tag:blogger.com,1999:blog-1812431336777691886.post6628527664035444633..comments2024-02-29T03:57:00.088-05:00Comments on The Mermaid's Tale: K13 and the spread (or simultaneous emergence) of drug resistance in malaria parasitesAnne Buchananhttp://www.blogger.com/profile/09212151396672651221noreply@blogger.comBlogger9125tag:blogger.com,1999:blog-1812431336777691886.post-10317847122797557272014-11-20T10:02:26.685-05:002014-11-20T10:02:26.685-05:00Oh, but look! There's a 'happy gene'!Oh, but look! There's a <a href="http://www.theguardian.com/science/2014/nov/20/happy-gene-romantic-relationship-serotonin-romance" rel="nofollow">'happy gene'!</a>Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-60969772826801323572014-11-20T09:34:32.896-05:002014-11-20T09:34:32.896-05:00Yes, I completely agree. I didn't mean to sug...Yes, I completely agree. I didn't mean to suggest that the gene evolved because of malaria. However, from what you've written and what I've seen elsewhere, the gene is functionally related to the biology of malaria, even if there's no reason to assume it evolved because of malaria. It's sort of what Gould and Lewontin called a 'spandrel' in the sense that, if I understand things, it exists for some biological function in the 'normal' organism but took on a new function in the presence of the parasite.Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-89445928224001600732014-11-20T09:25:13.340-05:002014-11-20T09:25:13.340-05:00I agree, Dan. I always go back to genes 'for&#...I agree, Dan. I always go back to genes 'for' spermatozoa... expressed all over the developing embryo. That is, given pleiotropy, perhaps the best one can say is, 'this variant of this gene does this in this context." Whether or not the full context (genomic background/environment) can ever be known is another question.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-18661719857456836712014-11-20T09:21:51.889-05:002014-11-20T09:21:51.889-05:00Hi Ken,
Put that way, yes. But typically when pe...Hi Ken, <br />Put that way, yes. But typically when people are talking about a gene "for" something, I think there is an assumption that the genes function is directly related to it. That is, there tends to be a perception that the gene is intended to do something specific - probably what the gene is normally associated with. In this situation at least its not that way at all. For whatever reason, when there is a mutation in this gene, it happens to help the parasite out when it is exposed to a specific drug. So perhaps what I mean, but didn't really flesh out, is that the concept of a gene being "for something" can be a bit strange given that a gene can be related to multiple outcomes. But perhaps even the concept of a gene as some discrete, easily definable entity is also a bit strange. Anonymoushttps://www.blogger.com/profile/05068601494828074316noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-81700838229531605532014-11-20T09:08:16.272-05:002014-11-20T09:08:16.272-05:00Dan,
Doesn't the evidence that the variants se...Dan,<br />Doesn't the evidence that the variants seem (at least in the Nature paper, which listed several criteria) to be related to rapid adaptation, and malaria is a highly plausible cause given the pattern, make the phrase 'resistance gene' at least sensible (in the same sense that one calls BRCA a 'breast cancer' gene)? In this case, what is selected is K13's de facto resistance functions.Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-35926852888990525452014-11-20T09:02:21.226-05:002014-11-20T09:02:21.226-05:00Hi Anonymous,
I mostly agree - my question about w...Hi Anonymous,<br />I mostly agree - my question about whether K13 is a resistance gene was a rhetorical question. Anonymoushttps://www.blogger.com/profile/05068601494828074316noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-37869268494748010242014-11-20T08:53:28.203-05:002014-11-20T08:53:28.203-05:00If I correctly read the Ariey et al paper in Natur...If I correctly read the Ariey et al paper in Nature last January, that Dan cited, there are several mutations in the 'propeller' part of the K13 gene, that were separately tested for artemisinin resistance. I think each case includes just one such mutation, not multiple ones in the same copy of the gene.<br /><br />If my reading is correct, what is found is that several different codon-changing mutations are associated with some quantitative differences in parasite clearance. The differences vary by mutation, and they overlap normal to some extent. The different mutations do not (apparently) inactivate the gene as "anonymous" assumes, but in differing ways destabilize the protein. This seems consistent with Dan's description of the data.<br /><br />The quantitative aspects probably aren't the same as inactivating mutations, but whether that's a major difference, a point that quantitative vs qualitative effects could be useful in applying treatment or prevention approaches etc. is something I have no idea about. <br /><br />That the authors show evidence of selection certainly suggests that this is an important part of the protein and that the evolutionary reconstruction makes sense.<br /><br />Multiple independent, regionally different genetic pathways to something strongly selected is what we should expect, is what the malaria story has previously shown (globins, G6PD, etc), and seems to show how challenging this all still is.<br /><br />So this is a very interesting post!Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-57344085406112482582014-11-20T08:32:45.130-05:002014-11-20T08:32:45.130-05:00The question here would be what sorts of mutations...The question here would be what sorts of mutations have been found. Are they all inactivating mutations? Or are some changes of other types, like regulatory. Or of unknown effect (at least unknown from informatic analysis)? Most 'disease' genes are found to have many different mutations in different patients, and only a few are clearly understood in terms of what they do to the protein. So knowing what's been found so far would be important and probably many people are working on this?Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-34546352438724282462014-11-20T08:02:33.186-05:002014-11-20T08:02:33.186-05:00Calling K13 a artemisinin resistance gene is a bit...Calling K13 a artemisinin resistance gene is a bit like calling CCR5 a HIV resistance gene. Just about any inactivating mutation will confer this resistance. Perhaps K13 allows artemisinin to enter the cell and disrupt some process, but the malaria parasite can survive without K13.Anonymousnoreply@blogger.com