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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations.
Mol Psychiatry 2005 Dec
PMID:Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm. 1617 14

The biological underpinnings of human intelligence remain enigmatic. There remains the greatest confusion and controversy regarding mechanisms that enable humans to conceptualize, plan, and prioritize, and why they are set apart from other animals in their cognitive abilities. Here we demonstrate that the basic neuronal building block of the cerebral cortex, the pyramidal cell, is characterized by marked differences in structure among primate species. Moreover, comparison of the complexity of neuron structure with the size of the cortical area/region in which the cells are located revealed that trends in the granular prefrontal cortex (gPFC) were dramatically different to those in visual cortex. More specifically, pyramidal cells in the gPFC of humans had a disproportionately high number of spines. As neuron structure determines both its biophysical properties and connectivity, differences in the complexity in dendritic structure observed here endow neurons with different computational abilities. Furthermore, cortical circuits composed of neurons with distinguishable morphologies will likely be characterized by different functional capabilities. We propose that 1. circuitry in V1, V2, and gPFC within any given species differs in its functional capabilities and 2. there are dramatic differences in the functional capabilities of gPFC circuitry in different species, which are central to the different cognitive styles of primates. In particular, the highly branched, spinous neurons in the human gPFC may be a key component of human intelligence.
Anat Rec A Discov Mol Cell Evol Biol 2006 Jan
PMID:Specializations of the granular prefrontal cortex of primates: implications for cognitive processing. 1634 14

A number of previous studies have suggested the involvement of phosphoinositide 3-kinase (PI3K) in Toll-like receptor (TLR) signaling. However, there have also been a number of conflicting reports. The PI3K inhibitor wortmannin greatly enhanced TLR-mediated inducible nitric-oxide synthase (iNOS) expression and cytokine production in the mouse macrophage cell line Raw264.7. The effect of wortmannin was common to TLR2, -3, -4, and -9 and was accompanied by activation of nuclear factor-kappaB and up-regulation of cytokine mRNA production. We were surprised to find that another PI3K inhibitor, LY294002, strongly suppressed the production of iNOS and cytokines. This effect of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) was based on its inhibitory effect on mRNA synthesis. Expression of dominant-negative mutants of PI3K in macrophages augmented the lipopolysaccharideinduced expression of iNOS. Introduction of a pH1 vector producing short hairpin RNA that targets a catalytic subunit of PI3K (p110beta) also enhanced the TLR-mediated responses. Thus, the augmentation of TLR signals by wortmannin was mediated through the inhibition of PI3K, whereas the effect of LY294002 was not explained by its effect on PI3K. These discrepancies in the effects of pharmacological inhibitors in TLR-signaling may have caused confusion regarding the role of PI3K in innate immunity.
Mol Pharmacol 2006 May
PMID:Opposite effects of wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride on toll-like receptor-mediated nitric oxide production: negative regulation of nuclear factor-{kappa}B by phosphoinositide 3-kinase. 1647 2

Aspects of cytochrome P450 (CYP) nomenclature are addressed. The rules for naming a P450 are outlined, though individuals should not name their own genes. The nomenclature is presented as a unifying principle to enhance communication across disciplines. Because of the historical nature of gene sequencing, sometimes names have to be changed, but this is kept to a bare minimum to avoid confusion in the literature. CYP names have now reached four digits owing to proliferation of CYP families in the fungi and lower eukaryotes. For example, CYP5034A1 is from Ustilago maydis. P450 sequence motifs are described that are useful in making global alignments. CYP clans are defined as clusters of CYP families. The clan names are useful in describing higher-order evolution of the gene superfamily. The nomenclature of orthologs and pseudogenes is also discussed.
Methods Mol Biol 2006
PMID:Cytochrome P450 nomenclature, 2004. 1671 69

The original definition of aerobic dive limit (ADL) was the dive duration after which there is an increase in post-dive concentration of lactate in the blood of Weddell seals freely diving in the field. The only other species in which such measurements have been made is the emperor penguin. For all other species, aerobic dive limit has been calculated (cADL) by dividing usable oxygen stores with an estimation of the rate of oxygen consumption during diving. Unfortunately, cADL is often referred to as the aerobic dive limit, implying that it is equivalent to that determined from the measurement of post-dive blood lactate concentration. However, this is not so, as at cADL all of the usable oxygen would have been consumed, whereas Weddell seals and emperor penguins can dive for at least 2-3 times longer than their ADL. Thus, at ADL, there is still some usable oxygen remaining in the stores. It is suggested that to avoid continued confusion between these two terms, the former is called diving lactate threshold (DLT), as it is somewhat analogous to the lactate threshold in exercising terrestrial vertebrates. Possible explanations of how some species routinely dive beyond their cADL are also discussed.
Comp Biochem Physiol A Mol Integr Physiol 2006 Sep
PMID:Aerobic dive limit. What is it and is it always used appropriately? 1684 44

A number of statistical tests have been proposed to detect positive Darwinian selection affecting a few amino acid sites in a protein, exemplified by an excess of nonsynonymous nucleotide substitutions. These tests are often more powerful than pairwise sequence comparison, which averages synonymous (d(S)) and nonsynonymous (d(N)) rates over the whole gene. In a recent study, however, Hughes AL and Friedman R (2005. Variation in the pattern of synonymous and nonsynonymous difference between two fungal genomes. Mol Bio Evol. 22: 1320-1324) argue that d(S) and d(N) are expected to fluctuate along the sequence by chance and that an excess of nonsynonymous differences in individual codons is no evidence for positive selection. The authors compared codons in protein-coding genes from the genomes of 2 yeast species, Saccharomyces cerevisiae and Saccharomyces paradoxus. They calculated the proportions of synonymous and nonsynonymous differences per site (p(S) and p(N)) in every codon and discovered that p(N) is often greater than p(S) and that among some codons p(S) and p(N) are negatively correlated. The authors argued that these results invalidate previous tests of codons under positive selection. Here I discuss several errors of statistics in the analysis of Hughes and Friedman, including confusion of statistics with parameters, arbitrary data filtering, and derivation of hypotheses from data. I also apply likelihood ratio tests of positive selection to the yeast data and illustrate empirically that Hughes and Friedman's criticisms on such tests are not valid.
Mol Biol Evol 2006 Dec
PMID:On the varied pattern of evolution of 2 fungal genomes: a critique of Hughes and Friedman. 1574 15

To translate basic research findings into clinical practice, it is essential that information about mutations and variations in the human genome are communicated easily and unequivocally. Unfortunately, there has been much confusion regarding the description of genetic sequence variants. This is largely because research articles that first report novel sequence variants do not often use standard nomenclature, and the final genomic sequence is compiled over many separate entries. In this article, we discuss issues crucial to clear communication, using examples of genes that are commonly assayed in clinical laboratories. Although molecular diagnostics is a dynamic field, this should not inhibit the need for and movement toward consensus nomenclature for accurate reporting among laboratories. Our aim is to alert laboratory scientists and other health care professionals to the important issues and provide a foundation for further discussions that will ultimately lead to solutions.
J Mol Diagn 2007 Feb
PMID:Standard mutation nomenclature in molecular diagnostics: practical and educational challenges. 1725 29

Our groups have previously identified in independent studies the gene At2g28160 as a central transcription factor that is required for up-regulation of iron deficiency responses in Arabidopsis roots. At2g28160 has been named in different ways in our previous studies, namely FRU=FER-LIKE REGULATOR OF IRON UPTAKE [M. Jakoby, H.Y. Wang, W. Reidt, B. Weisshaar, P. Bauer, FRU (BHLH029) is required for induction of iron mobilization genes in Arabidopsis thaliana, FEBS Lett. 577 (2004) 528-534], BHLH029 [M.A. Heim, M. Jakoby, M. Werber, C. Martin, B. Weisshaar, P.C. Bailey, The basic helix-loop-helix transcription factor family in plants: a genome-wide study of protein structure and functional diversity, Mol. Biol. Evol. 20 (2003) 735-747; Y.X. Yuan, J. Zhang, D.W. Wang, H.Q. Ling, AtbHLH29 of Arabidopsis thaliana is a functional ortholog of tomato FER involved in controlling iron acquisition in strategy I plants, Cell Res. 15 (2005) 613-621] or FIT1=Fe-DEFICIENCY-INDUCED TRANSCRIPTION FACTOR1 [E.P.Colangelo, M.L. Guerinot, The essential basic helix-loop-helix protein FIT1 is required for the iron deficiency response, Plant Cell 12 (2004) 3400-3412.] To avoid any confusion in the future we propose a common name for At2g28160 in Arabidopsis, namely FIT=FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR.
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PMID:FIT, the FER-LIKE IRON DEFICIENCY INDUCED TRANSCRIPTION FACTOR in Arabidopsis. 1746 30

Land snails are renowned model organisms in evolutionary ecology, but extensive morphological variation and lack of readily available diagnostic characters often invite taxonomic confusion among closely related species. Satsuma (Luchuhadra) largillierti is an arboreal land snail endemic to Okinawa Island, Japan, in which extensive geographic variation in shell morphology has long caused taxonomic complication. To establish robust species limits among S. largillierti and its allies, we perform molecular and morphological analyses of snails sampled from the entire range of Luchuhadra. Analyses of the mitochondrial cytochrome oxidase subunit 1 gene and nuclear ribosomal internal transcribed spacer sequences divide S. largillierti into two, reproductively isolated groups. Each of these groups includes Satsuma erabuensis and Satsuma sooi, respectively, which occur on a nearby island and were traditionally regarded as distinct species. Morphometric analysis of the genitalia further provides clear difference between the two groups, whereas differentiation in shell morphology is slight if any. These results indicate that the traditional taxonomy has overly depended on inadequate morphological difference and a priori information of island geography, which resulted in oversimplification of complex speciation history in Luchuhadra.
Mol Phylogenet Evol 2007 Nov
PMID:Cryptic genetic divergence and associated morphological differentiation in the arboreal land snail Satsuma (Luchuhadra) largillierti (Camaenidae) endemic to the Ryukyu Archipelago, Japan. 1750 12

Partial mitochondrial COI sequences (barcoding fragment) were explored for the understanding of the species boundaries of Baetis vernus group taxa (Ephemeroptera, Baetidae) in northern Europe. We sampled all species of this group occurring in Finland, but focused on taxa for which morphological and taxonomical confusion have been most apparent. The sequence matrix comprised 627 nucleotides for 96 specimens, and was analysed using parsimony. Results provided strong evidence that Baetis macani Kimmins and B. vernus Curtis comprise morphologically cryptic but molecularly distinct taxa, as intraspecific uncorrected divergences within haplogroups ranged between 0.3% and 1.4% and interspecific divergences were from 13.1% to 16.5%. These interesting findings prompt for further taxonomic studies of B. vernus taxa using more extensive specimen sampling from the known distributional areas in the Palaearctic/Holarctic region for better understanding of haplotype distributions. We stress the importance of integration of morphological and molecular data, and the necessity to employ additional nuclear DNA sequence data.
Mol Phylogenet Evol 2008 Jan
PMID:MtDNA COI barcodes reveal cryptic diversity in the Baetis vernus group (Ephemeroptera, Baetidae). 1802 96


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