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The techniques of genetic analysis discussed in the previous chapters depend on the availability of two or more alleles for a gene of interest. Where do these alleles come from? The short answer is mutation. Humans have an interesting relationship with mutation. From our perspective, mutations can be extraordinarily useful, since mutations are need for evolution to occur.Mutation is also essential for the domestication and improvement of almost all of our food. On the other hand, mutations are the cause of many cancers and other diseases, and can be devastating to individuals. Yet, the vast majority of mutations probably go undetected.In this section, we will examine some of the causes and effects of mutations.
4: Mutation and Variation - Biology
Genetic variation is a measure of the variation that exists in the genetic makeup of individuals within population.
Assess the ways in which genetic variance affects the evolution of populations
- Genetic variation is an important force in evolution as it allows natural selection to increase or decrease frequency of alleles already in the population.
- Genetic variation can be caused by mutation (which can create entirely new alleles in a population), random mating, random fertilization, and recombination between homologous chromosomes during meiosis (which reshuffles alleles within an organism’s offspring).
- Genetic variation is advantageous to a population because it enables some individuals to adapt to the environment while maintaining the survival of the population.
- genetic diversity: the level of biodiversity, refers to the total number of genetic characteristics in the genetic makeup of a species
- crossing over: the exchange of genetic material between homologous chromosomes that results in recombinant chromosomes
- phenotypic variation: variation (due to underlying heritable genetic variation) a fundamental prerequisite for evolution by natural selection
- genetic variation: variation in alleles of genes that occurs both within and among populations
Genetic variation is a measure of the genetic differences that exist within a population. The genetic variation of an entire species is often called genetic diversity. Genetic variations are the differences in DNA segments or genes between individuals and each variation of a gene is called an allele.For example, a population with many different alleles at a single chromosome locus has a high amount of genetic variation. Genetic variation is essential for natural selection because natural selection can only increase or decrease frequency of alleles that already exist in the population.
Genetic variation is caused by:
- random mating between organisms
- random fertilization
- crossing over (or recombination) between chromatids of homologous chromosomes during meiosis
The last three of these factors reshuffle alleles within a population, giving offspring combinations which differ from their parents and from others.
Genetic variation in the shells of Donax variabilis: An enormous amount of phenotypic variation exists in the shells of Donax varabilis, otherwise known as the coquina mollusc. This phenotypic variation is due at least partly to genetic variation within the coquina population.
Evolution and Adaptation to the Environment
Low genetic diversity in the wild cheetah population: Populations of wild cheetahs have very low genetic variation. Because wild cheetahs are threatened, their species has a very low genetic diversity. This low genetic diversity means they are often susceptible to disease and often pass on lethal recessive mutations only about 5% of cheetahs survive to adulthood.
Variation allows some individuals within a population to adapt to the changing environment. Because natural selection acts directly only on phenotypes, more genetic variation within a population usually enables more phenotypic variation. Some new alleles increase an organism’s ability to survive and reproduce, which then ensures the survival of the allele in the population. Other new alleles may be immediately detrimental (such as a malformed oxygen-carrying protein) and organisms carrying these new mutations will die out. Neutral alleles are neither selected for nor against and usually remain in the population. Genetic variation is advantageous because it enables some individuals and, therefore, a population, to survive despite a changing environment.
Some species display geographic variation as well as variation within a population. Geographic variation, or the distinctions in the genetic makeup of different populations, often occurs when populations are geographically separated by environmental barriers or when they are under selection pressures from a different environment. One example of geographic variation are clines: graded changes in a character down a geographic axis.
Sources of Genetic Variation
Gene duplication, mutation, or other processes can produce new genes and alleles and increase genetic variation. New genetic variation can be created within generations in a population, so a population with rapid reproduction rates will probably have high genetic variation. However, existing genes can be arranged in new ways from chromosomal crossing over and recombination in sexual reproduction. Overall, the main sources of genetic variation are the formation of new alleles, the altering of gene number or position, rapid reproduction, and sexual reproduction.
Molecular Cell Biology. 4th edition.
The development and function of an organism is in large part controlled by genes. Mutations can lead to changes in the structure of an encoded protein or to a decrease or complete loss in its expression. Because a change in the DNA sequence affects all copies of the encoded protein, mutations can be particularly damaging to a cell or organism. In contrast, any alterations in the sequences of RNA or protein molecules that occur during their synthesis are less serious because many copies of each RNA and protein are synthesized.
Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.
4: Mutation and Variation - Biology
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PERSPECTIVE: EVOLUTIONARY DEVELOPMENTAL BIOLOGY AND THE PROBLEM OF VARIATION
1 Laboratory for Development and Evolution, University Museum of Zoology, Department of Zoology, Downing Street, University of Cambridge, Cambridge CB2 3EJ, United Kingdom, [email protected]
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One of the oldest problems in evolutionary biology remains largely unsolved. Which mutations generate evolutionarily relevant phenotypic variation? What kinds of molecular changes do they entail? What are the phenotypic magnitudes, frequencies of origin, and pleiotropic effects of such mutations? How is the genome constructed to allow the observed abundance of phenotypic diversity? Historically, the neo-Darwinian synthesizers stressed the predominance of micromutations in evolution, whereas others noted the similarities between some dramatic mutations and evolutionary transitions to argue for macromutationism. Arguments on both sides have been biased by misconceptions of the developmental effects of mutations. For example, the traditional view that mutations of important developmental genes always have large pleiotropic effects can now be seen to be a conclusion drawn from observations of a small class of mutations with dramatic effects. It is possible that some mutations, for example, those in cis-regulatory DNA, have few or no pleiotropic effects and may be the predominant source of morphological evolution. In contrast, mutations causing dramatic phenotypic effects, although superficially similar to hypothesized evolutionary transitions, are unlikely to fairly represent the true path of evolution. Recent developmental studies of gene function provide a new way of conceptualizing and studying variation that contrasts with the traditional genetic view that was incorporated into neo-Darwinian theory and population genetics. This new approach in developmental biology is as important for microevolutionary studies as the actual results from recent evolutionary developmental studies. In particular, this approach will assist in the task of identifying the specific mutations generating phenotypic variation and elucidating how they alter gene function. These data will provide the current missing link between molecular and phenotypic variation in natural populations.
Corresponding Editor: H. A. Orr
David L. Stern "PERSPECTIVE: EVOLUTIONARY DEVELOPMENTAL BIOLOGY AND THE PROBLEM OF VARIATION," Evolution 54(4), 1079-1091, (1 August 2000). https://doi.org/10.1554/0014-3820(2000)054[1079:PEDBAT]2.0.CO2
Received: 24 August 1999 Accepted: 1 February 2000 Published: 1 August 2000
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Genetic Variation Causes
Alfred Pasieka / Science Photo Library / Getty Images
Genetic variation occurs mainly through DNA mutation, gene flow (movement of genes from one population to another), and sexual reproduction. Due to the fact that environments are unstable, populations that are genetically variable will be able to adapt to changing situations better than those that do not contain genetic variation.
- DNA Mutation: A mutation is a change in the DNA sequence. These variations in gene sequences can sometimes be advantageous to an organism. Most mutations that result in genetic variation produce traits that confer neither an advantage or disadvantage. Mutations lead to genetic variation by altering genes and alleles in a population. They may impact an individual gene or an entire chromosome. Although mutations change an organism's genotype (genetic makeup), they may not necessarily change an organism's phenotype.
- Gene Flow: Also called gene migration, gene flow introduces new genes into a population as organisms migrate into a new environment. New gene combinations are made possible by the availability of new alleles in the gene pool. Gene frequencies may also be altered by the emigration of organisms out of a population. The immigration of new organisms into a population may help organisms better adapt to changing environmental conditions. The migration of organisms out of a population could result in a lack of genetic diversity.
- Sexual Reproduction: Sexual reproduction promotes genetic variation by producing different gene combinations. Meiosis is the process by which sex cells or gametes are created. Genetic variation occurs as alleles in gametes are separated and randomly united upon fertilization. The genetic recombination of genes also occurs during crossing over or the swapping of gene segments in homologous chromosomes during meiosis.
Mutations can involve the duplication of large sections of DNA, usually 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, detectable by their sequence homology.  Novel genes are produced by several methods, commonly 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 all four arose from a single ancestral gene.  Another advantage of duplicating a gene (or even an entire genome) is that this increases engineering redundancy this allows one gene in the pair to acquire a new function while the other copy performs the original function.   Other types of mutation occasionally create new genes from previously noncoding DNA.  
Changes in chromosome number may involve even larger mutations, where segments of the DNA within chromosomes break and then rearrange. For example, in the Homininae, two chromosomes fused to produce human chromosome 2 this fusion did not occur in the lineage of the other apes, and they retain these separate chromosomes.  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 likely 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, and 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, and 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 accumulate within the gene pool and 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 but one might change the color of one of the butterfly's offspring, making it harder (or easier) for predators to see. If this color change is advantageous, the chances of this butterfly's surviving and producing its own offspring are a little better, and 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.   Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise-permanently mutated somatic cells.
Beneficial mutations can improve reproductive success.  
Four classes of mutations are (1) spontaneous mutations (molecular decay), (2) mutations due to error-prone replication bypass of naturally occurring DNA damage (also called error-prone translesion synthesis), (3) errors introduced during DNA repair, and (4) induced mutations caused by mutagens. Scientists may also deliberately introduce mutant sequences through DNA manipulation for the sake of scientific experimentation.
One 2017 study claimed that 66% of cancer-causing mutations are random, 29% are due to the environment (the studied population spanned 69 countries), 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. 
Spontaneous mutation Edit
Spontaneous mutations occur with non-zero probability even given a healthy, uncontaminated cell. Naturally occurring oxidative DNA damage is estimated to occur 10,000 times per cell per day in humans and 100,000 times per cell per day in rats.  Spontaneous mutations can be characterized by the specific change: 
- – A 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.  – Loss of a purine base (A or G) to form an apurinic site (AP site). – Hydrolysis changes a normal base to an atypical base containing a keto group in place of the original amine group. Examples include C → U and A → HX (hypoxanthine), which can be corrected by DNA repair mechanisms and 5MeC (5-methylcytosine) → T, which is less likely to be detected as a mutation because thymine is a normal DNA base. – Denaturation of the new strand from the template during replication, followed by renaturation in a different spot ("slipping"). This can lead to insertions or deletions.
Error-prone replication bypass Edit
There is increasing evidence that the majority of spontaneously arising mutations are due to error-prone replication (translesion synthesis) past DNA damage in the template strand. In mice, the majority of mutations are caused by translesion synthesis.  Likewise, in yeast, Kunz et al.  found that more than 60% of the spontaneous single base pair substitutions and deletions were caused by translesion synthesis.
Errors introduced during DNA repair Edit
Although naturally occurring double-strand breaks occur at a relatively low frequency in DNA, their repair often causes mutation. Non-homologous end joining (NHEJ) is a major pathway for repairing double-strand breaks. NHEJ involves removal of a few nucleotides to allow somewhat inaccurate alignment of the two ends for rejoining followed by addition of nucleotides to fill in gaps. As a consequence, NHEJ often introduces mutations. 
Induced mutation Edit
Induced mutations are alterations in the gene after it has come in contact with mutagens and environmental causes.
Induced mutations on the molecular level can be caused by:
- Chemicals (e.g., Bromodeoxyuridine (BrdU)) (e.g., N-ethyl-N-nitrosourea (ENU). These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can mutate the DNA only when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions.
- Agents that form DNA adducts (e.g., ochratoxin A) 
- DNA intercalating agents (e.g., ethidium bromide) converts amine groups on A and C to diazo groups, altering their hydrogen bonding patterns, which leads to incorrect base pairing during replication.
- light (UV) (including non-ionizing radiation). 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.  . Exposure to ionizing radiation, such as gamma radiation, can result in mutation, possibly resulting in cancer or death.
Whereas in former times mutations were assumed to occur by chance, or induced by mutagens, molecular mechanisms of mutation have been discovered in bacteria and across the tree of life. As S. Rosenberg states, "These mechanisms reveal a picture of highly regulated mutagenesis, up-regulated temporally by stress responses and activated when cells/organisms are maladapted to their environments—when stressed—potentially accelerating adaptation."  Since they are self-induced mutagenic mechanisms that increase the adaptation rate of organisms, they have some times been named as adaptive mutagenesis mechanisms, and include the SOS response in bacteria,  ectopic intrachromosomal recombination  and other chromosomal events such as duplications. 
By effect on structure Edit
The sequence of a gene can be altered in a number of ways.  Gene mutations have varying effects on health depending on where they occur and whether they alter the function of essential proteins. Mutations in the structure of genes can be classified into several types.
Large-scale mutations Edit
Large-scale mutations in chromosomal structure include:
- Amplifications (or gene duplications) or repetition of a chromosomal segment or presence of extra piece of a chromosome 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, increasing the dosage of the genes located within them.
- 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 (e.g., bcr-abl).
- Large scale changes to the structure of chromosomes called chromosomal rearrangement that can lead to a decrease of fitness but also to speciation in isolated, inbred populations. These include:
- : interchange of genetic parts from nonhomologous chromosomes. : reversing the orientation of a chromosomal segment.
- Non-homologous chromosomal crossover.
- Interstitial deletions: an intra-chromosomal deletion that removes a segment of DNA from a single chromosome, thereby apposing previously distant genes. For example, cells isolated from a human astrocytoma, a type of brain tumor, were found to have a chromosomal deletion removing sequences between the Fused in Glioblastoma (FIG) gene and the receptor tyrosine kinase (ROS), producing a fusion protein (FIG-ROS). The abnormal FIG-ROS fusion protein has constitutively active kinase activity that causes oncogenic transformation (a transformation from normal cells to cancer cells).
- 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. Due to the triplet nature of gene expression by codons, the insertion or deletion 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 is. (For example, the code CCU GAC UAC CUA codes for the amino acids proline, aspartic acid, tyrosine, and leucine. If the U in CCU was deleted, the resulting sequence would be CCG ACU ACC UAx, which would instead code for proline, threonine, threonine, and part of another amino acid or perhaps a stop codon (where the x stands for the following nucleotide).) By contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation.
- A point substitution mutation results in a change in a single nucleotide and can be either synonymous or nonsynonymous.
- A synonymous substitution replaces a codon with another codon that codes for the same amino acid, so that the produced amino acid sequence is not modified. Synonymous mutations occur due to the degenerate nature of the genetic code. If this mutation does not result in any phenotypic effects, then it is called silent, but not all synonymous substitutions are silent. (There can also be silent mutations in nucleotides outside of the coding regions, such as the introns, because the exact nucleotide sequence is not as crucial as it is in the coding regions, but these are not considered synonymous substitutions.)
- A nonsynonymous substitution replaces a codon with another codon that codes for a different amino acid, so that the produced amino acid sequence is modified. Nonsynonymous substitutions can be classified as nonsense or missense mutations:
- A missense mutation changes a nucleotide to cause substitution of a different amino acid. This in turn can render the resulting protein nonfunctional. Such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1-mediated ALS.  On the other hand, 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. For example, a change from AAA to AGA will encode arginine, a chemically similar molecule to the intended lysine. In this latter case the mutation will have little or no effect on phenotype and therefore be neutral.
- 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. This sort of mutation has been linked to different diseases, such as congenital adrenal hyperplasia. (See Stop codon.)
By effect on function Edit
- Loss-of-function mutations, also called inactivating mutations, result in the gene product having less or no function (being partially or wholly inactivated). When the allele has a complete loss of function (null allele), it is often called an amorph or amorphic mutation in the Muller's morphs schema. Phenotypes associated with such mutations are most often recessive. Exceptions are when the organism is haploid, or when the reduced dosage of a normal gene product is not enough for a normal phenotype (this is called haploinsufficiency). mutations, also called activating mutations, change the gene product such that its effect gets stronger (enhanced activation) or even is superseded by a different and abnormal function. When the 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. Several of Muller's morphs correspond to gain of function, including hypermorph (increased gene expression) and neomorph (novel function). In December 2017, the U.S. government lifted a temporary ban implemented in 2014 that banned federal funding for any new "gain-of-function" experiments that enhance pathogens "such as Avian influenza, SARS and the Middle East Respiratory Syndrome or MERS viruses." 
- Dominant negative mutations (also called antimorphic mutations) have an altered gene product that acts antagonistically to the wild-type allele. These mutations usually result in an altered molecular function (often inactive) and are characterized by a dominant or semi-dominant phenotype. In humans, dominant negative mutations have been implicated in cancer (e.g., mutations in genes p53, ATM, CEBPA and PPARgamma ). Marfan syndrome is caused by mutations in the FBN1 gene, located on chromosome 15, which encodes fibrillin-1, a glycoprotein component of the extracellular matrix.  Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.  , after Mullerian classification, are characterized by altered gene products that acts with decreased gene expression compared to the wild type allele. Usually, hypomorphic mutations are recessive, but haploinsufficiency causes some alleles to be dominant. are characterized by the control of new protein product synthesis. are mutations that lead to the death of the organisms that carry the mutations.
- A back mutation or reversion is a point mutation that restores the original sequence and hence the original phenotype. 
By effect on fitness (harmful, beneficial, neutral mutations) Edit
In genetics, it is sometimes useful to classify mutations as either harmful or beneficial (or neutral):
- A harmful, or deleterious, mutation decreases the fitness of the organism. Many, but not all mutations in essential genes are harmful (if a mutation does not change the amino acid sequence in an essential protein, it is harmless in most cases).
- A beneficial, or advantageous mutation increases the fitness of the organism. Examples are mutations that lead to antibiotic resistance in bacteria (which are beneficial for bacteria but usually not for humans).
- A neutral mutation has no harmful or beneficial effect on the organism. Such mutations occur at a steady rate, forming the basis for the molecular clock. In the neutral theory of molecular evolution, neutral mutations provide genetic drift as the basis for most variation at the molecular level. In animals or plants, most mutations are neutral, given that the vast majority of their genomes is either non-coding or consists of repetitive sequences that have no obvious function ("junk DNA"). 
Large-scale quantitative mutagenesis screens, in which thousands of millions of mutations are tested, invariably find that a larger fraction of mutations has harmful effects but always returns a number of beneficial mutations as well. For instance, in a screen of all gene deletions in E. coli, 80% of mutations were negative, but 20% were positive, even though many had a very small effect on growth (depending on condition).  Note that gene deletions involve removal of whole genes, so that point mutations almost always have a much smaller effect. In a similar screen in Streptococcus pneumoniae, but this time with transposon insertions, 76% of insertion mutants were classified as neutral, 16% had a significantly reduced fitness, but 6% were advantageous. 
This classification is obviously relative and somewhat artificial: a harmful mutation can quickly turn into a beneficial mutations when conditions change. For example, the mutations that led to lighter skin in caucasians, are beneficial in regions that are less exposed to sunshine but harmful in regions near the equator. Also, there is a gradient from harmful/beneficial to neutral, as many mutations may have small and mostly neglectable effects but under certain conditions will become relevant. Also, many traits are determined by hundreds of genes (or loci), so that each locus has only a minor effect. For instance, human height is determined by hundreds of genetic variants ("mutations") but each of them has a very minor effect on height,  apart from the impact of nutrition. Height (or size) itself may be more or less beneficial as the huge range of sizes in animal or plant groups shows.
Distribution of fitness effects (DFE) Edit
Attempts have been made to infer the distribution of fitness effects (DFE) using mutagenesis experiments and theoretical models applied to molecular sequence data. DFE, as used to determine the relative abundance of different types of mutations (i.e., strongly deleterious, nearly neutral or advantageous), is relevant to many evolutionary questions, such as the maintenance of genetic variation,  the rate of genomic decay,  the maintenance of outcrossing sexual reproduction as opposed to inbreeding  and the evolution of sex and genetic recombination.  DFE can also be tracked by tracking the skewness of the distribution of mutations with putatively severe effects as compared to the distribution of mutations with putatively mild or absent effect.  In summary, the DFE plays an important role in predicting evolutionary dynamics.   A variety of approaches have been used to study the DFE, including theoretical, experimental and analytical methods.
- Mutagenesis experiment: The direct method to investigate the DFE is to induce mutations and then measure the mutational fitness effects, which has already been done in viruses, bacteria, yeast, and Drosophila. For example, most studies of the DFE in viruses used site-directed mutagenesis to create point mutations and measure relative fitness of each mutant.  In Escherichia coli, one study used transposon mutagenesis to directly measure the fitness of a random insertion of a derivative of Tn10.  In yeast, a combined mutagenesis and deep sequencing approach has been developed to generate high-quality systematic mutant libraries and measure fitness in high throughput.  However, given that many mutations have effects too small to be detected  and that mutagenesis experiments can detect only mutations of moderately large effect DNA sequence data analysis can provide valuable information about these mutations.
- Molecular sequence analysis: With rapid development of DNA sequencing technology, an enormous amount of DNA sequence data is available and even more is forthcoming in the future. Various methods have been developed to infer the DFE from DNA sequence data.  By examining DNA sequence differences within and between species, we are able to infer various characteristics of the DFE for neutral, deleterious and advantageous mutations.  To be specific, the DNA sequence analysis approach allows us to estimate the effects of mutations with very small effects, which are hardly detectable through mutagenesis experiments.
One of the earliest theoretical studies of the distribution of fitness effects was done by Motoo Kimura, an influential theoretical population geneticist. His neutral theory of molecular evolution proposes that most novel mutations will be highly deleterious, with a small fraction being neutral.   Hiroshi Akashi more recently proposed a bimodal model for the DFE, with modes centered around highly deleterious and neutral mutations.  Both theories agree that the vast majority of novel mutations are neutral or deleterious and that advantageous mutations are rare, which has been supported by experimental results. One example is a study done on the DFE of random mutations in vesicular stomatitis virus.  Out of all mutations, 39.6% were lethal, 31.2% were non-lethal deleterious, and 27.1% were neutral. Another example comes from a high throughput mutagenesis experiment with yeast.  In this experiment it was shown that the overall DFE is bimodal, with a cluster of neutral mutations, and a broad distribution of deleterious mutations.
Though relatively few mutations are advantageous, those that are play an important role in evolutionary changes.  Like neutral mutations, weakly selected advantageous mutations can be lost due to random genetic drift, but strongly selected advantageous mutations are more likely to be fixed. Knowing the DFE of advantageous mutations may lead to increased ability to predict the evolutionary dynamics. Theoretical work on the DFE for advantageous mutations has been done by John H. Gillespie  and H. Allen Orr.  They proposed that the distribution for advantageous mutations should be exponential under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.   
In general, it is accepted that the majority of mutations are neutral or deleterious, with advantageous mutations being rare however, the proportion of types of mutations varies between species. This indicates two important points: first, the proportion of effectively neutral mutations is likely to vary between species, resulting from dependence on effective population size second, the average effect of deleterious mutations varies dramatically between species.  In addition, the DFE also differs between coding regions and noncoding regions, with the DFE of noncoding DNA containing more weakly selected mutations. 
By inheritance Edit
In multicellular organisms with dedicated reproductive cells, mutations can be subdivided into germline mutations, which can be passed on to descendants through their reproductive cells, and somatic mutations (also called acquired mutations),  which involve cells outside the dedicated reproductive group and which are not usually transmitted to descendants.
Diploid organisms (e.g., humans) contain two copies of each gene—a paternal and a maternal allele. Based on the occurrence of mutation on each chromosome, we may classify mutations 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. mutations or a genetic compound consists of two different mutations in the paternal and maternal alleles. 
Germline mutation Edit
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. A constitutional mutation can also occur very soon after fertilisation, or continue from a previous constitutional mutation in a parent.  A germline mutation can be passed down through subsequent generations of organisms.
The distinction between germline and somatic mutations is important in animals that have a dedicated germline to produce reproductive cells. However, it is of little value in understanding the effects of mutations in plants, which lack a dedicated germline. The distinction is also blurred in those animals that reproduce asexually through mechanisms such as budding, because the cells that give rise to the daughter organisms also give rise to that organism's germline.
A new germline mutation not inherited from either parent is called a de novo mutation.
Somatic mutation Edit
A change in the genetic structure that is not inherited from a parent, and also not passed to offspring, is called a somatic mutation.  Somatic mutations are not inherited by an organism's offspring because they do not affect the germline. However, they are passed down to all the progeny of a mutated cell within the same organism during mitosis. A major section of an organism therefore might carry the same mutation. These types of mutations are usually prompted by environmental causes, such as ultraviolet radiation or any exposure to certain harmful chemicals, and can cause diseases including cancer. 
With plants, some somatic mutations can be propagated without the need for seed production, for example, by grafting and stem cuttings. These type of mutation have led to new types of fruits, such as the "Delicious" apple and the "Washington" navel orange. 
Human and mouse somatic cells have a mutation rate more than ten times higher than the germline mutation rate for both species mice have a higher rate of both somatic and germline mutations per cell division than humans. 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. 
Special classes Edit
- Conditional mutation is a mutation that has wild-type (or less severe) phenotype under certain "permissive" environmental conditions and a mutant phenotype under certain "restrictive" conditions. For example, a temperature-sensitive mutation can cause cell death at high temperature (restrictive condition), but might have no deleterious consequences at a lower temperature (permissive condition).  These mutations are non-autonomous, as their manifestation depends upon presence of certain conditions, as opposed to other mutations which appear autonomously.  The permissive conditions may be temperature,  certain chemicals,  light  or mutations in other parts of the genome. Invivo mechanisms like transcriptional switches can create conditional mutations. For instance, association of Steroid Binding Domain can create a transcriptional switch that can change the expression of a gene based on the presence of a steroid ligand.  Conditional mutations have applications in research as they allow control over gene expression. This is especially useful studying diseases in adults by allowing expression after a certain period of growth, thus eliminating the deleterious effect of gene expression seen during stages of development in model organisms.  DNA Recombinase systems like Cre-Lox recombination used in association with promoters that are activated under certain conditions can generate conditional mutations. Dual Recombinase technology can be used to induce multiple conditional mutations to study the diseases which manifest as a result of simultaneous mutations in multiple genes.  Certain inteins have been identified which splice only at certain permissive temperatures, leading to improper protein synthesis and thus, loss-of-function mutations at other temperatures.  Conditional mutations may also be used in genetic studies associated with ageing, as the expression can be changed after a certain time period in the organism's lifespan. 
- Replication timing quantitative trait loci affects DNA replication.
In order to categorize a mutation as such, the "normal" sequence must be obtained from the DNA of a "normal" or "healthy" organism (as opposed to a "mutant" or "sick" one), it should be identified and reported ideally, it should be made publicly available for a straightforward nucleotide-by-nucleotide comparison, and agreed upon by the scientific community or by a group of expert geneticists and biologists, who have the responsibility of establishing the standard or so-called "consensus" sequence. This step requires a tremendous scientific effort. Once the consensus sequence is known, the mutations in a genome can be pinpointed, described, and classified. The committee of the Human Genome Variation Society (HGVS) has developed the standard human sequence variant nomenclature,  which should be used by researchers and DNA diagnostic centers to generate unambiguous mutation descriptions. In principle, this nomenclature can also be used to describe mutations in other organisms. The nomenclature specifies the type of mutation and base or amino acid changes.
- Nucleotide substitution (e.g., 76A>T) – The number is the position of the nucleotide from the 5' end the first letter represents the wild-type nucleotide, and the second letter represents the nucleotide that replaced the wild type. In the given example, the adenine at the 76th position was replaced by a thymine.
- If it becomes necessary to differentiate between mutations in genomic DNA, mitochondrial DNA, and RNA, a simple convention is used. For example, if the 100th base of a nucleotide sequence mutated from G to C, then it would be written as g.100G>C if the mutation occurred in genomic DNA, m.100G>C if the mutation occurred in mitochondrial DNA, or r.100g>c if the mutation occurred in RNA. Note that, for mutations in RNA, the nucleotide code is written in lower case.
Mutation rates vary substantially across species, and the evolutionary forces that generally determine mutation are the subject of ongoing investigation.
In humans, 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. This number has been established by sequencing thousands of human trios, that is, two parents and at least one child. 
The genomes of RNA viruses are based on RNA rather than DNA. The RNA viral genome can be double-stranded (as in DNA) or single-stranded. In some of these viruses (such as the single-stranded human immunodeficiency virus), replication occurs quickly, and there are no mechanisms to check the genome for accuracy. This error-prone process often results in mutations.
Changes in DNA caused by mutation in a coding region of DNA can cause errors in protein sequence that may result in partially or completely non-functional proteins. Each cell, in order to function correctly, depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. One study on the comparison of genes between different species of Drosophila suggests that if a mutation does change a protein, the mutation will most likely be harmful, with an 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. Studies have shown that only 7% of point mutations in noncoding DNA of yeast are deleterious and 12% in coding DNA are deleterious. The rest of the mutations are either neutral or slightly beneficial. 
Inherited disorders Edit
If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases. In particular, if there is a mutation in a DNA repair gene within a germ cell, humans carrying such germline mutations may have an increased risk of cancer. A list of 34 such germline mutations is given in the article DNA repair-deficiency disorder. An example of one is albinism, a mutation that occurs in the OCA1 or OCA2 gene. Individuals with this disorder are more prone to many types of cancers, other disorders and have impaired vision.
DNA damage can cause an error when the DNA is replicated, and this 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. Each cell has a number of pathways through which enzymes recognize and repair damages in DNA. Because DNA can be damaged in many ways, 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.
Role in carcinogenesis Edit
On the other hand, a mutation may occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell within the same organism. The accumulation of 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 (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 happens often in living organisms, but it is difficult to measure the rate. Measuring this rate is important in predicting the rate at which people may develop cancer. 
Point mutations may arise from spontaneous mutations that occur during DNA replication. The rate of mutation may be increased by mutagens. Mutagens can be physical, such as radiation from UV rays, X-rays or extreme heat, or chemical (molecules that misplace base pairs or disrupt the helical shape of DNA). Mutagens associated with cancers are often studied to learn about cancer and its prevention.
Prion mutations Edit
Prions are proteins and do not contain genetic material. However, prion replication has been shown to be subject to mutation and natural selection just like other forms of replication.  The human gene PRNP codes for the major prion protein, PrP, and is subject to mutations that can give rise to disease-causing prions.
Although mutations that cause changes in protein sequences can be harmful to an organism, on occasions the effect may be positive in a given environment. In this case, the mutation may enable the mutant organism to withstand particular environmental stresses better than wild-type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Examples include the following:
HIV resistance: a specific 32 base pair deletion in human CCR5 (CCR5-Δ32) confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes.  One possible explanation of the etiology of the relatively high frequency of CCR5-Δ32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People with this mutation were more likely to survive infection thus its frequency in the population increased.  This theory could explain why this mutation is not found in Southern Africa, which remained untouched by bubonic plague. A newer theory suggests that the selective pressure on the CCR5 Delta 32 mutation was caused by smallpox instead of the bubonic plague. 
Malaria resistance: An example of a harmful mutation is sickle-cell disease, a blood disorder in which the body produces an abnormal type of the oxygen-carrying substance hemoglobin in the red blood cells. One-third of all indigenous inhabitants of Sub-Saharan Africa carry the allele, because, in areas where malaria is common, there is a survival value in carrying only a single sickle-cell allele (sickle cell trait).  Those with only one of the two alleles of the sickle-cell disease are more resistant to malaria, since the infestation of the malaria Plasmodium is halted by the sickling of the cells that it infests.
Antibiotic resistance: Practically all bacteria develop antibiotic resistance when exposed to antibiotics. In fact, bacterial populations already have such mutations that get selected under antibiotic selection.  Obviously, such mutations are only beneficial for the bacteria but not for those infected.
Lactase persistence. 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. 
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, creating new forms and new species, potentially instantaneously,  in a sudden jump.  This was envisaged as driving evolution, which was limited by the supply of mutations.
Before Darwin, biologists commonly believed in saltationism, the possibility of large evolutionary jumps, including immediate speciation. For example, in 1822 Étienne Geoffroy Saint-Hilaire argued that species could be formed by sudden transformations, or what would later be called macromutation.  Darwin opposed saltation, insisting on gradualism in evolution as in geology. In 1864, Albert von Kölliker revived Geoffroy's theory.  In 1901 the geneticist Hugo de Vries gave the name "mutation" to seemingly new forms that suddenly arose in his experiments on the evening primrose Oenothera lamarckiana, and in the first decade of the 20th century, mutationism, or as de Vries named it mutationstheorie,   became a rival to Darwinism supported for a while by geneticists including William Bateson,  Thomas Hunt Morgan, and Reginald Punnett.  
Understanding of mutationism is clouded by the mid-20th century portrayal of the early mutationists by supporters of the modern synthesis as opponents of Darwinian evolution and rivals of the biometrics school who argued that selection operated on continuous variation. In this portrayal, mutationism was defeated by a synthesis of genetics and natural selection that supposedly started later, around 1918, with work by the mathematician Ronald Fisher.     However, the alignment of Mendelian genetics and natural selection began as early as 1902 with a paper by Udny Yule,  and built up with theoretical and experimental work in Europe and America. Despite the controversy, the early mutationists had by 1918 already accepted natural selection and explained continuous variation as the result of multiple genes acting on the same characteristic, such as height.  
Mutationism, along with other alternatives to Darwinism like Lamarckism and orthogenesis, was discarded by most biologists as they came to see that Mendelian genetics and natural selection could readily work together mutation took its place as a source of the genetic variation essential for natural selection to work on. However, mutationism did not entirely vanish. In 1940, Richard Goldschmidt again argued for single-step speciation by macromutation, describing the organisms thus produced as "hopeful monsters", earning widespread ridicule.   In 1987, Masatoshi Nei argued controversially that evolution was often mutation-limited.  Modern biologists such as Douglas J. Futuyma conclude that essentially all claims of evolution driven by large mutations can be explained by Darwinian evolution. 
4 Main Theories of Genetic Evolution | Cell Biology
This theory was propounded by Jean Baptiste Lamarck (1744-1829), a French biologist, through his numerous writings.
There are four postulates of this theory as listed below:
i. Living organisms and their organs tend to increase in size during evolution.
ii. New organs develop in an organism if this development is needed for its survival.
iii. Those organs that are in frequent use will develop more and more, as their constant use will make them more developed, while the organs not being used, will tend to become more weak.
iv. The modifications thus produced, due to the use and disuse, in the traits of an organism will be inherited and would accumulate with time.
In short, his theory is termed as Theory of Use and Disuse. The theory may be explained with the help of following example. Giraffes feed on tree leaves. As the easily accessible leaves within the reach are exhausted, they will have to stretch their necks higher and higher in order to reach the level of the leaves.
This stretching will cause some increase in the length of their necks, which will be passed on to the next generation. In each generation, therefore, their necks will be subjected to this type of stretching its effect will accumulate over generations giving rise to the present day long necks of giraffes.
The theory of Lamarck was seriously criti­cised and is not accepted. Several experiments showed the ‘theory of inheritance of acquired characters’ to be incorrect. Many followers of Lamarck introduced various modifications of his theory, one of the important variations being that changes in the traits of organisms are induced by the environment (in place of the ‘need’ postu­lated by Lamarck).
Genetic Evolution: Theory # 2. Darwinism:
The theory of origin of species through natu­ral selection was proposed by Charles Darwin. Darwin visited several islands of the Atlantic Ocean near the coast of South America, and of South Pacific Ocean. He collected a vast amount of data on the biological entities in these islands.
His theory visualizes:
i. Normal reproduction by the members of a species, increases their number at a geo­metric rate. However, there are only limited food supplies and other environmental opportunities.
ii. As a result, members of the same species compete with each other for survival, which Darwin called, the struggle for existence.
iii. Members of a single species show variation for various traits, and Darwin assumed these variations to be hereditary. He suggested that the ‘fittest’ members of the species will ‘survive’ the ‘struggle for existence’ which he termed as ‘the survival of the fittest,’ and the factor responsible for this phenomenon was called natural selection.
Darwin, along with A. R. Wallace, conclu­ded that natural selection coupled with a change in the environment in which a species lives, bring about the evolution of a new species different from the parental species.
Thus the two main features of the Darwinian theory of evolution are:
(a) Origin of hereditary variations in a species, and
(b) Selective multi­plication of those variations which make the species more adapted to the prevailing environ­ment through natural selection.
According to this scheme, natural selection is the force which determines the direction in which evolution in a species would proceed, and the direction of this influence would depend on the prevailing environment. Thus natural selection is central to evo­lution, and this constitutes the Darwinian theory of evolution.
Natural selection can operate only when genetic variation exists in a population (individuals of a single species).
Darwin recog­nized two types of variation in living organisms:
(i) Continuous variations (quantitative in nature) and
(ii) Discontinuous or discrete variations (comparable to qualitative variation). Darwin visualized continuous variation as the basis for evolution. Several scientists have demonstrated the existence of considerable genetic variation within a species and attempted to elucidate the modes of origin of variations and selection of the variations so generated.
Genetic Evolution: Theory # 3. Mutation Theory:
This theory was put forth by Hugo de Vries (1840-1935), a Dutch botanist, who described a large number of discrete variations in Oenothera lamarckiana. He used the term mutation for the phenomenon of appearance of sudden heritable changes the various mutations were called new and separate species by him.
He suggested that new species could arise in a single step due to mutation. Further, since mutations are random, it was presumed that evolution is random, and does not proceed in a definite direction.
The theory of natural selection presumes that populations are expected to become pro­gressively more and more adapted to their envi­ronment, whereas mutationists consider that populations are pre-adapted and adaptations do not necessarily arise due to natural selection.
De Vries theory of mutation though sup­posed to be considered as gene mutation in Oenothera lamarckiana, was later shown to be due to translocation of chromosome segments.
Genetic Evolution: Theory # 4. Synthetic Theory:
Modern understandings in cytology, gene­tics, cytogenetics, population genetics and evo­lution gave a way for the formulation of a cohe­rent theory called modern synthesis around 1930s by S. Wright, H. J. Muller, Th. Dobzhansky, R. B. Goldschmidt, J. S. Huxley, R. A. Fisher, J. B.S. Haldane, Ernst Mayr and G. L. Stebbins.
With the advances in the understanding to chromosome behaviour and aberrations and their consequent effects, Stebbins discussed the ‘Synthetic Theory’ recognizing the following fac­tors:
(ii) Changes in structure and number of chromosome
(iii) Genetic recombination
The first three is to provide the genetic variability and the last two directing the evolutionary process. There are additional fac­tors namely migration of individuals from one population to another and hybridization between races, species or even related genera, increasing the genetic variability available to the popula­tions undergoing the process of evolution. Thus mutation, genetic recombination and natural.
Content: Mutation Vs Variation
Definition of Mutation
Mutation is said as spontaneous change, which occurs at the genome level of an organism. It can occur in germline cell or somatic cell, but if it occurs in a gamete or gonadal cell it is transferred to further generation, which is not the case in somatic or germline cells. Mutations result in the change in the DNA sequence, which can be due to harmful radiations, environmental factors, smokes, or errors while DNA replication.
Though the mutations during the cell replication are often recognised by the cell and are resolved, some mutations have the potential to cause damage and become the fixed mutation. These fixed mutations are inherited and affect positively, while some may show the ill effects too and disease such as sickle cell anaemia, thalassaemia may arise. If mutations affect the gene activity it may cause cancer also.
Hereditary or chromosomal mutation is the mutations that occur in the germ cell of an egg (female) or a sperm (male), such gene change is the transferred or carried into the further living and dividing new cell of the new developing organism. Chromosomal mutations play a larger role in changing the genome as the changes are brought during the process of meiosis.
Chromosomal level mutations are of various types, which can be numerical abnormalities and structural abnormalities. Numerical abnormalities are of two types aneuploidy and polyploidy, while structural abnormalities have five types named as deletions, inversions, translocations, rings formation. Apart from this, there are sex-linked mutations too, that are related to the mutations in the sex chromosomes.
Some mutations are beneficial and give a positive impact to an organism and so termed as beneficial mutations as they support the individual in adapting the situations of the environment, while some mutations may be harmful and attract to disorders and diseases.
Definition of Variation
Genetic variation is the word used to show the distinct features among different organisms, how they variate from one other from hairs to nails, hands, heights, colours, body shapes, etc. It describes the DNA sequence which variates one genome from other, how the living organisms are unique from one another.
Variations help to change and overcome the populations according to the change in the environment. These variations support the individual to survive and produce more of its own kind, hereby passing the variations to the next generations. Variations are the main way for the process of natural selections, as it eliminates the factor which hinders the path of variation.
Environmental variation or variation is seen in population due to change in the organism, while genetic variations are transferred from one generation to other. If the variation continuous from one generation to other and there is a slight difference in two organisms it is called as continuous, while if the variation does not continue in the upcoming generation, it is called as the discontinuous variation.
Mutations: Meaning, Characteristics and Detection | Genetics
In this article we will discuss about:- 1. Meaning of Mutations 2. Characteristics of Mutations 3. Classification 4. Types 5. Agents 6. Detections 7. Nutritional Deficiency Method 8. Spontaneous Mutations 9. Applications of Mutations in Crop Improvement.
- Meaning of Mutations
- Characteristics of Mutations
- Classification of Mutations
- Types of Mutations
- Agents of Mutations
- Detections of Mutations
- Nutritional Deficiency Method of Mutations
- Spontaneous Mutations
- Applications of Mutations in Crop Improvement
1. Meaning of Mutations:
Mutation refers to sudden heritable change in the phenotype of an individual. In the molecular term, mutation is defined as the permanent and relatively rare change in the number or sequence of nucleotides. Mutation was first discovered by Wright in 1791 in male lamb which had short legs.
Later on mutation was reported by Hugo de Vries in 1900 in Oenothera, Morgan (1910) in Drosophila (white eye mutant) and several others in various organisms. The term mutation was coined by de Vries.
2. Characteristics of Mutations:
Mutations have several characteristic features.
Some of the important characteristics of mutations are briefly presented below:
i. Nature of Change:
Mutations are more or less permanent and heritable changes in the phenotype of an individual. Such changes occur due to alteration in number, kind or sequence of nucleotides of genetic material, i.e., DNA in most of the cases.
Spontaneous mutations occur at a very low frequency. However, the mutation rate can be enhanced many fold by the use of physical and chemical mutagens.
The frequency of mutation for a gene is calculated as follows:
Frequency of gene mutation = M / M + N
where, M = number of individuals expressing mutation for a gene, and
N = number of normal individuals in a population.
iii. Mutation Rate:
Mutation rate varies from gene to gene. Some genes exhibit high mutation rate than others. Such genes are known as mutable genes, e.g., white eye in Drosophila. In some genomes, some genes enhance the natural mutation rate of other genes. Such genes are termed as mutator genes.
The example of mutator gene is dotted gene in maize. In some cases, some genes decrease the frequency of spontaneous mutations of other genes in the same genome, which are referred to as anti-mutator genes. Such gene has been reported in bacteria and bacteriophages.
iv. Direction of Change:
Mutations usually occur from dominant to recessive allele or wild type to mutant allele. However, reverse mutations are also known, e.g., notch wing and bar eye in Drosophila.
Mutations are generally harmful to the organism. In other words, most of the mutations have deleterious effects. Only about 0.1% of the induced mutations are useful in crop improvement. In majority of cases, mutant alleles have pleiotropic effects. Mutations give rise to multiple alleles of a gene.
vi. Site of Mutation:
Muton which is a sub-division of gene is the site of mutation. An average gene contains 500 to 1000 mutational sites. Within a gene some sites are highly mutable than others. These are generally referred to as hot spots. Mutations may occur in any tissue of an organism, i.e., somatic or gametic.
vii. Type of Event:
Mutations are random events. They may occur in any gene (nuclear or cytoplasmic), in any cell (somatic or reproductive) and at any stage of development of an individual.
The same type of mutation may occur repeatedly or again and again in different individuals of the same population. Thus, mutations are of recurrent nature.
3. Classification of Mutations:
Mutations can be classified in various ways. A brief classification of mutations on the basis of:
(7) Visibility is presented in Table 14.1.
4. Types of Mutants:
The product of a mutation is known as mutant. It may be a genotype or an individual or a cell or a polypeptide.
There are four main classes of identifiable mutants, viz:
These are briefly described below:
Morphological mutants refer to change in form, i.e., shape, size and colour. Albino spores in Neurospora, curly wings in Drosophila, dwarf peas, short legged sheep are some examples of morphological mutants.
In this class, the new allele is recognized by its mortal or lethal effect on the organism. When the mutant allele is lethal all individuals carrying such allele will die but when it is semi-lethal or sub-vital some of the individuals will survive.
iii. Conditional Lethal:
Some alleles produce a mutant phenotype under specific environmental conditions. Such mutants are called restrictive mutants. Under other conditions they produce normal phenotype and are called permissive. Such mutants can be grown under permissive conditions and then be shifted to restrictive conditions for evaluation.
iv. Biochemical Mutant:
Some mutants are identified by the loss of a biochemical function of the cell. The cell can assume normal function, if the medium is supplemented with appropriate nutrients. For example, adenine auxotroph’s can be grown only if adenine is supplied, whereas wild type does not require adenine supplement.
Mutagens refer to physical or chemical agents which greatly enhance the frequency of mutations. Various radiations and chemicals are used as mutagens. Radiations come under physical mutagens. A brief description of various physical and chemical mutagens is presented below:
Physical mutagens include various types of radiations, viz. X-rays, gamma rays, alpha particles, beta particles, fast and thermal (slow) neutrons and ultra violet rays (Table 14.2).
A brief description of these mutagens is presented below:
X-rays were first discovered by Roentgen in 1895. The wavelengths of X-rays vary from 10 -11 to 10 -7 . They are sparsely ionizing and highly penetrating. They are generated in X-rays machines. X-rays can break chromosomes and produce all types of mutations in nucleotides, viz., addition, deletion, inversion, transposition, transitions and trans-versions.
These changes are brought out by adding oxygen to deoxyribose, removing amino or hydroxyl group and forming peroxides. X-rays were first used by Muller in 1927 for induction of mutations in Drosophila.
In plants, Stadler in 1928 first used X-rays for induction of mutations in barley. Now X-rays are commonly used for induction of mutations in various crop plants. X-rays induce mutations by forming free radicals and ions.
Gamma rays are identical to X-rays in most of the physical properties and biological effects. But gamma rays have shorter wave length than X-rays and are more penetrating than X-rays. They are generated from radioactive decay of some elements like 14C, 60C, radium etc.
Of these, cobalt 60 is commonly used for the production of Gamma rays. Gamma rays cause chromosomal and gene mutations like X-rays by ejecting electrons from the atoms of tissues through which they pass. Now a days, gamma rays are also widely used for induction of mutations in various crop plants.
iii. Alpha Particles:
Alpha rays are composed of alpha particles. They are made of two protons and two neutrons and thus have double positive charge. They are densely ionizing, but lesser penetrating than beta rays and neutrons. Alpha particles are emitted by the isotopes of heavier elements.
They have positive charge and hence they are slowed down by negative charge of tissues resulting in low penetrating power. Alpha particles lead to both ionization and excitation resulting in chromosomal mutations.
iv. Beta Particles:
Beta rays are composed of beta particles. They are sparsely ionizing but more penetrating than alpha rays. Beta particles are generated from radioactive decay of heavier elements such as 3H, 32P, 35S etc. They are negatively charged, therefore, their action is reduced by positive charge of tissues. Beta particles also act by way of ionization and excitation like alpha particles and result in both chromosomal and gene mutations.
v. Fast and Thermal Neutrons:
These are densely ionizing and highly penetrating particles. Since they are electrically neutral particles, their action is not slowed down by charged (negative or positive) particles of tissues. They are generated from radioactive decay of heavier elements in atomic reactors or cyclotrons. Because of high velocity, these particles are called as fast neutrons.
Their velocity can be reduced by the use of graphite or heavy water to produce slow neutrons or thermal neutrons. Fast and thermal neutrons result in both chromosomal breakage and gene mutation. Since they are heavy particles, they move in straight line. Fast and thermal neutrons are effectively used for induction of mutations especially in asexually reproducing crop species.
vi. Ultraviolet Rays:
UV rays are non-ionizing radiations, which are produced from mercury vapour lamps or tubes. They are also present in solar radiation. UV rays can penetrate one or two cell layers. Because of low penetrating capacity, they are commonly used for radiation of micro-organisms like bacteria and viruses.
In higher organisms, their use is generally limited to irradiation of pollen in plants and eggs in Drosophila UV rays can also break chromosomes. They have two main chemical effects on pyrimidine’s.
The first effect is the addition of a water molecule which weakens the H bonding with its purine complement and permits localized separation of DNA strands. The second effect is to join pyrimidines to make a pyrimidine dimer.
This dimerization can produce TT, CC, UU and mixed pyrimidine dimers like CT. Dimerization interferes with DNA and RNA synthesis. Inter-strand dimers cross link nucleic acid chains, inhibiting strand separation and distribution.
There is a long list of chemicals which are used as mutagens. Detailed treatment of such chemicals is beyond the scope of this discussion.
The chemical mutagens can be divided into four groups, viz:
A brief description of some commonly used chemicals of these groups is presented below.
a. Alkylating Agents:
This is the most powerful group of mutagens. They induce mutations especially transitions and transversions by adding an alkyl group (either ethyl or methyl) at various positions in DNA. Alkylation produces mutation by changing hydrogen bonding in various ways.
The alkylating agents include ethyl methane sulphonate (EMS), methyl methane sulphonate (MMS), ethylene imines (EI), sulphur mustard, nitrogen mustard, etc.
Out of these, the first three are in common use. Since the effect of alkylating agents resembles those of ionizing radiations, they are also known as radiomimetic chemicals. Alkylating agents can cause various large and small deformations of base structure resulting in base pair transitions and transversions.
Transversions can occur either because a purine has been so reduced in size that it can accept another purine for its complement, or because a pyrimidine has been so increased in size that it can accept another pyrimidine for its complement. In both cases, diameter of the mutant base pair is close to that of a normal base pair.
b. Base Analogues:
Base analogues refer to chemical compounds which are very similar to DNA bases. Such chemicals sometimes are incorporated in DNA in place of normal base during replication. Thus, they can cause mutation by wrong base pairing. An incorrect base pairing results in transitions or transversions after DNA replication. The most commonly used base analogues are 5 bromo uracil (5BU) and 2 amino purine (2AP).
5 bromo uracil is similar to thymine, but it has bromine at the C5 position, whereas thymine has CH3 group at C5 position. The presence of bromine in 5BU enhances its tautomeric shift from keto form to the enol form. The keto form is a usual and more stable form, while enol form is a rare and less stable or short lived form. Tautomeric change takes place in all the four DNA bases, but at a very low frequency.
The change or shift of hydrogen atoms from one position to another either in a purine or in a pyrimidine base is known as tautomeric shift and such process is known as tautomerization.
The base which is produced as a result of tautomerization is known as tautomeric form or tautomer. As a result of tautomerization, the amino group (-NH2) of cytosine and adenine is converted into imino group (-NH). Similarly keto group (C = 0) of thymine and guanine is changed to enol group (-OH).
5BU is similar to thymine, therefore, it pairs with adenine (in place of thymine). A tautomer of 5BU will pair with guanine rather than with adenine. Since the tautomeric form is short-lived, it will change to keto form at the time of DNA replication which will pair with adenine in place of guanine.
In this way it results in AT GC and GC —> AT transitions. The mutagen 2AP acts in a similar way and causes AT <-> GC transitions. This is an analogue of adenine.
c. Acridine Dyes:
Acridine dyes are very effective mutagens. Acridine dyes include, pro-flavin, acridine orange, acridine yellow, acriflavin and ethidium bromide. Out of these, pro-flavin and acriflavin are in common use for induction of mutation. Acridine dyes get inserted between two base pairs of DNA and lead to addition or deletion of single or few base pairs when DNA replicates (Fig. 14.1).
Thus, they cause frameshift mutations and for this reason acridine dyes are also known as frameshift mutagens. Proflavin is generally used for induction of mutation in bacteriophages and acriflavin in bacteria and higher organisms.
d. Other Mutagens:
Other important chemical mutagens are nitrous acid and hydroxy amine. Their role in induction of mutation is briefly described here. Nitrous acid is a powerful mutagen which reacts with C6 amino groups of cytosine and adenine. It replaces the amino group with oxygen (+ to – H bond). As a result, cytosine acts like thymine and adenine like guanine.
Thus, transversions from GC —> AT and AT —> GC are induced. Hydroxylamine is a very useful mutagen because it appears to be very specific and produces only one kind of change, namely, the GC —> AT transition. All the chemical mutagens except base analogues are known as DNA modifiers.
6. Detection of Mutation:
Detection of mutations depends on their types. Morphological mutations are detected either by change in the phenotype of an individual or by change in the segregation ratio in a cross between normal (with marker) and irradiated individuals. The molecular mutations are detected by a change in the nucleotide, and a biochemical mutation can be detected by alteration in a biochemical reaction.
The methods of detection of morphological mutants have been developed mainly with Drosophila. Four methods, viz., (1) CIB method, (2) Muller’s 5 method, (3) attached X-chromosome method, and (4) curly lobe plum method are in common use for detection of mutations in Drosophila.
A brief description of each method is presented below:
This method was developed by Muller for detection of induced sex linked recessive lethal mutations in Drosophila male. In this technique, C represents a paracentric inversion in large part of X-chromosome which suppresses crossing over in the inverted portion. The I is a recessive lethal. Females with lethal gene can survive only in heterozygous condition.
The B stands for bar eye which acts as a marker and helps in identification of flies. The I and B are inherited together because C does not allow crossing over to occur between them. The males with CIB chromosome do not survive because of lethal effect.
The important steps of this method are as follows:
(a) A cross is made between CIB female and mutagen treated male. In F1 half of the males having normal X-chromosome will survive and those carrying CIB chromosome will die. Among the females, half have CIB chromosome and half normal chromosome (Fig. 14.2). From F1, females with CIB chromosome and male with normal chromosome are selected for further crossing.
(b) Now a cross is made between CIB female and normal male. This time the CIB female has one CIB chromosome and one mutagen treated chromosome received from the male in earlier cross.
This will produce two types of females, viz., half with CIB chromosome and half with mutagen treated chromosome (with normal phenotype). Both the progeny will survive. In case of males, half with CIB will die and other half have mutagen treated chromosome.
If a lethal mutation was induced in mutagen treated X-chromosome, the remaining half males will also die, resulting in absence of male progeny in the above cross. Absence of male progeny in F2 confirms the induction of sex linked recessive lethal mutation in the mutagen treated Drosophila male.
ii. Muller 5 Method:
This method was also developed by Muller to detect sex linked mutation in Drosophila. This method is an improved version of CIB method. This method differs from CIB method in two important aspects. First, this method utilizes apricot recessive gene in place of recessive lethal in CIB method. Second, the female is homozygous for bar apricot genes, whereas it is heterozygous for IB genes in CIB method.
In this method, the mutation is detected by the absence of wild males in F2 progeny. This method consists of following important steps (Fig. 14.3).
a. A homozygous bar apricot female is crossed with mutagen treated male. In F1 we get two types of progeny, viz., heterozygous bar females and bar apricot (Muller) males.
b. These F1 are inter-mated. This produces four types of individuals. Half of the females are homozygous bar apricot, and half are bar heterozygous. Among the males, half are bar apricot (Muller 5) and half should be normal. If a lethal mutation is induced, the normal male will be absent in the progeny.
iii. Attached X-Method:
This method is used to detect sex linked visible mutations in Drosophila. In this method a female in which two X-chromosomes are united or attached together is used to study the mutation (Fig. 14.4). Therefore, this method is known as attached X-method. The attached X females (XXY) are crossed to mutagen treated male. This cross gives rise to super females (XX-X), attached female (XXY), mutant male (XY) and YY.
The YY individuals die and super female also usually dies. The surviving male has received X-chromosome from mutagen treated male and Y chromosome from attached X-female. Since Y chromosome does not have corresponding allele of X-chromosome, even recessive mutation will express in such male which can be easily detected.
iv. Curly Lobe-Plum Method:
This method is used for detection of mutation in autosomes. In this method curly refers to curly wings, lobe to lobed eye and plum to plum or brownish eye. All these three genes are recessive lethal. Curly (CY) and lobed (L) genes are located in one chromosome and plum (Pm) in another but homologous chromosome.
Crossing over between these chromosomes cannot occur due to presence of inversion. Moreover, homozygous individuals for CYL or Pm cannot survive because of lethal effect. Only heterozygotes survive. Thus, this system is also known as balanced lethal system. This method consists of following steps (Fig. 14.5).
a. A cross is made between curly lobe plum (CYL/Pm) female and mutagen treated male. This produces 50% progeny as curly lobe and 50% as plum.
b. In the second generation cross is made between curly lobe female and curly lobe plum male. This will give rise to curly lobe plum, curly lobe and plum individuals in 1 : 1 : 1 ratio and homozygous curly will die due to lethal effect. From this progeny, curly lobe females and males are selected for further mating.
c. In third generation, a cross is made between curly lobe female carrying one mutagen treated autosome and curly lobe male also carrying treated autosome. This results in production of 50% progeny as curly lobe, 25% homozygous curly lobe which die and 25% progeny homozygous for treated autosomes.
This will express as autosomal recessive mutation and constitute one third of the surviving progeny. A comparison of different methods of detection of mutation in Drosophila is given in Table 14.4.
Detection of Mutations in Plants:
As stated earlier, the techniques of detection of induced mutations have been mostly developed on Drosophila. In plants, such techniques have not been developed properly. In plants, two methods are used for detection of mutations depending upon the visibility of mutations.
These methods are briefly described below:
i. Detection of Visible Mutations:
Visible mutations generally occur in qualitative or oligogenic characters. Such mutations are detected on the basis of altered phenotype.
This technique consists of following steps:
a. The seeds are treated with a mutagen. For this purpose an improved variety or strain is used.
b. The treated seeds are grown in the experimental field. These plants are known as M1 plants or M1 generation. These M1 plants are selfed to avoid outcrossing. The seeds obtained from M1 plants represent M2 generation of seed.
c. The seeds obtained from M1 plants are grown to obtain M2 plants. A sufficiently large population should be raised in M2 generation to obtain mutant phenotypes which generally occur at a low frequency.
d. A search is made to identify or to detect plants which differ from the parent variety. Such plants are isolated and their frequency is estimated. Such mutations are called macro- mutations.
In maize, a different procedure is used for detection of visible mutations. In maize, some stocks are homozygous for several recessive genes and other stocks are homozygous for several dominant genes. The seeds of homozygous dominant lines are treated with a mutagen and M1 plants are raised. These M1 plants are crossed with homozygous recessive stock.
The mutagen treated plants are used as females due to presence of some degree of male sterility in these plants as a consequence of mutagenic effect. The F1 progeny of such cross is grown and a search is made to detect plants with recessive phenotype for a specific gene. Presence of plants with recessive phenotype for a gene confirms induction of mutation.
ii. Detection of Invisible Mutation:
Invisible mutations usually occur in quantitative or polygenic characters like yield and protein content. Detection of such mutations requires quantitative measurement of such characters. For yields, the mutagen treated and untreated variety is grown in replicated trials.
If the yield of treated and untreated treatments differs significantly, the presence of mutation is indicated. Similarly, if the protein content of treated material differs significantly from the parent variety, it indicates that mutation has taken place. Such mutations are called as micro-mutations.
7. Nutritional Deficiency Method of Mutations:
This method of detection of induced mutations is used in micro-organisms like Neurospora. The normal strain is treated with a mutagen and then cultured on minimal medium. A minimal medium contains sugar, salt, inorganic acids, nitrogen and vitamin biotin. The normal strain of Neurospora grows well on the minimal medium, but a biochemical mutant fails to grow on such medium.
This confirms induction of mutation. Then minimal medium is supplemented with certain vitamins or amino acids, one by one and the growth is observed. The medium which results in normal growth of mutagen treated mould indicates that the mutant lacks synthesis of that particular vitamin or amino acid, addition of which to the minimal culture medium has resulted in normal growth of treated strain.
8. Spontaneous Mutations:
Naturally occurring mutations are known as spontaneous mutations. Such mutations are induced by chemical mutagens or radiations which are present in the external environment to which an organism is exposed. Temperature also affects the frequency of spontaneous mutations. A rise of 10°C in the temperature leads to fivefold increase in mutation rate in an organism exposed to such variation in temperature.
Drastic change of temperature in any direction produces still greater effect on mutation frequency. External environmental conditions of any type, i.e., either extremely high or low leads to increase in the mutation frequency.
Internal environment of an organism also plays an important role in the induction of spontaneous mutations. For example, spontaneous rearrangements of DNA bases result in base pair transitions. Similarly, errors in DNA repair or replication can cause spontaneous mutations.
9. Applications of Mutations in Crop Improvement:
Induced mutations are useful in crop improvement in five principal ways, viz:
(1) Development of improved varieties,
(2) Induction of male sterility,
(4) Creation of genetic variability, and
(5) Overcoming self-incompatibility.
These are briefly discussed below:
i. Development of Improved Varieties:
More than 2000 improved varieties (some directly and some by use of mutants in hybridization) have been developed through induced mutations in various field crops all over the world.
In India, induced mutations have been instrumental in developing improved varieties in wheat (NP 836, Sarbati Sonor’a, Pusa Lerma), barley (RDB 1), rice (Jagannath, IIT 48, NT 60), tomato, castor bean (Aruna, Sobhagya), cotton (MCU 7, MCU 10, Indore 2), groundnut (TGI), sugarcane (Co 8152, 8153) and several other crops.
Besides high yield, varieties have been developed with better quality, earliness, dwarfness, disease resistance and low toxin contents in various crops.
Improvement in quality has been achieved for protein content in wheat and rice, oil content in mustard and sugar content in sugarcane. Earliness has been achieved in castor (from 270 days to 140 days), rice and soybean. Dwarf varieties have been developed through the use of mutant parents in wheat, rice, Sorghum and pearl millet.
Disease resistance has been induced in oats to Victoria blight and crown rust in wheat for strip rust in barley for mildew in groundnut for leaf spot and stem rust in sugarcane for red rot in apple for mildew, etc. Low toxin content varieties have been developed in rapeseed and mustard for erusic acid and in Lathyrus sativa for neurotoxin content.
ii. Induction of Male Sterility:
Induced mutations have been useful in induction of male sterility in some crop plants. Genetic male sterility has been induced in durum wheat using radiations. CMS mutants have been induced in barley, sugarbeet, pearl millet and cotton. Use of GMS and CMS lines helps in reducing the cost of hybrid seed production.
iii. Production of Haploids:
Use of X-ray irradiated pollens has helped in production of haploids in many crops. Chromosome doubling of these haploids results in the development of inbred lines which can be utilized in the development of commercial hybrids.
iv. Creation of Genetic Variability:
Induced mutations are very effective in creating genetic variability for various economic characters in crop plants. Induced mutations have been used for increasing the range of genetic variability in barley, oats, wheat and many other crops. In asexually propagated crops like sugarcane and potato, somatic mutations may be useful, because the mutant plant can be multiplied as a clone.
v. Overcoming Self-Incompatibility:
Mutation of S gene by irradiation offers a solution to the production of self-fertile plants in self-incompatible species. This has been successful in case of Prunusovium. Besides this practical application in crop improvement, induced mutations are of fundamental interest in genetical studies.
Induced mutations have some limitations also. Most of the mutations are deleterious and undesirable. Identification of micro-mutations, which are more useful to a plant breeder is usually very difficult. Since mutations are produced at a very low frequency, a very large plant population has to be screened to identify and isolate desirable mutants.
This study adds to the body of evidence that college introductory biology students struggle to integrate molecular genetic concepts within their evolutionary reasoning. Specifically, we uncovered students’ difficulty incorporating the molecular basis of variation in their explanatory frameworks of evolution by natural selection.
The literature on evolution teaching and learning is rich with evidence that evolution as a whole is conceptually difficult for students ( Bishop and Anderson, 1990 Anderson etਊl., 2002 ). A recent metastudy of introductory biology students’ learning of natural selection across multiple courses and institutions reported that students achieved only modest learning gains ( Andrews etਊl., 2011 ), measured by an abbreviated version of the CINS ( Anderson etਊl., 2002 ) and a short constructed response ( Bishop and Anderson, 1990 Nehm and Reilly, 2007 ).
The results of our study align with previous reports showing that students’ explanations of natural selection largely fail to incorporate molecular genetic concepts like genetic variation and heredity ( Nehm and Schonfeld, 2008 Nehm and Ridgway, 2011 Bray Speth etਊl., 2009 Nieswandt and Bellomo, 2009 ). We further extend these findings with additional evidence that college introductory biology students consistently struggle to integrate the molecular basis of variation in their explanatory frameworks of evolution by natural selection. After a semester-long introductory biology course on genetics, evolution, and ecology, and despite instruction that emphasized the mechanisms underlying variation and included formative assessment and targeted feedback, nearly one-third of our students still did not incorporate mutation into their models.
Students Struggle to Represent the Origin of Variation
In week 7 of class, before the midterm exam, instruction focused extensively on mutation as the causal mechanism that generates variation. Despite modeling practice in class and explicit feedback, only 39% of all students included the concept of mutation in their midterm exam models ( Tableਃ ). Moreover, only 20% incorporated mutation as the causal mechanism explaining the origin of new alleles ( Tableਃ ). Instructors immediately identified this gap in students’ midterm models and designed a second targeted round of feedback following the midterm exam (see Methods and Figure S3). The proportion of students who incorporated mutation into their models of the origin of variation increased significantly (to 65%) on the final exam.
Mutation is an inherently difficult concept for various reasons. To begin with, it is a molecular-scale mechanism that explains organism- and population-scale outcomes. The science education literature has shown that constructing causal explanations of biological phenomena is difficult for learners. Students often resort to teleological and anthropomorphic explanations or fail to recognize the need to include causal or mechanistic reasoning when asked to articulate an explanation of biological change, particularly in the context of adaptation and evolution ( Abrams and Southerland, 2001 Southerland etਊl., 2001 Russ etਊl., 2008 ). Studies on learning about systems have shed further light on students’ apparent difficulty with reasoning about underlying mechanisms, as these studies demonstrate that novice learners tend to focus on the perceptually salient, structural aspects of systems ( Hmelo etਊl., 2000 Hmelo-Silver and Pfeffer, 2004 ), rather than their functions and behaviors. Micro-level components and implicit mechanisms pose a substantial learning challenge, especially when learners must infer them ( Chi etਊl., 1994 Hmelo-Silver etਊl., 2007 ) and connect causal processes across multiple levels. An additional issue further complicating the understanding of mutation is that it is a random event students often hold deep misconceptions about the role of random processes in the natural world ( Garvin-Doxas and Klymkowsky, 2008 ). On the basis of this understanding, we argue that articulating the role of random mutation as the underlying source of variation, unless explicit cues are provided or elicited, is an inference that requires retrospection: students need to recognize that the observable, heritable phenotypic variation within a population is caused by the existence of multiple alleles and that mutation events must have occurred at the molecular level in the past, causing the new alleles to exist. A systems-thinking skills hierarchy developed in the context of learning about natural systems places retrospection (with prediction) at the top, as one of the most advanced cognitive characteristics of systems thinking ( Ben-Zvi Assaraf and Orion, 2005 ).
It is possible that the improvement we observed in students’ ability to incorporate mutation into their models on the final exam was due, at least in part, to their developing systems-thinking skills and ability to reason causally and mechanistically about evolution. Of course, we cannot exclude that students were simply repeating information they obtained during feedback. Our data do not allow discriminating between these alternative explanations, nor do they allow us to separate students’ gains in conceptual understanding from their possible increased familiarity and proficiency with model building. However, it is evident that a single cycle of modeling, instruction, and feedback was not sufficient for the majority of the class, and after two cycles, we still observed that 35% of our students did not include mutation in their explanatory frameworks. It is noteworthy that in other reported assessments of students’ understanding of natural selection ( Nehm and Reilly, 2007 Nehm and Schonfeld, 2008 Bray Speth etਊl., 2009 ), students were not explicitly prompted to incorporate mutation, and we have no evidence of whether they had received feedback on how to include this concept in their explanations. In the course described in this study, instructors repeatedly emphasized the importance of representing mutation as the source of variation yet after repeated opportunities for practice and feedback, only 65% of students in the course incorporated mutation into their final exam models, and only 35% appropriately used it to explain the origin of new alleles ( Tableਃ ). We recognize that not all strategies for providing feedback are equally effective ( Hattie and Timperley, 2007 ) and that it may be necessary to critically evaluate the efficacy of different mechanisms of feedback that help students incorporate this concept into their explanatory frameworks.
Student Models of the Origin of Variation Become More Meaningful over Time
Students’ final models, overall, better conveyed the function that was required in the prompt (representing variation in a population and the origin of this variation Figureਂ ). Previous comprehensive analysis of all propositions in students’ models had revealed that the biological accuracy of individual propositions within models increased throughout the semester ( Dauer etਊl., 2013 ). Our results support the hypothesis that, as students’ language in defining individual relationships among structures became more accurate, their ability to represent the overall system function also improved.
These results were not uniform across student groups. For students who incorporated mutation into both models (group 1), the accuracy of propositions containing the mutation concept did not significantly change between the midterm and the final exam ( Tableਅ ). We observed, however, that students who did not incorporate mutation on the midterm but only on the final exam (group 2) used less accurate propositions than their group 1 peers. While this difference did not appear to be statistically significant, the p value was close enough to significance level (p = 0.06, α = 0.05) to warrant discussion of this outcome. It is possible that students who added mutation to their models late in the semester were still tentative on how to incorporate it. We may interpret this difference in terms of stages of cognitive structure development, which proceeds by accretionition of new concepts to existing knowledge𠅏ollowed by restructuring and tuning, major rearrangements and minor refinements of the network of relationships among new and old concepts ( Vosniadou and Brewer, 1987 Pearsall etਊl., 1997 Dauer etਊl., 2013 ). At midterm, group 1 students had already added mutation to their cognitive structure and accommodated it within the network of relationships among concepts in their evolution reasoning framework. Group 2 students added mutation later, and at the time of the final exam, they were still possibly tuning or restructuring their conceptual models to accommodate the new concept their propositions, thus, were less accurate than those of group 1.
In this study, we compared students’ GtE models of two different systems with clearly distinct surface features. At midterm, students modeled evolution of DDT resistance in mosquito populations (an instance of trait gain) on the final exam, the model context was that of a deleterious mutation in wolves, causing loss of ability to effectively walk and hunt (an instance of trait loss), which persisted due to isolation and inbreeding. Surface item features have been shown to affect the frequency of naïve and key concepts of evolution in students’ constructed explanations ( Nehm and Ha, 2011 ). Generally, students tend to include fewer key concepts and more naïve conceptions in cases of trait loss than in cases of trait gain, although the differences are less pronounced in within-species contexts. On the basis of this evidence, we would have predicted that students may incorporate mutation with similar or lower frequency in their final (wolf, trait loss) than in their midterm (mosquito, trait gain) model. The higher frequency that we observed on the final exam's models, therefore, may be attributed to learning. It is possible, however, that the frequency of the mutation concept may have been even higher on the final exam, had a trait-gain problem been presented. Future studies with a split-plot design in which distinct surface features are tested simultaneously may provide further insight.
Course instructors did not specifically address whether mutation should be represented as a structure or as a behavior and did not evaluate students’ models differently based on this choice. We observed, on the final exam model, a shift toward using mutation as a behavior as opposed to a structure ( Table ). One possible explanation for this shift is that the student models shown as examples in the postmidterm feedback activity happened to have mutation placed on arrows (Figure S3). Students may have interpreted that as a suggestion for improvement. Alternatively, we could interpret students’ later preference for placing mutation on arrows as an indication of a better appropriation of the concept and of biological language. Mutation is, in fact, a mechanism, and as such, it is more appropriately represented as a behavior (not as a physical structure) of the system. Although it is common among practicing biologists to refer to an altered genetic sequence as a mutation, in the context of introductory biology, we did not explore with students the nuances of the term in its various applications. Moreover, we observed that when using “mutation” as a structure, students typically would construct propositions like “mutation changes the nucleotide sequence” or “mutation creates a new allele,” wherein mutation was represented as an abstract agent causing a change. In this context, we interpreted students’ shift toward placing mutation on arrows rather than in boxes as an example of their progress toward a more accurate understanding.
Mechanistic Reasoning about Mutation Emerges in Models More Than in Short Answers
A segment of the class population was consistent in the quality of their reasoning about mutation across their models and short answers ( Figureਃ ). The vast majority of students who mentioned mutation in their short answers but not in their models ( Figureꀼ ) did so at a basic level. This suggests that their understanding of mutation still may have been weak and poorly integrated within their knowledge structure. Students were able to use the word “mutation” in their short answers without further qualifying the concept or explaining how mutation led to variation, but could not do the same in models. Incorporating a concept in a model, in fact, requires building at a minimum one meaningful connection to another concept.
At the other end of the spectrum, we observed a group of students who incorporated mutation at the best possible level in their models but failed to meet the same high explanatory standard in their short answers. Again, this suggests that the format of the modeling task is more conducive for eliciting causal and mechanistic reasoning than a short answer, even in the presence of a solid understanding. Nieswandt and Bellomo (2009) came to similar conclusions: students’ written responses about evolution had a fairly low explanatory power and failed to display “schematic knowledge” (the why of a system).
Our finding that students’ written responses tend to be less conducive to mechanistic reasoning than models may represent a limitation of this study, since we did not coach students to write explanations. In an instructional context in which explanations as a form of assessment are appropriately scaffolded ( McNeill etਊl., 2006 ), we might expect students to better articulate causal and mechanistic reasoning.
Implications for Teaching and Learning
Despite numerous calls for integrating evolutionary reasoning across the curriculum ( American Association for the Advancement of Science [AAAS], 2011 Olson and Labov, 2012 ), evolution teaching and learning remains largely fragmented. Traditional textbooks and curricula present evolution as a discrete topic and provide few opportunities for students to practice making the conceptual connections across levels of biological organization necessary for a complete and accurate understanding of evolution by natural selection ( Nehm etਊl., 2009 ). Instructional strategies that focus primarily on memorizing content while following textbook-driven compartmentalization of concepts do not promote the kinds of reasoning necessary to make sense of complex biological problems ( National Research Council, 2003 ).
Learning about biology from a systems perspective is increasingly recognized as both a challenge and a priority ( AAAS, 2011 ). In this course, we implemented a model-based pedagogy grounded in the cognitive sciences and aimed at fostering integrative and systems thinking. SBF models proved a suitable system representation tool, because this syntax overcame several limitations of concept maps ( Tripto etਊl., 2013 ). The modeling approach we described in this and other studies ( Dauer etਊl., 2013 Long etਊl. , 2014) promotes integrative thinking, as it requires students to repeatedly articulate the connections between genetics and evolution in a number of different contexts. Additional strategies that promote integration of genetics and evolution are grounded in using authentic DNA sequences ( Kalinowski etਊl., 2010 ) and case studies ( White etਊl., 2013 ) incorporating well-characterized genetic mutations, the resulting phenotypes, and known evolutionary outcomes.
Along with instruction that promotes integrative thinking, assessment needs to both elicit student reasoning across levels of organization and serve as a source for frequent formative feedback in support of meaningful learning and progressive restructuring and tuning of students’ knowledge frameworks. Using models as an assessment tool allowed instructors to rapidly gauge students’ understanding of mechanisms and functions and to provide timely and targeted feedback. Student models illuminated aspects of their thinking we might have otherwise missed had we exclusively relied on other types of constructed-response assessments such as written explanations.
In summary, we advocate evolution instruction that 1) explicitly connects molecular-level processes to organism- and population-level events in the context of multiple gene-to-evolution cases 2) relies on modes of assessment, such as conceptual modeling, that promote and reveal student reasoning about the causes and mechanisms underlying evolution by natural selection and 3) iteratively provides opportunities for students to practice constructing and using their explanatory frameworks and to receive formative feedback on their thinking.
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Small-scale mutations Edit
Small-scale mutations affect a gene in one or a few nucleotides. (If only a single nucleotide is affected, they are called point mutations.) Small-scale mutations include:
- add one or more extra nucleotides into the DNA. They are usually caused by transposable elements, or errors during replication of repeating elements. Insertions in the coding region of a gene may alter splicing of the mRNA (splice site mutation), or cause a shift in the reading frame (frameshift), both of which can significantly alter the gene product. Insertions can be reversed by excision of the transposable element. remove one or more nucleotides from the DNA. Like insertions, these mutations can alter the reading frame of the gene. In general, they are irreversible: Though exactly the same sequence might, in theory, be restored by an insertion, transposable elements able to revert a very short deletion (say 1–2 bases) in any location either are highly unlikely to exist or do not exist at all. , often caused by chemicals or malfunction of DNA replication, exchange a single nucleotide for another.  These changes are classified as transitions or transversions.  Most common is the transition that exchanges a purine for a purine (A ↔ G) or a pyrimidine for a pyrimidine, (C ↔ T). A transition can be caused by nitrous acid, base mispairing, or mutagenic base analogs such as BrdU. Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T ↔ A/G). An example of a transversion is the conversion of adenine (A) into a cytosine (C). Point mutations are modifications of single base pairs of DNA or other small base pairs within a gene. A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). As discussed below, point mutations that occur within the protein coding region of a gene may be classified as synonymous or nonsynonymous substitutions, the latter of which in turn can be divided into missense or nonsense mutations.
By impact on protein sequence Edit
The effect of a mutation on protein sequence depends in part on where in the genome it occurs, especially whether it is in a coding or non-coding region. Mutations in the non-coding regulatory sequences of a gene, such as 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 (e.g. pseudogenes, retrotransposons) are generally neutral, having no effect on phenotype – though intron mutations could alter the protein product if they affect mRNA splicing.
Mutations that occur in coding regions of the genome are more likely to alter the protein product, and can be categorized by their effect on amino acid sequence: