Editing Mutation (section)

==== Distribution of fitness effects (DFE) ====

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]],<ref>{{cite journal | vauthors = Charlesworth D, Charlesworth B, Morgan MT | title = The pattern of neutral molecular variation under the background selection model | journal = Genetics | volume = 141 | issue = 4 | pages = 1619–32 | date = December 1995 | doi = 10.1093/genetics/141.4.1619 | pmid = 8601499 | pmc = 1206892 | author-link1 = Deborah Charlesworth | author-link2 = Brian Charlesworth }}</ref> the rate of [[Pathogenomics#Gene Loss / Genome Decay|genomic decay]],<ref>{{cite journal | vauthors = Loewe L | title = Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA | journal = Genetical Research | volume = 87 | issue = 2 | pages = 133–59 | date = April 2006 | pmid = 16709275 | doi = 10.1017/S0016672306008123 | doi-access = free }}</ref> the maintenance of [[outcrossing]] [[sexual reproduction]] as opposed to [[inbreeding]]<ref>{{Cite book | vauthors = Bernstein H, Hopf FA, Michod RE | title = Molecular Genetics of Development | chapter = The molecular basis of the evolution of sex | series = Advances in Genetics | volume = 24 | pages = 323–70 | year = 1987 | pmid = 3324702 | doi = 10.1016/s0065-2660(08)60012-7 | isbn = 9780120176243 }}</ref> and the evolution of [[sex]] and [[genetic recombination]].<ref>{{cite journal | vauthors = Peck JR, Barreau G, Heath SC | title = Imperfect genes, Fisherian mutation and the evolution of sex | journal = Genetics | volume = 145 | issue = 4 | pages = 1171–99 | date = April 1997 | doi = 10.1093/genetics/145.4.1171 | pmid = 9093868 | pmc = 1207886 }}</ref> 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.<ref>{{cite journal | vauthors = Simcikova D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4 | bibcode = 2019NatSR...918577S }}</ref> In summary, the DFE plays an important role in predicting [[evolutionary dynamics]].<ref>{{cite journal | vauthors = Keightley PD, Lynch M | title = Toward a realistic model of mutations affecting fitness | journal = Evolution; International Journal of Organic Evolution | volume = 57 | issue = 3 | pages = 683–5; discussion 686–9 | date = March 2003 | pmid = 12703958 | doi = 10.1554/0014-3820(2003)057[0683:tarmom]2.0.co;2 | jstor = 3094781 | s2cid = 198157678 | author-link2 = Michael Lynch (geneticist) }}</ref><ref>{{cite journal | vauthors = Barton NH, Keightley PD | s2cid = 8934412 | title = Understanding quantitative genetic variation | journal = Nature Reviews Genetics | volume = 3 | issue = 1 | pages = 11–21 | date = January 2002 | pmid = 11823787 | doi = 10.1038/nrg700 | author-link1 = Nick Barton }}</ref> 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.<ref name="Sanjuán04">{{cite journal | vauthors = Sanjuán R, Moya A, Elena SF | title = The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 22 | pages = 8396–401 | date = June 2004 | pmid = 15159545 | pmc = 420405 | doi = 10.1073/pnas.0400146101 | bibcode = 2004PNAS..101.8396S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Carrasco P, de la Iglesia F, Elena SF | title = Distribution of fitness and virulence effects caused by single-nucleotide substitutions in Tobacco Etch virus | journal = Journal of Virology | volume = 81 | issue = 23 | pages = 12979–84 | date = December 2007 | pmid = 17898073 | pmc = 2169111 | doi = 10.1128/JVI.00524-07 }}</ref><ref>{{cite journal | vauthors = Sanjuán R | title = Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 365 | issue = 1548 | pages = 1975–82 | date = June 2010 | pmid = 20478892 | pmc = 2880115 | doi = 10.1098/rstb.2010.0063 }}</ref><ref>{{cite journal | vauthors = Peris JB, Davis P, Cuevas JM, Nebot MR, Sanjuán R | title = Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1 | journal = Genetics | volume = 185 | issue = 2 | pages = 603–9 | date = June 2010 | pmid = 20382832 | pmc = 2881140 | doi = 10.1534/genetics.110.115162 }}</ref> In ''[[Escherichia coli]]'', one study used [[transposon mutagenesis]] to directly measure the fitness of a random insertion of a derivative of [[Tn10]].<ref>{{cite journal | vauthors = Elena SF, Ekunwe L, Hajela N, Oden SA, Lenski RE | s2cid = 2267064 | title = Distribution of fitness effects caused by random insertion mutations in Escherichia coli | journal = Genetica | volume = 102–103 | issue = 1–6 | pages = 349–58 | date = March 1998 | pmid = 9720287 | doi = 10.1023/A:1017031008316 | author-link5 = Richard Lenski }}</ref> 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.<ref name="Hietpas11">{{cite journal | vauthors = Hietpas RT, Jensen JD, Bolon DN | title = Experimental illumination of a fitness landscape | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 19 | pages = 7896–901 | date = May 2011 | pmid = 21464309 | pmc = 3093508 | doi = 10.1073/pnas.1016024108 | bibcode = 2011PNAS..108.7896H | doi-access = free }}</ref> However, given that many mutations have effects too small to be detected<ref>{{cite journal | vauthors = Davies EK, Peters AD, Keightley PD | title = High frequency of cryptic deleterious mutations in Caenorhabditis elegans | journal = Science | volume = 285 | issue = 5434 | pages = 1748–51 | date = September 1999 | pmid = 10481013 | doi = 10.1126/science.285.5434.1748 }}</ref> and that mutagenesis experiments can detect only mutations of moderately large effect; DNA [[sequence analysis]] can provide valuable information about these mutations.

[[File:DFE in VSV.png|thumb|right|360px|The distribution of fitness effects (DFE) of mutations in [[vesicular stomatitis virus]]. In this experiment, random mutations were introduced into the virus by site-directed mutagenesis, and the [[Fitness (biology)|fitness]] of each mutant was compared with the ancestral type. A fitness of zero, less than one, one, more than one, respectively, indicates that mutations are lethal, deleterious, neutral, and advantageous.<ref name="Sanjuán04" />]]
* [[File:GOF diagram.png|thumb|This figure shows a simplified version of loss-of-function, switch-of-function, gain-of-function, and conservation-of-function 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.<ref>{{cite journal | vauthors = Loewe L, Charlesworth B | title = Inferring the distribution of mutational effects on fitness in Drosophila | journal = Biology Letters | volume = 2 | issue = 3 | pages = 426–30 | date = September 2006 | pmid = 17148422 | pmc = 1686194 | doi = 10.1098/rsbl.2006.0481 }}</ref><ref>{{cite journal | vauthors = Eyre-Walker A, Woolfit M, Phelps T | title = The distribution of fitness effects of new deleterious amino acid mutations in humans | journal = Genetics | volume = 173 | issue = 2 | pages = 891–900 | date = June 2006 | pmid = 16547091 | pmc = 1526495 | doi = 10.1534/genetics.106.057570 }}</ref><ref>{{cite journal | vauthors = Sawyer SA, Kulathinal RJ, Bustamante CD, Hartl DL | s2cid = 18051307 | title = Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection | journal = Journal of Molecular Evolution | volume = 57 | issue = 1 | pages = S154–64 | date = August 2003 | pmid = 15008412 | doi = 10.1007/s00239-003-0022-3 | author-link3 = Carlos D. Bustamante | citeseerx = 10.1.1.78.65 | bibcode = 2003JMolE..57S.154S }}</ref><ref>{{cite journal | vauthors = Piganeau G, Eyre-Walker A | title = Estimating the distribution of fitness effects from DNA sequence data: implications for the molecular clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 18 | pages = 10335–40 | date = September 2003 | pmid = 12925735 | pmc = 193562 | doi = 10.1073/pnas.1833064100 | bibcode = 2003PNAS..10010335P | doi-access = free }}</ref> 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.<ref name="Eyre-Walker07" /> 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.<ref name="Kimura-1983">{{cite book | vauthors = Kimura M |author-link=Motoo Kimura |year=1983 |title=The Neutral Theory of Molecular Evolution |location=Cambridge, UK; New York |publisher=[[Cambridge University Press]] |isbn=978-0-521-23109-1 |lccn=82022225 |oclc=9081989 |title-link=The Neutral Theory of Molecular Evolution }}</ref><ref>{{cite journal | vauthors = Kimura M | s2cid = 4161261 | title = Evolutionary rate at the molecular level | journal = Nature | volume = 217 | issue = 5129 | pages = 624–6 | date = February 1968 | pmid = 5637732 | doi = 10.1038/217624a0 | author-link = Motoo Kimura | bibcode = 1968Natur.217..624K }}</ref> A later proposal by Hiroshi Akashi proposed a [[Multimodal distribution|bimodal]] model for the DFE, with modes centered around highly deleterious and neutral mutations.<ref>{{cite journal | vauthors = Akashi H | title = Within- and between-species DNA sequence variation and the 'footprint' of natural selection | journal = Gene | volume = 238 | issue = 1 | pages = 39–51 | date = September 1999 | pmid = 10570982 | doi = 10.1016/S0378-1119(99)00294-2 }}</ref> 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]].<ref name="Sanjuán04" /> 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.<ref name="Hietpas11" /> 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.<ref>{{cite journal | vauthors = Eyre-Walker A | title = The genomic rate of adaptive evolution | journal = Trends in Ecology & Evolution | volume = 21 | issue = 10 | pages = 569–75 | date = October 2006 | pmid = 16820244 | doi = 10.1016/j.tree.2006.06.015 | bibcode = 2006TEcoE..21..569E }}</ref> 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]]<ref>{{cite journal | vauthors = Gillespie JH | author-link = John H. Gillespie |date=September 1984 |title=Molecular Evolution Over the Mutational Landscape |journal=Evolution |volume=38 |issue=5 |pages=1116–1129 |doi=10.2307/2408444 |pmid=28555784 |jstor=2408444}}</ref> and [[H. Allen Orr]].<ref>{{cite journal | vauthors = Orr HA | title = The distribution of fitness effects among beneficial mutations | journal = Genetics | volume = 163 | issue = 4 | pages = 1519–26 | date = April 2003 | doi = 10.1093/genetics/163.4.1519 | pmid = 12702694 | pmc = 1462510 | author-link = H. Allen Orr }}</ref> They proposed that the distribution for advantageous mutations should be [[exponential decay|exponential]] under a wide range of conditions, which, in general, has been supported by experimental studies, at least for strongly selected advantageous mutations.<ref>{{cite journal | vauthors = Kassen R, Bataillon T | s2cid = 6954765 | title = Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria | journal = Nature Genetics | volume = 38 | issue = 4 | pages = 484–8 | date = April 2006 | pmid = 16550173 | doi = 10.1038/ng1751 }}</ref><ref>{{cite journal | vauthors = Rokyta DR, Joyce P, Caudle SB, Wichman HA | s2cid = 20296781 | title = An empirical test of the mutational landscape model of adaptation using a single-stranded DNA virus | journal = Nature Genetics | volume = 37 | issue = 4 | pages = 441–4 | date = April 2005 | pmid = 15778707 | doi = 10.1038/ng1535 }}</ref><ref>{{cite journal | vauthors = Imhof M, Schlotterer C | title = Fitness effects of advantageous mutations in evolving Escherichia coli populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 3 | pages = 1113–7 | date = January 2001 | pmid = 11158603 | pmc = 14717 | doi = 10.1073/pnas.98.3.1113 | bibcode = 2001PNAS...98.1113I | doi-access = free }}</ref>

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.<ref name="Eyre-Walker07" /> In addition, the DFE also differs between coding regions and [[Noncoding DNA|noncoding region]]s, with the DFE of noncoding DNA containing more weakly selected mutations.<ref name="Eyre-Walker07" />