Given that @colewd may never answer it, some viewers may be curious. A quick scan over at Ensembl lists possibly 1,000+ that are either uncertain, benign, or likely benign. Around 600 are listed as pathogenic or likely pathogenic. Not sure how many are duplicates, but it is safe to say there is a lot of neutral and/or beneficial variation in the human population for MYH7. It is rather strange that @gpuccio never includes this in his calculations [/sarcasm].
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If there are so many neutral or near neutral variations how are they not getting fixed in the population of mammals with so many species types and generations over long periods?
Donât jellyfish have some equivalent of sarcomeres? Iâm curious about the amino acid sequences in their muscle proteins, afaik they have muscles.
For the same reason that most lottery tickets arenât winners.
This is also a red herring. You are trying to deflect the problems that these variants pose for your main thesis.
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Itâs a legitimate question that you are dodging without thought. I acknowledge that the human neutral variation is an interesting point I just donât have an answer. The non fixation may indicate there are problems we donât understand.
The irony is killing me. You are dodging MYH7 variation in the human population.
Didnât we already have a lengthy thread trying to teach you about the rate of fixation for neutral mutations?
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Yes and it indicates that we should see almost saturation of fixed neutral mutations in mammals.
Red herring.
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But virtually all of those have low penetrance, so they also are present in healthy relatives of those who have cardiomyopathy. New ones are identified on a weekly basis.
Thatâs almost an incisive question, Bill, but it is not useful because you predictably loaded it with false assumptions.
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The âpopulation of mammalsâ is not relevant here. These are specific to humans. How does that fit with what we know (or in your case, likely deny) about human evolutionary history?
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How did you determine that none of these alleles have been fixed in human populations?
They do, but sarcomeres themselves are a recent evolutionary (or design) innovation.
But even some in the field donât seem to grasp that sarcomeric myosins, despite having the label âconventional,â are evolutionary new and highly specialized.
There are lots of others, enough to support the joke (only a joke, @colewd) that myosins are most of junk DNA.
Are you claiming different species of humans?
No, Bill, I am not.
https://www.pnas.org/content/early/2016/06/01/1606950113
The MYH7 gene is highly constrained for genetic variation (6). Few loss-of-function variants are observed in population cohorts, and identified pathogenic variants are mainly missense. However, although many missense genetic variants in MYH7 cause HCM, not all genetic changes within the gene lead to disease. There are competing hypotheses regarding the localization of pathogenic missense variants within MYH7 , analysis of which can offer insight into the underlying mechanism of HCM. Investigators have suggested enrichment of pathogenic variants in many of the functional domains of β-cardiac myosin, including the converter domain, actin-binding site, and ATP-binding domain (7ââ9). However, others have suggested there is no regional enrichment for HCM variation within MYH7 (4, 10). These inconsistencies could be due to limited sample sizes or to a lack of reference cohorts for comparison. Without information about the natural distribution of rare variants within MYH7 , it is impossible to distinguish regions of disease-variant enrichment from regions of increased genetic tolerance (11). In addition, some putatively pathogenic variants are later found at higher than expected allele frequencies in large, ethnically diverse population reference cohorts (12). The study suggesting enriched domains lacked reference cohorts; when a reference cohort was compared against genetic variants from a small sample of patients with HCM, the study failed to detect any significant enrichment for disease-associated variants (10). In addition, a focus on the linear sequence of the gene or previously discovered functional domains could overlook novel functional regions or enrichments spanning multiple domains. These discrepancies point to the need to test for regional HCM variant enrichment within MYH7 using both a large patient population and a large reference cohort while also accounting for the 3D structure of β-cardiac myosin.
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Thatâs an important one to bold for @colewd.
You might find it interesting to see who the common person is between that paper and our paper:
https://www.pnas.org/content/114/42/11115
And letâs not forget this gem from Bill:
Bill, after reading these papers, do you really think that thereâs even the slightest chance that you understand this better than I do at the system level?
How do you know that it doesnât ?
The sarcasm are inappropriate here for the level of polymorphism in the human population, whatever huge it may be, has only a marginal impact on FI. To see this, see my posts at 29 and 34.
So, if I understand you well, you think that for a given complex function, there are many local optima, ie., many alternative solutions, in the sequence space. Letâs take the example of the beta chain of ATP synthase. This protein has 529 AAs, exhibits 334 identities between E. Coli and humans, and, according to gpuccioâs methodology, this translates to an FI of 1297 bits. You contest gpuccioâs calculation of FI because he only considers one functional island for the protein whereas you think there are many. But the question here is how many?
Do you realize that in order to reduce the FI of the beta chain of ATP synthase from 1297 bits to below 500 bits, you have to postulate that there are at least 10^240 alternative solutions in the sequence space that can implement the same complex function! Given that there is no evidence whatsoever that other alternative solutions exist for the beta chain of ATP synthase, I would say that to believe there exists 10^240 amounts to believe in Santa Claus.
Do you realize no one has ever shown natural evolutionary processes canât produce or increase what you call âFIâ so your numbers are meaningless?
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Okay, I see you still believe in Santa ClausđItâs your right after all.
I can do math.
Exactly.
âFIâ doesnât measure sequence conservation. It doesnât measure functional sequence space. It doesnât measure total sequence space.
Itâs a fantasy.
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