Genetic Mutation....Could scientists create dragons using CRISPR gene editing?"Consider, for example, the dragon. Basic physics will almost certainly combine with biological constraints to prevent the creation of flying or fire-breathing dragons.

Is it possible to have "too many" mutations? What about "too few"? While mutations are necessary for evolution, they can damage existing adaptations as well. What is a mutation?
A photograph shows approximately 100 different species of beetle arranged in an oval pattern against a black background. The beetles vary in the size of their bodies, the length of their legs, their coloration, and the shape and size of their mandibles.
The diversity of beetle species.
Genetic mutation is the basis of species diversity among beetles, or any other organism.
© 2009 Courtesy of John C. Abbot, Abbott Nature Photography. All rights reserved. View Terms of Use
Mutations are changes in the genetic sequence, and they are a main cause of diversity among organisms. These changes occur at many different levels, and they can have widely differing consequences. In biological systems that are capable of reproduction, we must first focus on whether they are heritable; specifically, some mutations affect only the individual that carries them, while others affect all of the carrier organism's offspring, and further descendants. For mutations to affect an organism's descendants, they must: 1) occur in cells that produce the next generation, and 2) affect the hereditary material. Ultimately, the interplay between inherited mutations and environmental pressures generates diversity among species.

Although various types of molecular changes exist, the word "mutation" typically refers to a change that affects the nucleic acids. In cellular organisms, these nucleic acids are the building blocks of DNA, and in viruses they are the building blocks of either DNA or RNA. One way to think of DNA and RNA is that they are substances that carry the long-term memory of the information required for an organism's reproduction. This article focuses on mutations in DNA, although we should keep in mind that RNA is subject to essentially the same mutation forces.

If mutations occur in non-germline cells, then these changes can be categorized as somatic mutations. The word somatic comes from the Greek word soma which means "body", and somatic mutations only affect the present organism's body. From an evolutionary perspective, somatic mutations are uninteresting, unless they occur systematically and change some fundamental property of an individual--such as the capacity for survival. For example, cancer is a potent somatic mutation that will affect a single organism's survival. As a different focus, evolutionary theory is mostly interested in DNA changes in the cells that produce the next generation.

Are Mutations Random?
The statement that mutations are random is both profoundly true and profoundly untrue at the same time. The true aspect of this statement stems from the fact that, to the best of our knowledge, the consequences of a mutation have no influence whatsoever on the probability that this mutation will or will not occur. In other words, mutations occur randomly with respect to whether their effects are useful. Thus, beneficial DNA changes do not happen more often simply because an organism could benefit from them. Moreover, even if an organism has acquired a beneficial mutation during its lifetime, the corresponding information will not flow back into the DNA in the organism's germline. This is a fundamental insight that Jean-Baptiste Lamarck got wrong and Charles Darwin got right.

However, the idea that mutations are random can be regarded as untrue if one considers the fact that not all types of mutations occur with equal probability. Rather, some occur more frequently than others because they are favored by low-level biochemical reactions. These reactions are also the main reason why mutations are an inescapable property of any system that is capable of reproduction in the real world. Mutation rates are usually very low, and biological systems go to extraordinary lengths to keep them as low as possible, mostly because many mutational effects are harmful. Nonetheless, mutation rates never reach zero, even despite both low-level protective mechanisms, like DNA repair or proofreading during DNA replication, and high-level mechanisms, like melanin deposition in skin cells to reduce radiation damage. Beyond a certain point, avoiding mutation simply becomes too costly to cells. Thus, mutation will always be present as a powerful force in evolution.

Types of Mutations
So, how do mutations occur? The answer to this question is closely linked to the molecular details of how both DNA and the entire genome are organized. The smallest mutations are point mutations, in which only a single base pair is changed into another base pair. Yet another type of mutation is the nonsynonymous mutation, in which an amino acid sequence is changed. Such mutations lead to either the production of a different protein or the premature termination of a protein.

As opposed to nonsynonymous mutations, synonymous mutations do not change an amino acid sequence, although they occur, by definition, only in sequences that code for amino acids. Synonymous mutations exist because many amino acids are encoded by multiple codons. Base pairs can also have diverse regulating properties if they are located in introns, intergenic regions, or even within the coding sequence of genes. For some historic reasons, all of these groups are often subsumed with synonymous mutations under the label "silent" mutations. Depending on their function, such silent mutations can be anything from truly silent to extraordinarily important, the latter implying that working sequences are kept constant by purifying selection. This is the most likely explanation for the existence of ultraconserved noncoding elements that have survived for more than 100 million years without substantial change, as found by comparing the genomes of several vertebrates (Sandelin et al., 2004).

Mutations may also take the form of insertions or deletions, which are together known as indels. Indels can have a wide variety of lengths. At the short end of the spectrum, indels of one or two base pairs within coding sequences have the greatest effect, because they will inevitably cause a frameshift (only the addition of one or more three-base-pair codons will keep a protein approximately intact). At the intermediate level, indels can affect parts of a gene or whole groups of genes. At the largest level, whole chromosomes or even whole copies of the genome can be affected by insertions or deletions, although such mutations are usually no longer subsumed under the label indel. At this high level, it is also possible to invert or translocate entire sections of a chromosome, and chromosomes can even fuse or break apart. If a large number of genes are lost as a result of one of these processes, then the consequences are usually very harmful. Of course, different genetic systems react differently to such events.

Finally, still other sources of mutations are the many different types of transposable elements, which are small entities of DNA that possess a mechanism that permits them to move around within the genome. Some of these elements copy and paste themselves into new locations, while others use a cut-and-paste method. Such movements can disrupt existing gene functions (by insertion in the middle of another gene), activate dormant gene functions (by perfect excision from a gene that was switched off by an earlier insertion), or occasionally lead to the production of new genes (by pasting material from different genes together).

Effects of Mutations
A line graph shows the probability density of mutational effects. A log scale of mutational effects is shown on the x-axis, and probability density is shown on the y-axis. The line follows the shape of a right-skewed bell curve. Probability density increases as mutational effects increase from 10-10 to 10-4, where the curve peaks. As mutational effects increase from 10 4 to 1, probability density decreases. All mutational effects equal to or less than 10-10 are shown as a spike at 10-10 on the x-axis.
View Full-Size ImageFigure 1: The overwhelming majority of mutations have very small effects.
This example of a possible distribution of deleterious mutational effects was obtained from DNA sequence polymorphism data from natural populations of two Drosophila species. The spike at 10-10 includes all smaller effects, whereas effects are not shown if they induce a structural damage that is equivalent to selection coefficients that are 'super-lethal' (see Loewe and Charlesworth 2006 for more details).
© 2008 Nature Education All rights reserved. View Terms of Use
A single mutation can have a large effect, but in many cases, evolutionary change is based on the accumulation of many mutations with small effects. Mutational effects can be beneficial, harmful, or neutral, depending on their context or location. Most non-neutral mutations are deleterious. In general, the more base pairs that are affected by a mutation, the larger the effect of the mutation, and the larger the mutation's probability of being deleterious.

To better understand the impact of mutations, researchers have started to estimate distributions of mutational effects (DMEs) that quantify how many mutations occur with what effect on a given property of a biological system. In evolutionary studies, the property of interest is fitness, but in molecular systems biology, other emerging properties might also be of interest. It is extraordinarily difficult to obtain reliable information about DMEs, because the corresponding effects span many orders of magnitude, from lethal to neutral to advantageous; in addition, many confounding factors usually complicate these analyses. To make things even more difficult, many mutations also interact with each other to alter their effects; this phenomenon is referred to as epistasis. However, despite all these uncertainties, recent work has repeatedly indicated that the overwhelming majority of mutations have very small effects (Figure 1; Eyre-Walker & Keightley, 2007). Of course, much more work is needed in order to obtain more detailed information about DMEs, which are a fundamental property that governs the evolution of every biological system.

Estimating Rates of Mutation
Many direct and indirect methods have been developed to help estimate rates of different types of mutations in various organisms. The main difficulty in estimating rates of mutation involves the fact that DNA changes are extremely rare events and can only be detected on a background of identical DNA. Because biological systems are usually influenced by many factors, direct estimates of mutation rates are desirable. Direct estimates typically involve use of a known pedigree in which all descendants inherited a well-defined DNA sequence. To measure mutation rates using this method, one first needs to sequence many base pairs within this region of DNA from many individuals in the pedigree, counting all the observed mutations. These observations are then combined with the number of generations that connect these individuals to compute the overall mutation rate (Haag-Liautard et al., 2007). Such direct estimates should not be confused with substitution rates estimated over phylogenetic time spans.

Summary
Mutation rates can vary within a genome and between genomes. Much more work is required before researchers can obtain more precise estimates of the frequencies of different mutations. The rise of high-throughput genomic sequencing methods nurtures the hope that we will be able to cultivate a more detailed and precise understanding of mutation rates. Because mutation is one of the fundamental forces of evolution, such work will continue to be of paramount importance.

References and Recommended Reading
Drake, J. W., et al. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998)

Eyre-Walker, A., & Keightley, P. D. The distribution of fitness effects of new mutations. Nature Reviews Genetics 8, 610–618 (2007) doi:10.1038/nrg2146 (link to article)

Haag-Liautard, C., et al. Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007) doi:10.1038/nature05388 (link to article)

Loewe, L., & Charlesworth, B. Inferring the distribution of mutational effects on fitness in Drosophila. Biology Letters 2, 426–430 (2006)

Lynch, M., et al. Perspective: Spontaneous deleterious mutation. Evolution 53, 645–663 (1999)

Orr, H. A. The genetic theory of adaptation: A brief history. Nature Review Genetics 6, 119–127 (2005) doi:10.1038/nrg1523 (link to article)

Sandelin, A., et al. Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genomics 5, 99 (2004)

www.nature.com/scitable/topicpage/genetic-mutation-1127

"Consider, for example, the dragon. Basic physics will almost certainly combine with biological constraints to prevent the creation of flying or fire-breathing dragons.

But is it possible dragons could ever exist beyond the pages of Celtic mythology or the celluloid of fantasy film?
Academics have suggested in a recent essay the creation of large, winged dragons using cutting-edge genome editing is not beyond the realms of possibility.
Is the seemingly far-fetched idea a flier or, like dragon's breath, just hot air? The BBC asked the authors.
'Not impossible'
The essay in The American Journal of Bioethics said spectacular animals could be brought to life using a targeted gene-editing system known as CRISPR-CAS9.
Co-authors Prof Hank T Greely, director of the Centre for Law and the Biosciences at Stanford Law School, and Prof R Alta Charo, Professor of Bioethics and Law at Wisconsin Law School, said their dragon suggestion was "somewhat tongue-in-cheek" but "not impossible".
"There are the possibilities of spectacles," they wrote. "Animals and plants not created for personal use but to be exhibited.

"But a very large reptile that looks at least somewhat like the European or Asian dragon (perhaps with flappable if not flyable wings) could be someone's target of opportunity."
And it may not be as improbable as it seems at first blush.
CRISPR and other similar techniques involve DNA being inserted, replaced, or removed from a genome using artificially engineered nucleases.

The method has been adopted by scientists around the world.
CRISPRs (clustered regularly interspaced short palindromic repeats) are sections of DNA, while CAS-9 (CRISPR-associated protein 9) is an enzyme.
They are found in bacteria, which use them to disable attacks from viruses.
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They have led to the creation of patented "GloFish" that shine under UV light, the eradication of horns from certain cattle species, manipulation of crops and attempts to produce hypo-allergenic cats.
Artist Eduardo Kac even commissioned a French geneticist to create Alba, a genetically modified "glowing" rabbit.
Debate
Debate has raged over whether CRISPR, which occurs as part of a bacterial process, could be safely and ethically used on humans since 2012.
But professors Greely and Charo argue its potential to produce "CRISPR critters" is "likely to be overlooked" by legislators and regulators "because they are unexpected".
The method is "cheaper and easier" than older forms of genetic engineering and can be done "outside the traditional laboratory setting".
Their essay looks at the possible uses of CRISPR for de-extinction of wild species - such as 700,000-year-old horses - for domestic de-extinction - such as tomato species - and for making creatures of "personal whim".
They point out that Harvard geneticist George Church is using CRISPR to edit Asian elephant cell lines to give them some woolly mammoth genes.
Woolly mammothsImage copyrightTHINKSTOCK
Image caption
Geneticist are working on cloning or engineering woolly mammoths
Asked about the likelihood of dragons, the co-authors said: "We imagine it would be low although not impossible with respect to appearance (the fire-breathing and flying aspects are undoubtedly beyond any plausible genetic engineering).
"In the US, the determining factor is usually cost as compared to return-on-investment, where cost can be substantial given the regulatory hurdles.
"Does this mean some determined and well-funded geneticist might do this as an artistic experiment, similar to the work done on the fluorescing rabbit?
"Yes. But the operative word is 'might'."
A potential process could involve modifications to an existing large reptile - for instance, a Komodo dragon.
Problems
The professors said, even if scientists knew how to make them larger, there would likely be problems with the creature's mass increasing faster than its surface area or its bone cross-sections.
The first issue could make the animals overheat; the second might mean the edited reptile's bones would be too weak to hold its weight.
"If and when we actually come to understand in detail what every specific DNA sequence does and how they all fit together, though, all bets are off - things could move more quickly," they added.
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What does a CRISPR expert think?
Thinkstock
Dr Sam Sternberg - formerly of the University of California's Doudna Lab, which pioneered work with CRISPR-CAS9 - said his boundaries were stretched when Minnesota firm Recombinetics announced it had used a gene-editing technology to dehorn certain types of cattle.
However, he is not hopeful genetic engineers could ever cross the Rubicon to create dragons.
"You're talking about, not just one or a few changes, you're talking about massive changes and it gets to the point where, how much can you cut and paste the DNA that causes some of the traits of one species to another?
"I would say it's probably bordering on impossible/never going to happen."
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Even if the difficulties connected with gene editing could be overcome, there remains the tricky task of assisted reproduction with an existing lizard species.
Giving birth to any edited dragon would involve taking stem cells from, say, a Komodo dragon before inserting an altered nucleus into an egg for in vitro fertilization (IVF) in an adult komodo.
GloFish in an aquariumImage copyrightGETTY IMAGES
Image caption
Bright GloFish were genetically modified for fluorescence in aquariums
That would be no mean feat; in December scientists carried out the first successful IVF on dogs after decades of trying.
"If you got access to Komodo dragons and could quickly resolve the regulatory, stem cell, and assisted reproduction problems, you could start tinkering.
"But it would likely take a very long time before you could hope to get something that looked much like a dragon," Prof Greely and Prof Charo said.
So, how far off might all this be?
"A while," they said.

www.bbc.com/news/uk-wales-35111760

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