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Although there are various Conus species with publicly available transcriptome and proteome data, no genome assembly has been reported yet. Here, using Chinese tubular cone snail (C. betulinus) as a representative, we sequenced and assembled the first Conus genome with original identification of 133 genome-widely distributed conopeptide genes. After integration of our genomics, transcriptomics, and peptidomics data in the same species, we established a primary genetic central dogma of diverse conopeptides, assuming a rough number ratio of 1:1:1:10s for the total genes: transcripts: proteins: post-translationally modified peptides. This ratio may be special for this worm-hunting Conus species, due to the high diversity of various Conus genomes and the big number ranges of conopeptide genes, transcripts, and peptides in previous reports of diverse Conus species. Only a fraction (45.9%) of the identified conotopeptide genes from our achieved genome assembly are transcribed with transcriptomic evidence, and few genes individually correspond to multiple transcripts possibly due to intraspecies or mutation-based variances. Variable peptide processing at the proteomic level, generating a big diversity of venom conopeptides with alternative cleavage sites, post-translational modifications, and N-/C-terminal truncations, may explain how the 133 genes and 123 transcripts can generate thousands of conopeptides in the venom of individual C. betulinus. We also predicted many conopeptides with high stereostructural similarities to the putative analgesic ω-MVIIA, addiction therapy AuIB and insecticide ImI, suggesting that our current genome assembly for C. betulinus is a valuable genetic resource for high-throughput prediction and development of potential pharmaceuticals.
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In 2011, a trial next-generation shotgun survey with low quality for C. bullataus genome was reported13. Recently, targeted sequencing of venom genes from 32 Conus genomes14 characterized various conopeptide superfamilies. Unpublished genome data for C. consors were also deposited at NCBI (under the accession number GCA_004193615.1) for public availability. Here, we generated the first genome assembly for the predominant vermivorous Chinese tubular cone snail (C. betulinus; Fig. 1a) in the South China Sea to shed light on the representative genome structure of Conus species, and attempted to illustrate a preliminary genetic central dogma of conopeptides for high-throughput development of novel marine drugs. By integration of present genomics and peptidomics data, along with our previously published transcriptomics results in the same species, we tried to establish a rough number ratio for the total genes/transcripts/proteins/post-translationally modified peptides in this representative Conus species. Our achieved genome assembly will definitely become a valuable genetic resource for high-throughput prediction of conopeptide genes and transcripts, and lay a solid foundation for in-depth investigations on Conus biology and conopeptide pharmacology.
Next-generation high-throughput sequencing technologies have opened up new opportunities for genome-wide studies on various animals, plants, and bacteria. In the present study, we combined Illumina short reads and PacBio long reads to generate the first Conus genome assembly, which revealed a primary genetic central dogma of conopeptides in the representative C. betulinus.
In summary, this is the first report of a Conus genome assembly. With the integration of multi-omics (genomics, transcriptomics and peptidomics) data, we attempted to illustrate the special genetic central dogma of conopeptides in C. betulinus, assuming that the primary number ratio for total conopeptide genes: transcripts: proteins: post-translationally modified peptides is 1:1:1:10s. Some predicted conopeptides in our present study are similar to the well-known analgesic ω-MVIIA, addiction therapy AuIB and insecticide ImI in cysteine backbone and 3D structure, suggesting that these novel peptides could be developed as pharmaceutical candidates.
The 3D structures of MVIIA, AuIB and ImI were downloaded from the public PDB database ( ). Models of the conopeptides were built using the MVIIA (PDB:1OMG), AuIB (PDB:1MXN) and ImI (PDB:2BC7) as templates in MODELLER (version 9v12)61,62 as described previously8. All modeling images were generated with PyMol ( ).
Subluxation syndrome is a legitimate, potentially testable, theoretical construct for which there is little experimental evidence. Acceptable as hypothesis, the widespread assertion of the clinical meaningfulness of this notion brings ridicule from the scientific and health care communities and confusion within the chiropractic profession. We believe that an evidence-orientation among chiropractors requires that we distinguish between subluxation dogma vs. subluxation as the potential focus of clinical research. We lament efforts to generate unity within the profession through consensus statements concerning subluxation dogma, and believe that cultural authority will continue to elude us so long as we assert dogma as though it were validated clinical theory.
The traditional chiropractic lesion has not been the focus of systematic clinical research for the purpose of determining its meaningfulness (or lack thereof). In the absence of scientific validation, the propagation of unsubstantiated claims for many chiropractors favorite mediating variable is an obstacle to scientific credibility and cultural authority for the profession. It is our purpose to remind the profession of the implications and consequences of offering subluxation dogmatically, rather than as a plausible and testable proposition.
The dogmatic character of subluxation beliefs is exemplified by several assertions offered by the Association of Chiropractic Colleges (ACC) (see Table 1). Intended as a means of fostering greater unity among the chiropractic colleges, the ACC's "Paradigm" statement on subluxations has since been widely endorsed by national and international membership societies [28]. In effect, the ACC Paradigm has become the standard (if not official) position of a broad segment of the profession. There are several problems with the Paradigm.
Secondly, the dogmatism of the ACC's unsubstantiated claim that subluxations "may influence organ system function and general health" is not spared by the qualifier "may." The phrase could mean that subluxations influence "organ system function and general health" in some but not all cases, or that subluxation may not have any health consequences. Although the latter interpretation is tantamount to acknowledging the hypothetical status of subluxation's putative effects, this meaning seems unlikely in light of the ACC's statement that chiropractic addresses the "preservation and restoration of health" through its focus on subluxation. Both interpretations beg the scientific questions: do subluxation and its correction "influence organ system function and general health"?
We contend that attempts to foster unity (among the schools or in the wider profession) at the expense of scientific integrity is ultimately self-defeating. To be sure, the profession's lack of cultural authority is based in part upon our characteristic disunity. However, attempts to generate unity by adoption of a common dogma can only bring scorn and continued alienation from the wider health care community and the public we all serve.
The diversity of altered function attributed to subluxation and "nerve interference" parallels in some respects the "nervism" [40] and "spinal irritation" [41] of nineteenth century neurology and physiology. When coupled with vitalistic concepts of "Innate Intelligence," subluxation theories expand upon the "nature-trusting heresy" [42] of those earlier times. Unlike the therapeutic nihilism recommended by some nineteenth century physicians, many chiropractors' faith in nature gives rise to extensive regimens of subluxation correction [43]. The breadth of contemporary, uncritical speculations bearing on subluxation is captured in the boast of a chiropractic leader: "Rigor mortis is the only thing we can't help" [44]. Seaman [45] argues that "many chiropractic practices are guided by dogmatism instead of philosophy and science." In short, many chiropractors practice as though subluxation is clinically relevant, but seemingly without recognition that maybe it's not. When challenged, many chiropractors respond not with data, but by avowing "the chiropractic principle": subluxation.
The irony here is extreme. Having established the legal meaningfulness of a hypothetical construct whose clinical relevance has yet (if ever) to be scientifically demonstrated, chiropractors now find themselves competing with physical therapists and others over the right to correct subluxations. The greatest absurdity of the situation appears to be missed by all parties concerned: subluxation is "real" because Congress has said so. Data seem irrelevant in this context. Monetary concerns clearly outweigh the issue of scientific validation, and the dogma of subluxation has now spread beyond the chiropractic profession.
Ironically, there is an image of the chiropractor, which seems reasonably well-accepted by many members of the public and whose basis has already garnered some substantial research support [2, 3]: the chiropractor as provider of manipulative/adjustive services. Whether the profession can loosen its self-imposed shackle to subluxation dogma is unclear.
...It is my contention that a battle between philosophy and science does not and cannot exist within the chiropractic profession or any other discipline. I contend that the real battle is between the great majority of chiropractors who unknowingly allow dogmatism to guide the practice of chiropractic and the extremely rare variety of chiropractor who's practice of chiropractic is guided by philosophy and science [45].