. At heterozygous gene loci, the two alleles interact to produce the phenotype. In complete dominance, the effect of one allele in a heterozygous genotype masks the effect of the other; the allele that mas
Tumor protein p53 known as p53, cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53, is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 and Trp53. This homolog is crucial in multicellular organisms, where it prevents cancer formation, functions as a tumor suppressor; as such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene; the name p53 was given in 1979 describing the apparent molecular mass. However, the actual mass of the full-length p53 protein based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it is. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa.
All these p53 proteins are called the p53 isoforms. The TP53 gene is the most mutated gene in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. In humans, the TP53 gene is located on the short arm of chromosome 17; the gene spans 20 kb, with a non-coding exon 1 and a long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals. In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this cancer susceptibility. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.
A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer. Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer. Another 2011 study found that the p53 homozygous genotype was associated with a increased risk for renal cell carcinoma. An acidic N-terminus transcription-activation domain known as activation domain 1, which activates transcription factors.
The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75 involved in the regulation of several pro-apoptotic genes. Activation domain 2 important for apoptotic activity: residues 43-63. Proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92. Central DNA-binding core domain. Contains one zinc atom and several arginine amino acids: residues 102-292; this region is responsible for binding the p53 co-repressor LMO3. Nuclear Localization Signaling domain, residues 316-325. Homo-oligomerisation domain: residues 307-355. Tetramerization is essential for the activity of p53 in vivo. C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393. A tandem of nine-amino-acid transactivation domains was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below: The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported.
9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300, GCN5 and PC4, regulatory protein MDM2 and replication protein A. Mutations that deactivate p53 in cancer occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, thus prevents transcriptional activation of these genes; as such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53. Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner. P53 plays a role in regulation or progression through the cell cycle and genomic stability by means of several mechanisms: It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging, it can arrest growth by holding the cell c
Chromosome 13 is one of the 23 pairs of chromosomes in humans. People have two copies of this chromosome. Chromosome 13 spans about 114 million base pairs and represents between 3.5 and 4% of the total DNA in cells. The following are some of the gene count estimates of human chromosome 13; because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 13. For complete list, see the link in the infobox on the right; the following diseases and disorders are some of those related to genes on chromosome 13: The following conditions are caused by changes in the structure or number of copies of chromosome 13: Retinoblastoma: A small percentage of retinoblastoma cases are caused by deletions in the region of chromosome 13 containing the RB1 gene.
Children with these chromosomal deletions may have mental retardation, slow growth, characteristic facial features. Researchers have not determined which other genes are located in the deleted region, but a loss of several genes is responsible for these developmental problems. Trisomy 13: Trisomy 13 occurs when each cell in the body has three copies of chromosome 13 instead of the usual two copies. Trisomy 13 can result from an extra copy of chromosome 13 in only some of the body's cells. In a small percentage of cases, trisomy 13 is caused by a rearrangement of chromosomal material between chromosome 13 and another chromosome; as a result, a person has the two usual copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. These cases are called translocation trisomy 13. Extra material from chromosome 13 disrupts the course of normal development, causing the characteristic signs and symptoms of trisomy 13. Researchers are not yet certain how this extra genetic material leads to the features of the disorder, which include abnormal cerebral functions, a small cranium, non functional eyes and heart defects.
Other chromosomal conditions: Partial monosomy 13q is a rare chromosomal disorder that results when a piece of the long arm of chromosome 13 is missing. Infants born with partial monosomy 13q may exhibit low birth weight, malformations of the head and face, skeletal abnormalities, other physical abnormalities. Mental retardation is characteristic of this condition; the mortality rate during infancy is high among individuals born with this disorder. All cases of partial monosomy 13q occur randomly for no apparent reason. National Institutes of Health. "Chromosome 13". Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 13". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06