Editing Cystic fibrosis (section)

===Evolution===
The ΔF508 mutation is estimated to have occurred up to 52,000 years ago.<ref name="pmid11556136">{{cite journal | vauthors = Wiuf C | title = Do delta F508 heterozygotes have a selective advantage? | journal = Genetical Research | volume = 78 | issue = 1 | pages = 41–47 | date = August 2001 | pmid = 11556136 | doi = 10.1017/S0016672301005195 | citeseerx = 10.1.1.174.7283 }}</ref> Numerous hypotheses have been advanced as to why such a lethal allele has persisted and spread in the human population. Other common autosomal recessive diseases such as [[sickle-cell anemia]] have been found to protect carriers from other diseases, an [[evolutionary trade-off]] known as [[heterozygote advantage]]. Resistance to the following have all been proposed as possible sources of heterozygote advantage:
* [[Cholera]]: With the discovery that [[cholera toxin]] requires normal host CFTR proteins to function properly, it was hypothesized that carriers of mutant ''CFTR'' alleles benefited from resistance to cholera and other causes of diarrhea.<ref name="pmid7524148">{{cite journal | vauthors = Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ | title = Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model | journal = Science | volume = 266 | issue = 5182 | pages = 107–109 | date = October 1994 | pmid = 7524148 | doi = 10.1126/science.7524148 | bibcode = 1994Sci...266..107G }}</ref><ref name="pmid20110149">{{cite journal | vauthors = Alfonso-Sánchez MA, Pérez-Miranda AM, García-Obregón S, Peña JA | title = An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations | journal = Medical Hypotheses | volume = 74 | issue = 6 | pages = 989–992 | date = June 2010 | pmid = 20110149 | doi = 10.1016/j.mehy.2009.12.018 }}</ref> Further studies have not confirmed this hypothesis.<ref name="pmid7714835">{{cite journal | vauthors = Cuthbert AW, Halstead J, Ratcliff R, Colledge WH, Evans MJ | title = The genetic advantage hypothesis in cystic fibrosis heterozygotes: a murine study | journal = The Journal of Physiology | volume = 482 | issue = Pt 2 | pages = 449–454 | date = January 1995 | pmid = 7714835 | pmc = 1157742 | doi = 10.1113/jphysiol.1995.sp020531 }}</ref><ref name="pmid11055897">{{cite journal | vauthors = Högenauer C, Santa Ana CA, Porter JL, Millard M, Gelfand A, Rosenblatt RL, Prestidge CB, Fordtran JS | title = Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion | journal = American Journal of Human Genetics | volume = 67 | issue = 6 | pages = 1422–1427 | date = December 2000 | pmid = 11055897 | pmc = 1287919 | doi = 10.1086/316911 }}</ref>
* [[Typhoid fever|Typhoid]]: Normal CFTR proteins are also essential for the entry of [[Salmonella Typhi|''Salmonella'' Typhi]] into cells,<ref name="pmid9590693">{{cite journal | vauthors = Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G, Ratcliff R, Evans MJ, Colledge WH | title = Salmonella typhi uses CFTR to enter intestinal epithelial cells | journal = Nature | volume = 393 | issue = 6680 | pages = 79–82 | date = May 1998 | pmid = 9590693 | doi = 10.1038/30006 | s2cid = 5894247 | bibcode = 1998Natur.393...79P }}</ref> suggesting that carriers of mutant ''CFTR'' genes might be resistant to [[typhoid fever]]. No ''in vivo'' study has yet confirmed this. In both cases, the low level of cystic fibrosis outside of Europe, in places where both cholera and typhoid fever are [[endemic (epidemiology)|endemic]], is not immediately explicable.
* [[Diarrhea]]: The prevalence of CF in Europe might be connected with the development of cattle domestication. In this hypothesis, carriers of a single mutant ''CFTR'' allele had some protection from diarrhea caused by [[lactose intolerance]], before the mutations that created lactose tolerance appeared.<ref name="pmid17180122">{{cite journal | vauthors = Modiano G, Ciminelli BM, Pignatti PF | title = Cystic fibrosis and lactase persistence: a possible correlation | journal = European Journal of Human Genetics | volume = 15 | issue = 3 | pages = 255–259 | date = March 2007 | pmid = 17180122 | doi = 10.1038/sj.ejhg.5201749 | hdl-access = free | s2cid = 4650571 | hdl = 2108/29185 }}</ref>
* [[Tuberculosis]]: Another possible explanation is that carriers of the mutant allele could have some resistance to tuberculosis.<ref name="pmid17015291">{{cite journal | vauthors = Poolman EM, Galvani AP | title = Evaluating candidate agents of selective pressure for cystic fibrosis | journal = Journal of the Royal Society, Interface | volume = 4 | issue = 12 | pages = 91–98 | date = February 2007 | pmid = 17015291 | pmc = 2358959 | doi = 10.1098/rsif.2006.0154 }}</ref><ref name="Williams-2006">{{cite journal |doi=10.1016/j.cub.2006.09.009 |title=Footprint fears for new TB threat |year=2006 | vauthors = Williams N |s2cid=2346727 |journal=Current Biology |volume=16 |issue=19 |pages=R821–R822|doi-access=free |bibcode=2006CBio...16.R821W }}</ref> This hypothesis is based on the thesis that ''CFTR'' mutant allele carriers have insufficient action in one of their enzymes – arylsulphatase – which is necessary for ''Mycobacterium tuberculosis'' virulence. As ''M. tuberculosis'' would use its host's sources to affect the individual, and due to the lack of enzyme it could not present its virulence, being a carrier of ''CFTR ''mutant allele could provide resistance against tuberculosis.<ref name="pmid12796199">{{cite journal | vauthors = Tobacman JK | title = Does deficiency of arylsulfatase B have a role in cystic fibrosis? | journal = Chest | volume = 123 | issue = 6 | pages = 2130–2139 | date = June 2003 | pmid = 12796199 | doi = 10.1378/chest.123.6.2130 }}</ref>