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Research Article

Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes

  • Ivan Nagaev mail,

    To whom correspondence should be addressed. E-mail: ivan.nagaev@.gu.se

    Affiliation: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

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  • Maria Bokarewa,

    Affiliation: Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

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  • Andrej Tarkowski,

    Affiliation: Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

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  • Ulf Smith

    Affiliation: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

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  • Published: December 20, 2006
  • DOI: 10.1371/journal.pone.0000031

Reader Comments (2)

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Discrepancies in the chromosomal location of human resistin

Posted by Beckleyj on 20 Feb 2007 at 17:04 GMT

The 2004 study by Chumakov et al [12], which identifies human resistin as homologous to mXCP1, locates hXCP1 on chromosome 3 and hXCP2 (RELMbeta) on chromosome 19. This is exactly the opposite of the 2003 phylogenomics study by Yang et al [22], which identified what they thought was resistin (presumably hXCP1) on chromosome 19, and the human RELMbeta homolog on chromosome 3. In table 1 is in agreement with the Yang et al study. But why did the Chumakov et al paper find different results? Furthermore, why have the findings of this 2004 paper been largely ignored in the current resistin literature?


RE: Discrepancies in the chromosomal location of human resistin

Ivan1 replied to Beckleyj on 22 Feb 2007 at 11:20 GMT

Diverse results for chromosomal mapping were obtained because of different methods. As it is denoted in both papers, the BLAST was used against the HTGS database at the NCBI. Citing the NCBI, the HTGS is “Unfinished High Throughput Genomic Sequences: phases 0, 1 and 2 (finished, phase 3 HTG sequences are in nr)”. Thus, the content of the HTGS database is constantly changing, so the BLAST results vary. But Yang et al. [22] exploited both various sources in NCBI plus Ensembl and some phylogenetic tools, which can show chromosomal synteny and gene orthology.
In fact, the data from the NCBI, being consistent with Ensembl and Celera, are present in Table 1. It also shows that Holcomb et al. [1], by using similar approach, originally misidentified human RETNLB/FIZZ2 as RETNLA/FIZZ1, a nonexistent trait in man. Whether Chumakov et al. [12] did the same mistake or improperly designated human RETNLB and mouse Retnla by identical names – XCP2 and Xcp2 – is unclear because of ambiguous definitions used; namely, regulatory and/or functional homologues or analogues. According to Phylogenetics, homolog(ous) and analog(ous) are opposite terms; see Life Science Glossary or Wikipedia or many other relevant sources one can easily find on the web.
To some extent, above discrepancies might be the reason why paper by Chumakov et al. [12] is ignored. However, their principal finding that human and mouse resistins being homologous have different regulatory, expressional and functional characteristics plus the existence of mouse Retnlg gene, an analog of human resistin – this, first and foremost, was not realized and consequently the paper was disregarded.
In order to explain why homologous resistins in human and rodents are exceedingly different, I have done a new phylogenetic study in all major groups of mammals - Prototheria or egg-laying mammals, Metatheria or marsupials and Eutheria or placentals (manuscript). This analysis revealed that both genes, resistin and resistin like beta, have matching orthologs in all mammalian taxa, but not in bird outgroup or other vertebrates. Thus, resistin gene family is a mammalian-specific trait and its evolution can confer the speciation of mammals. It was found that Rodentia has diverged from all other placentals and hence present an independent or parallel evolution. My findings are consistent with conclusions of another work published recently Cannarozzi G, Schneider A, Gonnet G (2007) A phylogenomic study of human, dog, and mouse. PLoS Comput Biol 3(1): e2. doi:10.1371/journal.pcbi.0030002.
I found other genes that evolved only in mammalian evolution and they also showed the same root separation of monophyletic clade of rodents from the clade of other placentals. Another finding, that interleukin 6 (Il6) in rodents is analogous to interleukin 6 (IL6) in other placental species (explicitly, these genes evolved from different ancestor genes), effectively confirms the independent evolution, so the entire Resistin research do. Thus, rodents are not closely related to us as it was thought before. Therefore, mice and rats cannot be used as appropriate animal model of human biology. Quite the opposite, comparison of our independent evolutions, when different strategies have been employed in respond to similar challenges, can disclose both biological rewards and costs, by other words, molecular evolutionary bases of human diseases.
I would appreciate all external in support of and opposing opinions. In addition to the resistin study, I know other various supporting facts, like rodents have unique additional layer of trophoblasts in their placenta; different host-pathogen interaction, for example, so-called murine toxin of Yersinia pestis is selectively active in rodents; homologous traits, like retinoblastoma, give tissue-differing tumors.