A mutation is an alteration in the nucleotide sequence of the genome of an organism.



Mutations result from errors during DNA  replication: mitosis, or meiosis or other types of damage to DNA, such as kpyrimidine dimers caused by exposure to ultraviolet radiation which can 


cause an error during other forms of repair, or cause an error during replication.



Mutations may also be the result of 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- the phenotype.



Mutations are involved in  normal and abnormal biological processes: : evolution, cancer, and the development of the immune system.



Mutation is the ultimate resource  of all genetic variation.



Mutation types of change in sequences may have no effect, alter the product of a gene, or prevent the gene from functioning properly or completely. 



Mutations can also occur in nongenic regions. 



When a mutation changes a protein produced by a gene, the result is likely to be harmful.



Mutations are generally categorize as either arising in the germline or somatic mutations acquired during life.



Deleterious germline mutations usually the two conditions that manifest in children, affect multiple organs, and occur in pedigrees.



Somatic mutations  are considered to be the origin of cancer, the major disease of older adults, and they produce cancer cell phenotypes.



Somatic mutations or a cause of a wide variety of human diseases.



Genomic sequencing has revealed that healthy cells in all tissues bear heavy mutational burdens, and that mutations are not exceptional but normal.



The presence of cancer-gene mutations in healthy organs has blurred the genomics border between cancer and healthy tissues and between constitutional and acquired disease.



Cancer mutations have been traditionally described as sporadic genetic changes occurring later in life, on the background of uniformly healthy cells.



Evolution relates to genetic diversity and adaptation to the environment.



The mutation rate is higher in somatic cells than  in germline cells, and a positive selection of somatic mutations by the environment predominates.



Despite the suggestion that mutations have negative connotations, almost all genetic alterations, germline and somatic, or harmless.



Mutations are either  neutral, that is not altering the phenotype of a cell, or deleterious leading to cellular senescence or death.



Mutations can have series functional consequences, including altered organ development, multi system syndromes in adults, and aberrant immune function and disease.




An estimated 70% of amino acid polymorphisms that have damaging effects, and the remainder being either neutral or marginally beneficial.



Due to the damaging effects that mutations can have on genes, there are  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 sections of DNA, usually through genetic recombination.



DNA duplications are a major source of raw material for evolving new genes.



Most genes belong to larger gene families of shared ancestry, detectable by their sequence homology.



Unique  genes are produced  through the duplication and mutation of an ancestral gene, or by recombining parts of different genes to form new combinations with new functions.



Protein domains mixed together to produce genes encoding new proteins with novel properties.



Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. 



Sequences of DNA that can move about the genome make up a major fraction of the genetic material have been important in the evolution of genomes.



Mobile DNA sequences that move within a genome, they can mutate or delete existing genes and thereby produce genetic diversity.



Nonlethal mutations accumulate within the gene pool and increase the amount of genetic variation.



Some genetic changes within the gene pool can be reduced by natural selection, while other mutations may accumulate and result in adaptive changes.



Neutral mutations are those whose effects do not influence the fitness of an individual. 



The overwhelming majority of mutations have no significant effect on a personal fitness.



DNA repair mechanisms are able to repair  most changes before they become permanent mutations.



There are 4 classes of mutations:



spontaneous mutations



mutations due to error-prone replication



errors introduced during DNA repair, 



induced mutations caused by mutagens. 



Studies suggest 66% of cancer-causing mutations are random, 29% are due to the environment and 5% are inherited.



Humans on average pass 60 new mutations to their children but fathers pass more mutations depending on their age with every year adding two new mutations to a child.



Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans.



Spontaneous mutations are characterized by the specific change:



Tautomerism, when base is changed by the repositioning of a hydrogen atom, altering the hydrogen bonding pattern of that base, resulting in incorrect base pairing during replication.



Depurination, the loss of a purine base (A or G) to form an apurinic site.



Deamination when hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. 



Slipped strand mispairing – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot leading to insertions or deletions.



The majority of spontaneously arising mutations are due to error-prone replication past DNA damage in the template strand. 



Naturally occurring double-strand breaks occur at a relatively low frequency in DNA, and their repair often causes mutation. 



The non-homologous end joining is a major pathway for repairing double-strand breaks.



The non-homologous end joining involves removal of a few nucleotides to allow inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps: often introducing  mutations.



Induced mutations can occur as alterations in the gene can occur after it is in contact with mutagens and environmental phenomena.



Such induced mutations on the molecular level can be caused by:









Base analogs 



Alkylating agents



The above agents can mutate both replicating and non-replicating DNA. 



Base analogs can mutate the DNA only when the analog is incorporated in replicating the DNA. 



Somatic mutations can arise due to endogenous in exogenous mutational processes. 



Exogenous mutagens include chemicals such as tobacco, aflatoxin B1, and chemotherapy agents, ionized radiation and ultraviolet light. 



All of the above damage DNA, generating mutations when damage bases are incorrectly repaired or copied.



Mutations can also arise from cell intrinsic processes, such as errors that occurred during DNA replication, reactive oxygen species, impaired DNA repair, and activity of viruses. 



There is a linear accumulation of mutations with increasing age.



Chemical mutagens lead to transitions, transversions, or deletions.



Two nucleotide bases in DNA—cytosine and thymine—are most vulnerable to radiation that can change their properties. 



UV light can induce adjacent pyrimidine bases in a DNA strand to become covalently joined as a pyrimidine dimer. 



UV radiation, in particular longer-wave UVA, can also cause oxidative damage to DNA.



Ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer.



There are five types of chromosomal mutations.



Mutations in the structure of genes can be classified into several types.



Large-scale mutations: 


Amplifications, or gene duplications, or repetition of a chromosomal segment or presence of extra piece of a chromosome, a broken piece of a chromosome may become attached to a homologous or non-homologous chromosome so that some of the genes are present in more than two doses leading to multiple copies of all chromosomal regions, deletions of large chromosomal regions, leading to loss of the genes within those regions, 


mutations whose effect is to juxtapose previously separate pieces of DNA, potentially bringing together separate genes to form functionally distinct fusion genes.



Chromosomal rearrangements  can lead to a decrease of fitness, and 


chromosomal translocations.



Chromosomal inversions.



Non-homologous chromosomal crossover.



Interstitial deletions



Loss of heterozygosity



Small-scale mutations affect a gene in one or a few nucleotides: if asingle nucleotide is affected, they are called point mutations.



Small-scale mutations include: Insertions adding one or more extra nucleotides into the DNA; Deletions remove one or more nucleotides from the DNA. 



Substitution mutations, often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.



Such nucleotide changes are classified as transitions or transversions.



Most common transitions exchange a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T).u



The effect of a mutation on protein sequence depends on whether it is in a coding or non-coding region of the genome.



Mutations in the non-coding regulatory sequences of a gene (promoters, enhancers, and silencers) can alter levels of gene expression, but are less likely to alter the protein sequence. 



Mutations within introns and in regions with no known biological function have no effect on phenotype.



Mutations occurring in coding regions of the genome are more likely to alter the protein product.



A frameshift mutation is caused by insertion or deletion of a number of nucleotides that is not evenly divisible by three from a DNA sequence. 



The insertion or deletion of a triplet codon can disrupt the reading frame, or the grouping of the codons, resulting in a completely different translation from the original.



The earlier in the sequence the deletion or insertion occurs, the more altered the protein produced  becomes.



A point substitution mutation results in a change in a single nucleotide.



A point substitution mutation can be either synonymous or nonsynonymous.



A synonymous substitution replaces a codon with another codon that codes for the same amino acid.



With a  synonymous point substitution that the produced amino acid sequence is not modified. 



In a nonsynonymous substitution a codon is replaced with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. 



Nonsynonymous substitutions are classified as nonsense or missense mutations.



A missense mutation changes a nucleotide to cause substitution of a different amino acid,which can render the resulting protein nonfunctional: 


Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.



If a missense mutation occurs in an amino acid codon that results in the use of a different, but chemically similar, amino acid, then sometimes little or no change is rendered in the protein. 



A nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product. 



Stop codon mutations are linked to different diseases, such as congenital adrenal hyperplasia.



Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function.



Gain-of-function mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. 



When a new allele is created, a heterozygote containing the newly created allele as well as the original will express the new allele; genetically this defines the mutations as dominant phenotypes. 



Dominant negative mutations have an altered gene product that acts antagonistically to the wild-type allele,


resulting in altered molecular functioning .



Dominant negative mutations are characterized by a dominant or semi-dominant phenotype. 



Dominant negative mutations in genes p53, ATM, CEBPA and PPARgamma are associated with malignancies.



The  dominant negative mutation in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix causes the Marfan syndrome.



Marfan syndrome is an example of dominant negative mutation and haploinsufficiency.



Hypomorphs are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele. 



Lethal mutations are mutations that lead to the death of those carrying the mutation.



A harmful mutation decreases fitness.



A beneficial, or advantageous mutation increases fitness.



A neutral mutation has no beneficial or harmful effect.



Such neutral mutations provide the genetic drift as the basis for most variation at the molecular level.


A nearly neutral mutation is may be slightly deleterious or advantageous.


Most  nearly neutral mutations are slightly deleterious.


Relatively few mutations are advantageous, those that are play an important role in evolutionary changes.


Mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations, called acquired mutations, which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.


Humans contain two copies of each gene, a paternal and a maternal allele. 


Based on the occurrence of mutation on each chromosome, mutations are classified into three types:


A wild type or homozygous non-mutated organism is one in which neither allele is mutated.


A heterozygous mutation is a mutation of only one allele.


A homozygous mutation is an identical mutation of both the paternal and maternal alleles.


Compound heterozygous mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles.


A germline mutation in the reproductive cells of an individual gives rise to a constitutional mutation in the offspring, that is, a mutation that is present in every cell. 


Germline mutations can be passed down through subsequent generations of organisms.


A new germline mutation not inherited from either parent is called a de novo mutation.


A somatic change in the genetic structure is not inherited from a parent, and also not passed to offspring.


Somatic mutations are not inherited by offspring because they do not affect the germline. 


Somatic mutations are passed down to all the progeny of a mutated cell within the same organism during mitosis. 


Somatic mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer.


Human somatic cells have a mutation rate more than ten times higher than the germline mutation rate.



The disparity in mutation rate between the germline and somatic tissues likely reflects the greater importance of genome maintenance in the germline than in the soma.


Some mutations depend upon presence of certain conditions, as opposed to other mutations which appear autonomously.


Such permissive conditions may be temperature, certain chemicals, light or mutations in other parts of the genome.


Transcriptional switches can create conditional mutations: 


Steroid ligand mutations


Amino acid substitutions


Amino acid deletions


The mutation rate is about 50-90 de novo mutations per genome per generation, that is, each human accumulates about 50-90 novel mutations that were not present in his or her parents. 


The genomes of RNA viruses replication occurs quickly, and there are no mechanisms to check the genome for accuracy, and  error-prone process often results in mutations.


DNA mutations in a coding region of DNA can cause errors in protein sequence that may result in partially or completely non-functional proteins. 


Each cells function correctly, depends on thousands of proteins to function in the right places at the right times. 


When a mutation alters a protein a medical condition can result.


It is estimated 70 percent of amino acid polymorphisms having damaging effects, and the remainder being either neutral or weakly beneficial.


Some mutations alter a gene’s DNA base sequence but do not change the protein made by the gene. 


If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells: hereditary disease.


A mutation in a DNA repair gene within a germ cell, may predispose to an increased risk of cancer.


Albinism, is a result of a mutation that occurs in the OCA1 or OCA2 gene is associated with  many types of cancers, other disorders and have impaired vision.


DNA damage can cause an error when the DNA is replicated.


Such an error of replication can cause a gene mutation that, in turn, could cause a genetic disorder. 


DNA damages are repaired by the DNA repair system of the cell. 


The process of DNA repair is an important way in which the body protects itself from disease. 


Once DNA damage has given rise to a mutation, the mutation cannot be repaired.


Mutations may occur in a somatic cell and such mutations will be present in all descendants of this cell.


Accumulating certain mutations over generations of somatic cells is part of cause of malignant transformation, from normal cell to cancer cell.


Cells with heterozygous loss-of-function mutations present, that is with one good copy of gene and one mutated copy, may function normally with the unmutated copy until the good copy has been spontaneously somatically mutated. 


This kind of mutation rate is important in predicting the rate at which people may develop cancer.


Point mutations may result  from spontaneous mutations that occur during DNA replication. 


The rate of mutation development may be increased by mutagens. 


Mutagens can be due to radiation from UV rays, X-rays or extreme heat, or chemical changes which that misplace base pairs or disrupt the helical shape of DNA.


On occasion mutations  effects may be positive in a given environment: 


A specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes.


Malaria resistance: sickle-cell disease, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait).


A mutation allowed humans to express the enzyme lactase after they are naturally weaned from breast milk, allowing adults to digest lactose, which is likely one of the most beneficial mutations in recent human evolution.




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