APOB Arthur Hunt atherosclerosis Atherosclerosis Supplements biology blubber brown bears Cell (journal) cholesterol Clinical Chemistry Darwin Devolves devolution Evolution fat metabolism high fat diet hypobetalipoproteinaemia hypobetalipoproteinemia Intelligent Design Journal of Lipid Research Journal of Medical Genetics Latest lipoproteins Liu et al. (2014) mice Michael Behe mutations Nathan Lents Nature Reviews Genetics New Scientist Polar Bear Seminar polar bears PolyPhen-2 Richard Lenski S. Joshua Swamidass Shiping Liu T_aquaticus The Journal of Biological Chemistry

Polar Bear Seminar: New proof that Michael Behe ​​is right

Behe ​​

Crucial query within the discussion throughout Darwin Devolves is whether Michael Behe ​​rightly claimed that the polar bear APOB skilled disruptive mutations. Initially, flushing could seem shocking that this specific gene has develop into the middle of dialogue. In any case, Behe's guide presents many examples of genes with adaptive but degrading mutations. Perhaps all the eye is because APOB is among the examples he provides originally of the e-book.

Regardless of the cause, it’s clear from APOB that most everybody agrees and some things are less clear. The latter isn’t surprisingly controversial. As we all know, the Behe ​​thesis is cheap. It’s supported by good proof. Listed here are some the reason why this is the case. This submit is a collection of the Polar Bear Seminar collection, and presents lately unpublished evidence that strongly helps Bee's vision.

Where everyone agrees

Most everybody agrees that APOB helps regulate ldl cholesterol within the blood. Everybody also agrees that the gene has played an essential position within the improvement of polar bears with a brown bear. The polar bears needed to develop ways of coping with a high-fat food regimen, in all probability also for decreasing cholesterol. As Behe ​​explains in Darwin Devolves:

Probably the most strongly chosen mutations of the polar bear – and thus crucial for its survival – occurred in the APOB gene, which is involved in fats metabolism in mammals, together with humans. It isn’t shocking in itself as a result of the polar bear food plan incorporates a very giant portion of the fats (a lot larger than the brown bear weight-reduction plan) from the sealing plate, so we might anticipate metabolic modifications to adapt it.

what precisely did the polar bear modifications with APOB in comparison with different mammals?

(Darwin Devolves, pp. 16-17)

The last sentence raises the key query for dialogue: Did APOB mutations break down – as Behe ​​puts it "likely to break down or destroy the function of the protein that encodes the gene" – or whether they are constructive, enhance gene perform and perhaps create new biochemical features? One drawback is that no one knows precisely what APOB is doing in polar bears. As Behe ​​factors out, it is extremely troublesome to do experiments with "brash polar bears."

But what about APOB in people? This message offers new proof that human apoB proteins have a number of features reminiscent of blood ldl cholesterol removing and cholesterol loading Several Bee e-book critics assume that APOB's activity is to take away ldl cholesterol from blood, and that the polar ldl cholesterol cholesterol is lowered by constructive mutations in APOB Richard Lenski wrote that the mutations of APOB

won’t injury the protein in any respect, however quite probably improved certainly one of its activities, specifically the clearance of cholesterol from the blood of a species that remains at a really high degree.

It's attainable, however it is probably not needed. It turns out that in people, APOB produces a number of totally different proteins with totally different features. One of many features of the proteins produced by APOB is the loading of ldl cholesterol into the blood. Injury to the action of such a protein can result in a decrease in ldl cholesterol.

Actually, a number of medical research have found that unambiguous mutations in APOBs end in shortened and malfunctioning variations of apoB proteins related to decrease ldl cholesterol – probably related to polar bears. There isn’t any need – no valid purpose – for Behe's critics to assume that APOB's sole perform is to remove cholesterol from the blood and that the one means for APOB to scale back ldl cholesterol is a constructive mutation that increases this perform. APOB decaying mutations look like adequate for work.

However first we have to make clear a number of the false claims promoted by Behe's critics.

Reply by Joshua Swamidass

As mentioned in the above-mentioned collection, Behe ​​Darwin at Devolves referred to Liu et al. The authors carried out a computer research that predicted that mutations broken numerous polar bear genes. Particularly, APOB acquired the very best attainable score – 100% chance – that a computer program might produce a prediction that the gene was damaged. One of the crucial vital findings of the paper was that "a large part (about 50%) of the mutations were predicted to be functionally damaging" in positively selected polar bear genes, including APOB.

Some critics read Liu et al. much in another way. They argued that "the authors do not expect the fracture or damage of the polar bear's APOB" and that "There is no evidence of Behe ​​& # 39; s claim that APOB is weakened or reduced in polar bears."

The above-mentioned APOB corresponded above these critics in nice detail. Biologist Joshua Swamidass has now written a response referred to as "Is Polar Bear ApoB Damaged?" In it, he additionally claims that the thought that Liu et al. Consider that APOB is broken ”is totally and utterly incorrect. His lengthy discussions are appreciated, but he didn’t fulfill our request that critics give Liu et al. the place the authors conflict with their very own findings and find that APOB was not broken. As an alternative, he makes a wierd argument. Based on Swamidass, if the abstract doesn’t include the word "damaged" in describing APOB, then the authors can’t consider that the gene was broken. He writes:

Word that they didn’t call ApoB "damaged." Why not? There isn’t a cause to assume that ApoB is broken. The summaries are the conclusions, and this is the primary conclusion of this document.

Sometimes, the abstract incorporates the "home" conclusions of the scientific paper. Nevertheless, they’re basic summaries and by no means cover all the outcomes and results of a specific analysis. So when Dr. Swamidass is right that the abstract doesn’t use the word "damaged" this level is irrelevant. The authors use this phrase within the Results and Discussion section. There they are saying, as said above, that "a large part (about 50%) of the mutations were predicted to be functionally damaging." This is meant to cowl the APOB mutations of the gene, as proven in Determine 4 and the paper context. Dr. Swamidass has just rejected this language as a "borrowing mine" and was merely mistaken claiming that "they did not call APOB" damaged "or" There isn’t a purpose to assume that ApoB is damaged. "It is certainly not" utterly and utterly false "to note that the paper predicts that the gene was broken.

As well as, the abstract does not say that APOB was not broken. So if Swamidass is right that in all instances "The abstract is where the conclusions are presented", the paper has no logic to conclude that APOB is just not damaged, as a result of the summary does not imply it. Here is the key language of the summary:

One of the genes with the strongest evidence of selection, APOB encodes the low density lipoprotein (LDL) main lipoprotein element; APOB useful mutations can explain how polar bears can deal with lifetime elevated LDL levels related to high danger of human coronary heart disease.

The question is whether these mutations weakened or improved APOB exercise, however the abstract doesn’t deal with it in a method or one other. What’s necessary is that, as we’ve seen, the paper is able to absolutely deal with whether the genes are "damaged" – and when it does, it all the time predicts that the injury has occurred. Nevertheless, the abstract does not mean that the APOB is "damaged" or "damaged"; it simply does not cope with this specific challenge.

Properly, then paper area elsewhere, which was not damaged by APOB? No, it isn’t.

Swamidass tries once more

Dr. Swamidass quotes paper once more – language which we mentioned extensively in our previous APOB mail He focuses on a sentence stating that: "We propose that the shift to a diet consisting mainly of polar bear fatty acids caused adaptive changes in APOB, allowing the species to cope with high fatty acid intake by affecting effective cholesterol clearance from the blood. “Unfortunately, as already explained, that sentence does not state that APOB experienced constructive mutations. The sentence may be perfectly correct, but it merely states that mutations in APOB resulted in "effective clearance" of cholesterol from the blood. A language for "effective purification" means that the effective or remaining result of gene mutations is less ldl cholesterol within the blood. But the phrase, like some other paper, doesn’t imply that cholesterol is cleared of blood. Here is what we wrote earlier, just to verify:

When [Nathan] Lents and [Arthur] Hunt declare that APOB mutations "are likely to increase apoB activity," it's their very own speculation. They consider the statement within the doc that "adaptive changes in APOB" allowed the species to outlive from high fatty acid intake by contributing to the efficient blood clearance of cholesterol. " Perhaps this is true, however there isn’t any proof in the paper that the removing of cholesterol was carried out by constructive mutations. Certainly, as Behe ​​pointed out, cholesterol might be eradicated by decreasing the exercise of APOB

For a moment, I return to Behe ​​& # 39; s point that cholesterol may be removed by damaging APOB. It’s now that Swamidass places words within the mouth of the authors, claiming that APOB was not damaged.

Information from New Scientist

Dr. Then Swamidass mentions the information article in New Scientist. The article does not necessarily present the views of Liu et al., Nevertheless it says very similar to paper. Swamidass quotes from one paper writer: "The APOB variant of the polar bear must be with the transport and storage of cholesterol … Maybe it makes the process more efficient." As Liu et al., This claim doesn’t claim that useful modifications in APOB have been the result of mutations that have been degradable or constructive. As an alternative, it uses a very cautious language to take a position that "Maybe it makes the process more efficient." But what sort of mutations did the process intensify – decomposing or constructive? It doesn't say.

At this level, the critic might say, "The process of" more environment friendly "calling means that they believe that the function is improved or improved biochemically." When Michael Behe ​​reminds us of Darwin Devolves, "streamlining" the process might be achieved by decomposing means:

[A] a helpful mutation (in itself that the deletion mutation elevated the cell progress fee by 1-2%) to be a disruptive mutation through which the lack of present genetic capacity improved the survival of micro organism.

How can it’s? How can lack of potential be helpful? Properly, what could possibly be the fastest and easiest method to enhance your car's fuel mileage, different points are misplaced? A method is to eliminate unnecessary weight loss from spare tires, hoods or even doors or windshields. In fact, this stuff may be useful in some future circumstances, but when crucial think about your survival right now’s fuel mileage, it might be helpful to drop what you save. In the event you have been sinking on board and you must hold it on the floor till it received to the seashore, they threw them over heavy unnecessary gear, regardless of how refined computer systems, radios, cargo-winning survival strategy.

(Darwin Devolves, p. 176)

An important point in Darwin Devolves is that modifications that benefit the organism – even by making the method "more effective" – ​​might rely upon degradable modifications on the molecular degree. Solely finding a "more efficient" process shouldn’t be a vital contradiction to Behe's dissertation.

Swamidass then categorically quotes Richard Lensk, saying that APOB mutations "possibly improved some of its activity, ie, the clearance of cholesterol from the blood." But the next sentence within the news article – not Swamidass or his supply Richard Lenski quotes – admits that we don't even know APOB's activities in polar bears:

It's not clear what gene variants [of APOB] do for polar bears, but Nielsen hopes discover them by putting them

This is according to Liu et al. it states that "there is a puzzle of how polar bears can handle such lifetime elevated cholesterol levels." If the supply admits that we do not even know what APOB does or how the polar bears survive the high cholesterol, how can we mention that the supply claims that APOB mutations "improved some of its activities" (as Lenski wrote) or "enhance this function" (as Lents and Hunt wrote) a polar drug to lower ldl cholesterol?

Confusion About PolyPhen-2

Information of what APOB does in polar bears and how it helps them to deal with a fats food regimen, is the perfect evidence of how mutations affect the gene from the outcomes of Liu et al. By PolyPhen-2 , which in contrast the sequence of APOB within the polar shell to the sequence of APOB in other organisms and was then predicted to have hostile mutations. Still, in line with Swamidass, the claim that Liu et al. consider that APOB is broken "is completely and completely wrong." Properly, assuming that nobody in this dialogue is a reader, when the paper declares that the mutations "were predicted to be functionally damaging", after which never contradicts it, it seems clear what the authors say. Liu et al. by no means categorical any criticism of their PolyPhen-2 pc evaluation, which clearly anticipates gene injury. Swamidass, in turn, strongly criticizes Liu et al's pc evaluation. Nevertheless, his assertions in this case are usually not convincing as a result of they basically distort the best way the program works.

As famous, one polar bear mutation APOB obtained the very best potential score of the program – 100% chance – to foretell that the mutation was dangerous. Swamidass claims that when PolyPhen-2 detects a mutation "damaged", which suggests "phenotypically damaging, not biochemically damaged" as a result of "Polyphen does not attempt to predict" biochemical injury. "We’ve got already dealt with these claims, citing extensively PolyPhen-2 literature documenting that the program is designed to detect amino acid modifications that can biochemically injury the perform of the protein. The technical literature explains that this system:

  • predicts when a mutation "destroys the hydrophobic core of the protein, electrostatic interactions, interactions with ligands or other important protein properties"
  • predicts when the mutation is ""
  • "predicts the potential effect of amino acid substitutions on the stability and function of human proteins using structural and comparative evolution"
  • "predicts the impact of nsSNP [non-synonymous single nucleotide polymorphism] on the protein Gene Structure and Perform ”

All these analyzes precisely decide whether or not the protein has biochemical lesions. However we have now already denied the improper interpretation of Swamidass by PolyPhen-2. Learn it right here.

Swamidass is right at one level: PolyPhen-2 additionally predicts hostile phenotypic effects by evaluating mutations in a specific gene to mutations in human homologues recognized to trigger illness. The proof strongly helps Behe's claim that the polar bear APOB was in all probability damaged. As we will see, medical analysis has found that mutations that are recognized to break apoB proteins in humans may cause illnesses that significantly lower cholesterol in humans. It might be associated to occasions in the polar bear.

Injury to APOB Ldl cholesterol Decreases

No less than two biologies that are ID-criticized, and Joshua Swamidass On-line Dialogue Members assume that APOB has or might have a perform of removing blood cholesterol by decreasing this perform. One commentator, "T_aquaticus", writes:

ApoB seems to have two primary features: getting the cholesterol into the bloodstream and eradicating it from the bloodstream. Subsequently, lipid production and lipid clearance might affect high or low ranges of lipid within the bloodstream. … It is fascinating that ApoB occurs in two isoforms by post-transcription modification: apoB-48 and apoB-100. It might appear that the smaller isoform is liable for the transfer of weight-reduction plan lipids to the bloodstream. This may increasingly have a key to understanding potential lively sites for lipid production and lipid purification, and the potential results of certain mutations on these domains.

If one of the features of APOB is to get ldl cholesterol into the bloodstream, then decreasing this perform is more likely to lower ldl cholesterol. Even Nathan Lents, an avid Behe ​​critic who believes that APOB mutations constructively improved cholesterol removing from the blood, admits that "it is possible that APOB is somehow functionally reduced in polar bears compared to brown bear" because such mutations in APOB He might grant that this feature would "support" Bee's thesis.

Attainable may be actual

What Lents admits is possible, can truly be real. There’s good evidence that apoB proteins are involved in bringing cholesterol into the bloodstream, which suggests that degradable mutations can scale back cholesterol within the blood. As described by Liu et al. (2014) states that "ApoB enables the transport of fat molecules in blood plasma." When dealing with the gene, they point out the 2004 paper in medical chemistry, "lipid disorders and mutations in the APOB gene" that "[a] is a unique mRNA modification process that allows the APOB gene to make two structurally related but distinct isoforms with different functions":

] Two apoB forms of the APOB gene are produced by a singular post-transcriptional modification course of: apoB-48, required for the manufacturing of chylomicron within the small gut and apoB-100 required for the production of VLDL in the liver, in addition to being an integral part of VLDL. is an LDL receptor-mediated LDL particle endocytosis ligand.… ApoB-48 is required for chylomicron manufacturing, and apoB-100 is a vital constituent of VLDL and its metabolites, medium density lipoprotein (IDL) and LDL

thus contributing to cholesterol-carrying lipoproteins. and other lipoprotein particles via the blood It helps to charge cholesterol in the blood, which is why apoB levels correlate with LDL levels of cholesterol. Injury to these proteins may cause less ldl cholesterol within the blood. In truth, that is precisely what the writing says: "APOB gene errors can lead to both hypo- and hypercholesterolemia" as a result of "mutations in the APOB gene that cause the production of a truncated molecule can cause FHBL [familial hypobetalipoproteinemia] and hypocholesterolemia." levels of cholesterol are exceptionally low.

In Darwin Devolves, Behe ​​factors out that the the reason why genes typically adapt by way of degradable mutations are that degradable mutations are so widespread, particularly when in comparison with constructive mutations. In response to the Medical Chemistry Paper, "about 50 different mutations in APOB interfering with full-length apoB translation have been described," resulting in shortened types of the protein. These mutations correlate with "low concentrations of LDL cholesterol." The paper exhibits that mutations that effectively scale back ldl cholesterol injury:

FHBL is a uncommon autosomal disorder of the metabolism of residence proteins characterized by low plasma cholesterol, LDL cholesterol and apoB. Many nonsense, frame-shifting, and splicing mutations in the APOB gene resulting in prematurely cleaved apoB varieties have been reported in people with FHBL.

Particularly, the paper states that "defects" of APOB may cause lower levels of cholesterol:

Defects in the APOB gene might cause both hypocholesterolemia or hypercholesterolemia, relying on the mutation.

Many other papers have confirmed these findings:

  • Paper in The Journal of Biological Chemistry: Prolonged apoB varieties have been reported in FHBL topics, and states that homozygotes for these mutations are "at very low plasma LDL cholesterol. " In this doc, an irregular mutation was noticed which resulted in the same phenotype during which the mutation can also be degradable as a result of it "adversely affects the secretion of apoB and apoB-containing lipoproteins."
  • The Lipid Analysis notes state that even "hypocetalipoproteinemia heterozygotes are plasma levels of apoB and low density lipoprotein (LDL) -olesterol, which are quarter to half normal and are generally clinically asymptomatic," however in homozygotes, apoB and LDL- cholesterol levels are extremely low or undetectable. "The paper states that" it has been shown that hypobetalipoproteinemia was indeed associated with deficiencies in the apoB gene ", including" shortened "versions of the protein or insufficient quantities of the protein produced
  • Chapter in Online Genetic Disease and Molecular Bases of Genetic Illness, Lipoproteins Containing BB Apolipoproteins issues of biogenesis and excretion, states that there are two primary varieties of apoB proteins – apoB-48 and apoB-100. When describing hypobetalipoproteinemia, the chapter states that "the defects underlying this disorder are the apo B gene in most cases", typically because of "secreted forms of protein shortening".
  • One other paper within the lipid research journal, "Family Hypobetalipoproteinemia: Review", states that the disease is characterized by "<5% plasma concentration in total or LDL cholesterol or whole apolipopotein B", and typically it is because of APOB gene shortening assays .
  • The summary of the medical convention revealed in Atherosclerosis Supplements states that disruptive mutations in APOB cause "diseases caused by reduced plasma levels of apoB-containing lipoproteins:" Early coding modifications in APOB gene nervousness and body transfer truncated apoB have been found in FHBL: from.
  • Likewise, within the Journal of Medical Genetics it’s said that FHBL is "plasma concentrations of Cha ldl cholesterol and apolipoprotein B (APOB) of low low density lipoproteins (LDL). “The paper shows that many patients with“ low cholesterol ”had an“ APOB gene mutation that was mainly due to truncated forms of APOB ”. that some of these mutations brought about body transplants.
  • Nature Evaluations Genetics paper states that "different homozygous function-loss (LOF) mutations in the APOB or PCSK9 genes cause a monogenic syndrome called homozygous hypobetalipoproteinemia (HHbL) with virtually no LDL cholesterol."

It ought to now be noted that polar bears appear to have excessive ldl cholesterol in comparison with many different mammals and are unlikely to have accurate polar read analogs of human illnesses resembling hypocholesterolemia or FHBL of their normal state. (The above-mentioned literature exhibits that broken APOB may also cause larger cholesterol!) However when it is recognized that broken APOB reduces cholesterol, and because this might benefit polar bears to outlive with a fatty weight loss plan, there’s still a critical risk that damaged APOB in polar bears will help scale back cholesterol much more otherwise can be given to their food regimen. In fact, different genes are also more likely to contribute to helping polar bears management their oily weight loss plan. It’s also attainable that a damaged APOB can play other roles that assist the polar bears to deal with a greasy weight-reduction plan. Nevertheless, an important factor is:

Literature exhibits mutations that are clearly degradable – "loss of function" mutations and "nonsense, frame shift, and splicing in APOB that lead to premature cut apoB forms" – can scale back cholesterol. "possible" is just not only potential but actual, it should give Behe ​​& # 39; s doctoral dissertation that APOB decomposition mutations may also help polar bears to cope with their oily food plan. Many studies present that degradation of APOB causes cholesterol reduction. ]

The Mouse Research Defined

Within the Evolyn News difficulty, Behe ​​commented on the above-mentioned New Scientist Information Report, describing a mouse research that is in keeping with the research discussed here by demonstrating that APOB degrading mutations can lower cholesterol soy:

[W] without the good thing about help knowledge, Lensk's waxes are optimistic. He quotes the writer of the analysis and then emphasizes his own view in bold face :

”In a publication from this research, one of the papermakers, Rasmus Nielsen, stated:“ The APOB variant The polar bears must be with cholesterol transport and storage… Maybe it does process more efficient. "In other words, these mutations may not have damaged the protein at all, but quite possibly [19659076] one of its functions, namely the clearance of cholesterol from the blood of a species that can withstand a high-fat diet . ”

Lenski is nearly definitely fallacious in bold text. Right here's why. In 1995, scientists poured (destroyed) one APOB gene from two copies of a mouse mannequin – the identical gene chosen in polar bears. Although APOB itself has been involved in the larger strategy of transporting ldl cholesterol, mice lacking one copy of the APOB gene had lower plasma cholesterol levels than mice with two copies. (Mice lacking both copies died earlier than start.) What's more, researchers discovered that heterozygous mice have been shielded from diet-induced hypercholesterolemia by feeding a food regimen containing fats and ldl cholesterol.

The researchers admitted that they didn’t know it all got here together – how this effect on the complicated ldl cholesterol transport system was on account of gene breakdown. Nevertheless, there isn’t a ambiguity concerning the results of the mouse. Just by decreasing the quantity of APOB / exercise, mice are shielded from the consequences of a fatty weight-reduction plan. Deleting a replica of one gene might have enhanced the cholesterol removing course of, as Rasmus Nielsen speculates above the polar bear, nevertheless it did so by decreasing mouse APOB activity

the which means of mouse leads to deciphering the polar bear genome; As a result of the mice have experimental outcomes, it’s most troublesome to assume that APOB is cracked or clogged in polar bears. In mice with only half of APOB exercise, they shield them from a greasy eating regimen. For polar bears with mutated APOB genes, they shield them from a greasy weight loss plan. If these polar bear mutations lowered APOB activity by half or extra, we might anticipate an analogous protective impact because the mouse. Since pc evaluation also estimates that polar thread APOB mutations are more likely to be harmful, it is best to assume that mutations have brought about protein activity

. new activated proteins in polar bear. Somewhat, the only speculation is that the polar bear line mutations, which have been estimated to be probably dangerous by pc evaluation, have been certainly dulled by the activity of the APOB protein in that species – i.e. made it much less effective. Tämä molekyylihäviö aiheutti iloisen, korkeamman tason fenotyyppisen tuloksen – polaarineiden lisääntynyt sietokyky niiden rasvaisen ruokavalion suhteen.

Kappaleet tulevat nyt yhteen: paljon kuin ihmisillä, APOB: n yksi tehtävä hiirissä todennäköisesti liittyy kolesterolin lataaminen veriin. Geenin kopion poistaminen heikentää tätä toimintoa. Hiirillä, joilta puuttui yksi APOB: n kopio, oli siten alhaisempi kolesteroli ja suojaus rasvaa ravitsevaa ruokavaliota vastaan ​​

Juuri siksi, että vahingoittunut APOB voi vähentää kolesterolia ihmisillä ja hiirillä, ei tarkoita, että sama tarkka mekanismi toimii jääkarhoissa. Mutta nämä tiedot vahvistavat vahingoittuneen APOB-kolesterolin vähentämisen todennäköisyyden. Joten miksi jääkarhuilla on niin korkea kolesteroli? Samoin kuin hiirillä, on myös mahdollista, että vaurioitunut APOB aiheuttaa heille alhaisemman kolesterolin kuin heidän olisi pitänyt rasvaisen ruokavalionsa vuoksi. Kuten hiiren tutkimuksessa todettiin: "Kun ruokitaan ruokavaliossa, jossa on runsaasti rasvaa ja kolesterolia, heterosygoottiset hiiret suojataan ruokavalion aiheuttamalta hyperkolesterolemialta." Vahingoittunut APOB saattaa johtaa kolesterolin alenemiseen kuin olet odottanut, vaikka annettaisiin runsaasti rasvaa sisältävää ruokavaliota mukautuva etu. On myös mahdollista, että vaurioitunut jääkarhu APOB: lla on muitakin funktioita, jotka muuttavat korkean kolesterolin vaikutuksia: Sekä napakarhuissa että hiirissä vähemmän toimiva APOB saattaa tietysti tuntea tavalla suojata metaboliittisesti runsaasti rasvaa sisältävän ruokavalion vaikutuksia vastaan.

Enigmanin käsitteleminen

Liu et ai. said that it’s an “enigma” how polar bears cope with excessive ldl cholesterol, but they predicted that APOB was broken and gave an advantage to polar bears in dealing with their excessive fats food regimen. We will now handle a related enigma: how can a biochemically broken protein lead to a phenotypic advantage? Swamidass appears to not respect this risk, which led him to make more inaccurate claims about PolyPhen-2:

In the case of Polar Bear ApoB, we all know the mutations were not phenotypically damaging (they have been selected!), which is why most scientists (together with the unique authors) have appropriately interpreted them to be “change/improvement of function” mutations, not “biochemically damaging.”

Here, Swamidass advances a mistaken dichotomy where polar bear mutations can’t be chosen if PolyPhen-2 predicts they have been broken. There’s a serious drawback together with his argument: PolyPhen-2 predicted with 100 % certainty that APOB was damaged, yet clearly it was chosen. If PolyPhen-2 solely identifies phenotypic injury, how is it potential that it was chosen? The reply is that PolyPhen-2 does not solely determine phenotypic injury. It additionally identifies biochemical injury. In this case, APOB’s biochemical injury as detected by PolyPhen-2 might have led to a selectable phenotypic advantage: lower cholesterol. This mannequin now has empirical credibility because we all know that damaged APOB in people can lead to decrease ldl cholesterol. This is simply the type of end result Behe’s model would predict.

Mysteries Stay 

BeheLots of Behe’s critics consider, as Richard Lenski argued, that mutations in APOB “quite possibly improved one of its activities, namely the clearance of cholesterol from the blood.” However we don’t know precisely what APOB does in polar bears, and good proof exhibits that its perform was damaged. A better model is that mutations broken APOB’s perform to load ldl cholesterol into the blood, helping polar bears to effectively decrease ldl cholesterol. This feature is according to (a) the findings of the PolyPhen-2 evaluation, (b) medical research which show that damaging APOB can scale back cholesterol, and (c) the very fact that polar bears must by some means deal with a excessive fats food regimen.

Is this proposal right? It’s believable given what we all know, but many questions remain. What precisely does APOB do in polar bears? If it helps scale back cholesterol, why do polar bears nonetheless have excessive ldl cholesterol, and how do they deal with that? Polar bears don’t necessarily have one thing like human hypocholesterolemia, though everyone believes they have advanced mechanisms to cope with a weight-reduction plan of fatty seal blubber. Is damaged APOB making polar bear cholesterol levels lower than they might be even given their high-fat weight loss plan, very similar to within the mouse research? Is it additionally helping them deal with excessive cholesterol in some other approach? What other genes are involved with helping polar bears avoid atherosclerosis? Have been these mechanisms designed or did they evolve? Finally, any mannequin of APOB’s evolution — including (a) those that predict it amassed constructive mutations to raised remove cholesterol from the blood and (b) those that predict that it underwent degradative mutations to scale back cholesterol and/or deal with high cholesterol — must grapple with this difficult state of affairs. A lot work remains to be executed.

It’s in all probability because of the various unknowns that the authors of Liu et al. (2014) didn’t specifically conclude that APOB skilled constructive mutations to enhance some perform. They noticed that whatever polar bear APOB is doing, the result is “effective clearance” of cholesterol from the blood. However because the literature exhibits, and as even a few of Behe’s critics admit, one perform of APOB is loading ldl cholesterol into the blood, and that perform may be degraded by mutations in the gene, effectively decreasing cholesterol. Therefore Liu et al. didn’t declare that we know that the perform of APOB was enhanced.


Absent direct biochemical research of the exact perform of APOB in polar bears or direct empirical studies of the consequences of mutations in polar bear APOB, the perfect we will do is what the paper Liu et al. did: Examine variations of APOB in polar bears to recognized homologues in other species, and predict what the doubtless impression can be. This is precisely what the PolyPhen-2 program did. The paper thus reported that mutations in APOB and over a dozen different polar bears genes have been “predicted to be functionally damaging.” In truth, as already talked about, a type of mutations (which converted an aspartic acid to asparagine near the center of the protein at place 2623) was predicted with 100 % certainty to be damaging. Was this as a result of polar bear APOB amassed a mutation recognized in humans to wreck the proteins, causing illnesses that contain very low ldl cholesterol? Sadly the Liu et al. paper does not say. But to obtain a result of 100 % certainty that the mutation broken the protein makes this a critical risk value investigating.

At the very least, we will now definitively reject the thought of sure Behe critics that the one means mutations in APOB might scale back ldl cholesterol is by enhancing a perform that removes cholesterol from the blood. Behe’s hypothesis that APOB skilled broken mutations is affirmed not only by Liu et al. (2014), however can also be supported by a physique of peer-reviewed papers in medical journals that have discovered that unequivocally damaging mutations in APOB can lead to decrease ldl cholesterol. Far more work stays to be achieved to know precisely how polar bears cope with their high fat weight-reduction plan, however briefly, Behe’s proposed devolutionary model is viable. It’s plausible in mild of what we all know, and supported by proof.

Photograph credit: Nicholas Larimer by way of Unsplash.

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