Behe: Responding to the Polar Bear's Fat

[NLENTS (Nathan H. Lents)]

Behe responds to the polar bear post… kind of? Looks like he’s trying to backpedal without LOOKING like he’s backpedaling. I think?

https://evolutionnews.org/2019/02/coyne-and-polar-bears-why-you-should-never-rely-on-incompetent-reviewers/

But, omg, you guys called it, he refused to use my name! lolol And then he called @art “some other guy.” Coyne gets all the credit this time. Darn! Okay, I’m having a little too much fun with this. Gotta get back to work.

[Art (Arthur Hunt)]

Behe, in ENV:

It has been my experience that one very common way for opponents to try to discredit an argument is to exaggerate it, to ignore distinctions an author makes, and/or to change carefully qualified claims into bizarre absolutes. Why, here’s an example right here:

What Behe is saying is that harming genes is the only way that unguided mutations can ever help an organism.

Matti Leisola, in his review on Barnes and Noble:

Behe introduces new molecular-level facts that sink the Darwinian view of life once and for all: Darwinian mechanism sometimes helps survival of an organism but always by damaging or breaking genes. The conclusion is clear: life is the product of a mind.

Matti Leisola

[Rumraket (Mikkel R.)]

Behe assigns a “probably” or “possibly” damaging to all these amino acid substitutions, but does he go into why that is anywhere? What is it we (presumably) know that makes this the more likely option?

I hope he isn’t just begging the question to arrive at the conclusion he is seeking to convince us of.

Also, does he argue anywhere why we should think that all the mutations in the LTEE are “probably” damaging? What is it he thinks we know that make this the most likely possibility?

[Art (Arthur Hunt)]

@Rumraket

Behe assigns a “probably” or “possibly” damaging to all these amino acid substitutions

Actually Liu et al. do that. But Behe conveniently forgets the column from Table S7 that shows the outcome of using another tool, in which several of the changes he lists are predicted to be benign.

[T_aquaticus]

From the paper Behe is citing:

Nevertheless, we assessed the impact of polar bear—specific substitutions on human proteins for top-20 genes under positive selection by computational predictions: a large proportion (ca. 50%) of mutations were predicted to be functionally damaging (Figures 4C and 4D, Table S7).
https://www.cell.com/fulltext/S0092-8674(14)00488-7

Even with weak evidence from predictive computer algorithms, only around half are damaging. Behe seems to gloss over this fact. Fig. 4 from that paper is worth checking out. The largest proportion of mutations have a 0-20% probability of being damaging.

[Rumraket (Mikkel R.)]

He also assigns a “possibly” damaging to 10 out of about 25 of these amino acid substitutions. Well if he don’t actually know, then sure it’s “possible” they’re damaging. But how likely is that? If it’s 0.0000000000003% probable then it’s still “possible”.

This mere possibility of being damaging, if it is to be an argument in favor of his main thesis, should be significantly more likely than not.

His argument, as presented, is extremely weak.

[Art (Arthur Hunt)]

@Rumraket

This mere possibility of being damaging, if it is to be an argument in favor of his main thesis, should be significantly more likely than not.

His argument, as presented , is extremely weak.

In the essay Coyne points to, Nathan and I talk about data and comments apart from the computer predictions that make this very statement.

[T_aquaticus]

First, let’s look at the function of apoB:

What is also clear is that the ApoB on the LDL particle acts as a ligand for LDL receptors in various cells throughout the body (i.e., less formally, ApoB indicates fat carrying particles are ready to enter any cells with ApoB receptors and deliver fats carried within into the cells).
Apolipoprotein B - Wikipedia

apoB serves as a tag on cholesterol particles in the blood stream which bind to receptors on cells. Once bound, the cholesterol can be transported into the cell.

So what is happening in polar bears? If apoB were “damaged” then it would have a harder time filling its role as a tag for cholesterol transport. Instead, apoB appears to be doing a better job in its function.

Five of the nine cluster within the N-terminal βα1 domain of the APOB gene, although the region comprises only 22% of the protein (binomial test p value = 0.029). This domain encodes the surface region and contains the majority of functional domains for lipid transport. We suggest that the shift to a diet consisting predominantly of fatty acids in polar bears induced adaptive changes in APOB , which enabled the species to cope with high fatty acid intake by contributing to the effective clearance of cholesterol from the blood.
https://www.cell.com/fulltext/S0092-8674(14)00488-7

From what I can see, polar bear apoB isn’t broken or damaged. Instead, it is working better than it did before.

[Art (Arthur Hunt)]

This is a list of seventeen genes described in Liu et al. as being affected by missense mutations, and their classification according to computer predictions. I have made four groupings here so that readers can see how the computer predictions sort out: those genes whose associated misssense mutations are all benign, those bearing either benign or “possibly damaging” mutations, those with at least one “probably damaging” mutation, and those with missense changes are predicted to give differing outcomes (and may have only benign or possibly damaging mutations). Readers are invited to look into, and comment on, these, and especially on the prospects that these may be degraded or destroyed in the polar bear.

Benign:
EHD3
OR5D14
SH3PXD2B

Possibly damaging:
ABCC6
POLR1A

Probably damaging:
APOB
COL5A3
CUL7
LAMC3
LYST
OR8B8
VCL

Conflicting prediction:
AIM1
ARID5B
IPO4
TTN
XIRP1

[evograd (Blogging Graduate Student)]

Behe posts this at the end of the article:

It’s a list of all the variants predicted to be “possibly damaging” or “probably damaging” by Liu et al. The problem is that he doesn’t inform his audience that this table is only a subset of Liu et al’s table S7. He calls it the “relevant information” from table S7.

The actual table looks more like this:

Are we supposed to believe that Behe did that little switcharoo without thinking that a large fraction of his lay readers would just see a big list of entries saying “damaging” and come away with the impression that these were the majority of variants, or even all of them?

[Art (Arthur Hunt)]

@evograd

Are we supposed to believe that Behe did that little switcharoo without thinking that a large fraction of his lay readers would just see a big list of entries saying “damaging” and come away with the impression that these were the majority of variants, or even all of them?

Thank you, thank you, thank you.

[evograd (Blogging Graduate Student)]

@T_aquaticus

From what I can see, polar bear apoB isn’t broken or damaged. Instead, it is working better than it did before.

But y’see, it lost the ability to tag cholesterol particles at the level it was capable of previously! /s

[swamidass (S. Joshua Swamidass)]

@evograd

Are we supposed to believe that Behe did that little switcharoo without thinking that a large fraction of his lay readers would just see a big list of entries saying “damaging” and come away with the impression that these were the majority of variants, or even all of them?

NOTE: “damaging” in this table is a misnomer, and can mean “good change of function” or “bad change of function”

Table S7
Gene	Protein position	Ancestral AA	Polar bear AA	HDivPred	HDivProb	HVarPred	HVarProb
ABCC6	655	Q	H	probably damaging	0.966	possibly damaging	0.547
AIM1	530	T	S	benign	0.035	benign	0.018
AIM1	632	I	S	benign	0.002	benign	0.003
AIM1	821	N	K	possibly damaging	0.651	benign	0.122
APOB	716	N	K	possibly damaging	0.801	benign	0.265
APOB	749	D	E	possibly damaging	0.946	possibly damaging	0.807
APOB	2623	D	N	probably damaging	1	probably damaging	0.989
APOB	3920	T	P	possibly damaging	0.482	benign	0.088
APOB	4418	L	H	probably damaging	0.999	probably damaging	0.915
ARID5B	457	N	K	benign	0.126	benign	0.02
ARID5B	775	H	Q	benign	0.006	benign	0.002
ARID5B	787	S	R	benign	0.412	benign	0.133
ARID5B	875	H	Q	probably damaging	0.996	possibly damaging	0.731
COL5A3	149	R	S	probably damaging	0.999	probably damaging	0.993
COL5A3	694	K	N	probably damaging	0.998	probably damaging	0.991
COL5A3	963	P	T	benign	0.262	benign	0.249
COL5A3	1117	D	E	possibly damaging	0.955	possibly damaging	0.804
CUL7	508	D	N	possibly damaging	0.736	benign	0.159
CUL7	709	D	E	benign	0.002	benign	0.007
CUL7	1477	N	K	probably damaging	1	probably damaging	0.999
EHD3	269	K	N	benign	0.255	benign	0.197
IPO4	362	R	W	probably damaging	0.977	benign	0.339
LAMC3	791	D	E	probably damaging	0.992	probably damaging	0.971
LYST	1046	D	Y	possibly damaging	0.947	benign	0.272
LYST	1084	A	S	benign	0.045	benign	0.015
LYST	1140	F	L	benign	0	benign	0
LYST	1770	L	F	benign	0.005	benign	0.007
LYST	2672	N	K	benign	0.032	benign	0.021
LYST	2978	R	S	probably damaging	0.957	benign	0.445
LYST	3784	Q	H	probably damaging	0.998	probably damaging	0.983
OR5D14	57	F	L	benign	0	benign	0
OR5D14	306	L	F	benign	0.014	benign	0.021
OR8B8	48	L	V	probably damaging	0.999	probably damaging	0.998
POLR1A	413	K	N	possibly damaging	0.93	possibly damaging	0.496
POLR1A	1317	L	V	benign	0.001	benign	0.006
POLR1A	1467	G	V	benign	0.322	benign	0.233
SH3PXD2B	548	Q	H	benign	0.003	benign	0.002
TTN	995	S	I	possibly damaging	0.755	benign	0.277
TTN	5869	N	I	benign	0.326	benign	0.139
TTN	8261	E	D	benign	0.288	benign	0.109
TTN	8337	I	M	benign	0.188	benign	0.095
TTN	26365	E	D	probably damaging	0.992	possibly damaging	0.715
VCL	296	E	D	probably damaging	0.979	probably damaging	0.982
VCL	600	S	R	probably damaging	0.996	probably damaging	0.99
XIRP1	868	S	R	benign	0.145	benign	0.021
XIRP1	1266	G	R	benign	0.044	benign	0.019
XIRP1	1378	T	N	possibly damaging	0.718	benign	0.126
XIRP1	1592	S	R	benign	0.005	benign	0.005

[evograd (Blogging Graduate Student)]

For those keeping track, this is now a total of 8 response articles on ENV alone to the Science review and its “spin-offs” in the last week. They can’t be very busy.

[T_aquaticus]

@evograd

But y’see, it lost the ability to tag cholesterol particles at the level it was capable of previously! /s

Hehe. So true. When you assume something is designed from the get go then any change, no matter what it is, will be viewed as damaging. This seems to be a bias that runs through most ID literature.

[swamidass (S. Joshua Swamidass)]

@evograd

From what I can see, polar bear apoB isn’t broken or damaged. Instead, it is working better than it did before.

But y’see, it lost the ability to tag cholesterol particles at the level it was capable of previously! /s

This gets to a key point. Polar Bears NEED an APOB to function more effectively than it does for brown bears. So yes, the APOB (in a perverse sense) loses a lower level of function to get an a higher level of function. In what backwards sense is this “damaging”?

I’d point out too that these predictors are just predictors, and they are commonly used in cancer where, by convention, even gain of function mutations are called “damaging.” For this reason, they assume that a FUNCTIONAL mutation = DAMAGING mutation. This, however, is not correct in this case. The purportedly “damaging” mutations could very well be the gain of function mutations. Seee, for example, the score outputs for HDivPred and HVarPred:

http://genetics.bwh.harvard.edu/pph2/dokuwiki/_media/hg0720.pdf

Prediction outcome can be one of probably damaging, possibly damaging, or benign. “

Notice, it cannot be “improved function.” The reason why is that the program assumes that change of function mutations are damaging, and this is likely the case in cancer (in that they cause cancer). It is not true, however, in the case we are applying it.

[evograd (Blogging Graduate Student)]

I was just thinking about this, since I looked at the paper describing the program that makes the predictions:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855889/

It was trained on human disease-associated variants, but as far as I can tell there was no effort made to distinguish between “loss of function” and “gain of function” variants, for example.

[swamidass (S. Joshua Swamidass)]

@evograd

It was trained on human disease-associated variants, but as far as I can tell there was no effort made to distinguish between “loss of function” and “gain of function” variants, for example.

Exactly. All the program can do is flag mutations as “altering things from ‘normal’ somehow”. It is just by accident it is labeled “damaging.” This is well known in the field. The software, for example, does not have a category for “beneficial.”

[Art (Arthur Hunt)]

@evograd

It was trained on human disease-associated variants, but as far as I can tell there was no effort made to distinguish between “loss of function” and “gain of function” variants, for example.

I think it also takes into account aa side chain chemistry and possible structural changes. But yeah, it is based on human disease variants.

[Patrick]

@NLENTS

But, omg, you guys called it, he refused to use my name! lolol And then he called @art “some other guy.” Coyne gets all the credit this time. Darn! Okay, I’m having a little too much fun with this. Gotta get back to work.

@nlents It is worse than that! @swamidass is “some other guy” as it is his picture he uses.