Editing Evolvability (section)

==Applications==
Evolvability phenomena have practical applications. For [[protein engineering]] we wish to increase evolvability, and in medicine and agriculture we wish to decrease it. Protein evolvability is defined as the ability of the protein to acquire sequence diversity and conformational flexibility which can enable it to evolve toward a new function.<ref name="SoskineTawfik2010">{{cite journal | vauthors = Soskine M, Tawfik DS | title = Mutational effects and the evolution of new protein functions | journal = Nature Reviews Genetics | volume = 11 | issue = 8 | pages = 572–82 | date = August 2010 | pmid = 20634811 | doi = 10.1038/nrg2808 | s2cid = 8951755 }}</ref>

In [[protein engineering]], both rational design and [[directed evolution]] approaches aim to create changes rapidly through mutations with large effects.<ref>{{cite journal | vauthors = Carter PJ | title = Introduction to current and future protein therapeutics: a protein engineering perspective | journal = Experimental Cell Research | volume = 317 | issue = 9 | pages = 1261–9 | date = May 2011 | pmid = 21371474 | doi = 10.1016/j.yexcr.2011.02.013 }}</ref><ref>{{cite journal | vauthors = Bommarius AS, Blum JK, Abrahamson MJ | title = Status of protein engineering for biocatalysts: how to design an industrially useful biocatalyst | journal = Current Opinion in Chemical Biology | volume = 15 | issue = 2 | pages = 194–200 | date = April 2011 | pmid = 21115265 | doi = 10.1016/j.cbpa.2010.11.011 }}</ref> Such mutations, however, commonly destroy [[enzyme catalysis |enzyme function]] or at least reduce [[robustness (evolution) |tolerance to further mutations]].<ref>{{cite journal | vauthors = Tokuriki N, Tawfik DS | title = Stability effects of mutations and protein evolvability | journal = Current Opinion in Structural Biology | volume = 19 | issue = 5 | pages = 596–604 | date = October 2009 | pmid = 19765975 | doi = 10.1016/j.sbi.2009.08.003 }}</ref><ref>{{cite journal | vauthors = Wang X, Minasov G, Shoichet BK | title = Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs | journal = Journal of Molecular Biology | volume = 320 | issue = 1 | pages = 85–95 | date = June 2002 | pmid = 12079336 | doi = 10.1016/s0022-2836(02)00400-x }}</ref> Identifying evolvable proteins and manipulating their evolvability is becoming increasingly necessary in order to achieve ever larger functional modification of enzymes.<ref>{{cite journal | vauthors = O'Loughlin TL, Patrick WM, Matsumura I | title = Natural history as a predictor of protein evolvability | journal = Protein Engineering, Design & Selection | volume = 19 | issue = 10 | pages = 439–42 | date = October 2006 | pmid = 16868005 | doi = 10.1093/protein/gzl029 | doi-access = free }}</ref> Proteins are also often studied as part of the basic science of evolvability,  because the  biophysical properties and chemical functions can be easily changed by a few mutations.<ref name="pmid21408208">{{cite journal | vauthors = Salverda ML, Dellus E, Gorter FA, Debets AJ, van der Oost J, Hoekstra RF, Tawfik DS, de Visser JA | title = Initial mutations direct alternative pathways of protein evolution | journal = PLOS Genetics | volume = 7 | issue = 3 | pages = e1001321 | date = March 2011 | pmid = 21408208 | pmc = 3048372 | doi = 10.1371/journal.pgen.1001321 | doi-access = free }}</ref><ref name="pmid16581913">{{cite journal | vauthors = Bloom JD, Labthavikul ST, Otey CR, Arnold FH | title = Protein stability promotes evolvability | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 15 | pages = 5869–74 | date = April 2006 | pmid = 16581913 | pmc = 1458665 | doi = 10.1073/pnas.0510098103 | bibcode = 2006PNAS..103.5869B | doi-access = free }}</ref> More evolvable proteins can tolerate a broader range of amino acid changes and allow them to evolve toward new functions. The study of evolvability has fundamental importance for understanding very long term evolution of [[protein superfamilies]].<ref>{{cite journal | vauthors = Ranea JA, Sillero A, Thornton JM, Orengo CA | title = Protein superfamily evolution and the last universal common ancestor (LUCA) | journal = Journal of Molecular Evolution | volume = 63 | issue = 4 | pages = 513–25 | date = October 2006 | pmid = 17021929 | doi = 10.1007/s00239-005-0289-7 | bibcode = 2006JMolE..63..513R | s2cid = 25258028 }}</ref><ref>{{cite journal | vauthors = Dellus-Gur E, Toth-Petroczy A, Elias M, Tawfik DS | title = What makes a protein fold amenable to functional innovation? Fold polarity and stability trade-offs | journal = Journal of Molecular Biology | volume = 425 | issue = 14 | pages = 2609–21 | date = July 2013 | pmid = 23542341 | doi = 10.1016/j.jmb.2013.03.033 }}</ref><ref>{{cite book |last=Wagner |first=Andreas | name-list-style = vanc |author-link = Andreas Wagner |title=The origins of evolutionary innovations : a theory of transformative change in living systems |publisher=Oxford University Press |isbn=978-0-19-969259-0|date=2011-07-14 }}</ref><ref>{{cite book | first1 = Alessandro | last1 = Minelli | first2 = Geoffrey | last2 = Boxshall | first3 = Giuseppe | last3 = Fusco | name-list-style = vanc |title=Arthropod biology and evolution : molecules, development, morphology |publisher=Springer |isbn=978-3-642-36159-3| date = 2013-04-23 }}</ref><ref>{{cite journal | vauthors = Pigliucci M | title = Is evolvability evolvable? | journal = Nature Reviews Genetics | volume = 9 | issue = 1 | pages = 75–82 | date = January 2008 | pmid = 18059367 | doi = 10.1038/nrg2278 | s2cid = 3164124 | author-link = Massimo Pigliucci | url = https://philpapers.org/archive/PIGIEE.pdf }}</ref>

Many human diseases are capable of evolution. [[Viruses]], bacteria, fungi and cancers evolve to be resistant to host [[immune system |immune defences]], as well as [[pharmaceutical drug]]s.<ref>{{cite journal | vauthors = Merlo LM, Pepper JW, Reid BJ, Maley CC | title = Cancer as an evolutionary and ecological process | journal = Nature Reviews. Cancer | volume = 6 | issue = 12 | pages = 924–35 | date = December 2006 | pmid = 17109012 | doi = 10.1038/nrc2013 | s2cid = 8040576 }}</ref><ref>{{cite journal | vauthors = Pan D, Xue W, Zhang W, Liu H, Yao X | title = Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: a computational study | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1820 | issue = 10 | pages = 1526–34 | date = October 2012 | pmid = 22698669 | doi = 10.1016/j.bbagen.2012.06.001 }}</ref><ref>{{cite journal | vauthors = Woodford N, Ellington MJ | title = The emergence of antibiotic resistance by mutation | journal = Clinical Microbiology and Infection | volume = 13 | issue = 1 | pages = 5–18 | date = January 2007 | pmid = 17184282 | doi = 10.1111/j.1469-0691.2006.01492.x | doi-access = free }}</ref> These same problems occur in agriculture with [[pesticide]]<ref>{{cite journal | vauthors = Labbé P, Berticat C, Berthomieu A, Unal S, Bernard C, Weill M, Lenormand T | title = Forty years of erratic insecticide resistance evolution in the mosquito Culex pipiens | journal = PLOS Genetics | volume = 3 | issue = 11 | pages = e205 | date = November 2007 | pmid = 18020711 | pmc = 2077897 | doi = 10.1371/journal.pgen.0030205 | doi-access = free }}</ref> and [[herbicide]]<ref>{{cite journal | vauthors = Neve P |title=Challenges for herbicide resistance evolution and management: 50 years after Harper |journal=Weed Research |date=October 2007 |volume=47 |issue=5 |pages=365–369 |doi=10.1111/j.1365-3180.2007.00581.x|doi-access= |bibcode=2007WeedR..47..365N }}</ref> resistance. It is possible that we are facing the end of the effective life of most of available [[antibiotics]].<ref>{{cite journal | vauthors = Rodríguez-Rojas A, Rodríguez-Beltrán J, Couce A, Blázquez J | title = Antibiotics and antibiotic resistance: a bitter fight against evolution | journal = International Journal of Medical Microbiology | volume = 303 | issue = 6–7 | pages = 293–7 | date = August 2013 | pmid = 23517688 | doi = 10.1016/j.ijmm.2013.02.004 }}</ref> Predicting the evolution and evolvability<ref>{{cite journal | vauthors = Schenk MF, Szendro IG, Krug J, de Visser JA | title = Quantifying the adaptive potential of an antibiotic resistance enzyme | journal = PLOS Genetics | volume = 8 | issue = 6 | pages = e1002783 | date = June 2012 | pmid = 22761587 | pmc = 3386231 | doi = 10.1371/journal.pgen.1002783 | doi-access = free }}</ref> of our pathogens, and devising strategies to slow or circumvent the development of resistance, demands deeper knowledge of the complex forces driving evolution at the molecular level.<ref>{{cite journal | vauthors = Read AF, Lynch PA, Thomas MB | title = How to make evolution-proof insecticides for malaria control | journal = PLOS Biology | volume = 7 | issue = 4 | pages = e1000058 | date = April 2009 | pmid = 19355786 | pmc = 3279047 | doi = 10.1371/journal.pbio.1000058 | doi-access = free }}</ref>

A better understanding of evolvability is proposed to be part of an [[Extended Evolutionary Synthesis]].<ref>{{cite journal | vauthors = Pigliucci M | title = Do we need an extended evolutionary synthesis? | journal = Evolution; International Journal of Organic Evolution | volume = 61 | issue = 12 | pages = 2743–9 | date = December 2007 | pmid = 17924956 | doi = 10.1111/j.1558-5646.2007.00246.x | s2cid = 2703146 | author-link = Massimo Pigliucci | url = https://philpapers.org/archive/PIGDWN.pdf | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pigliucci M | title = An extended synthesis for evolutionary biology | journal = Annals of the New York Academy of Sciences | volume = 1168 | issue = 1 | pages = 218–28 | date = June 2009 | pmid = 19566710 | doi = 10.1111/j.1749-6632.2009.04578.x | author-link = Massimo Pigliucci | bibcode = 2009NYASA1168..218P | s2cid = 5710484 | url = https://philpapers.org/archive/PIGAES.pdf }}</ref><ref>{{cite journal | vauthors = Danchin É, Charmantier A, Champagne FA, Mesoudi A, Pujol B, Blanchet S | title = Beyond DNA: integrating inclusive inheritance into an extended theory of evolution | journal = Nature Reviews Genetics | volume = 12 | issue = 7 | pages = 475–86 | date = June 2011 | pmid = 21681209 | doi = 10.1038/nrg3028 | s2cid = 8837202 }}</ref>