Identifying genes underlying skin pigmentation differences among human populations

Skin pigmentation is a human phenotype that varies greatly among human populations and it has long been speculated that this variation is adaptive. We therefore expect the genes that contribute to these large differences in phenotype to show large allele frequency differences among populations and to possibly harbor signatures of positive selection. To identify the loci that likely contribute to among-population human skin pigmentation differences, we measured allele frequency differentiation among Europeans, Chinese and Africans for 24 human pigmentation genes from 2 publicly available, large scale SNP data sets. Several skin pigmentation genes show unusually large allele frequency differences among these populations. To determine whether these allele frequency differences might be due to selection, we employed a within-population test based on long-range haplotype structure and identified several outliers that have not been previously identified as putatively adaptive. Most notably, we identify the DCT gene as a candidate for recent positive selection in the Chinese. Moreover, our analyses suggest that it is likely that different genes are responsible for the lighter skin pigmentation found in different non-African populations. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Search for differences among t haplotypes in distorter and responder genes

Transmission ratio distortion due to the mouse t complex is though to be due to harmful effects of trans-acting distorter genes acting on a responder, with the t complex form of the responder being relatively resistant to this harmful action of the distorters. Previous work had indicated that naturally occurring t haplotypes differed in their responders or in distorters lying near the responder, with the result that animals doubly heterozygous for two responder-carrying haplotypes transmitted these haplotypes unequally. In the present work t haplotypes could be divided into three types on the basis of their transmission when doubly heterozygous with the responder-carrying partial haplotype tlowH. The majority, t0, t6, tw1, tw2 and tw73, were transmitted equally with tlowH, a second group, including tw5 and two haplotypes derived from it, were transmitted less frequently than tlowH, and the single member of a third group, tw32, was transmitted in excess of tlowH. This last result suggests that the underlying differences are in the responder itself, rather than in the distorters. Search for differences among t haplotypes in distorters produced some equivocal results possibly resulting from effects of genetic background. In particular, results of others suggesting presence of a fourth distorter, Tcd-4, were not confirmed.     

Differential differences in methylation status of putative imprinted genes among cloned swine genomes

DNA methylation is a major epigenetic modification in the mammalian genome that regulates crucial aspects of gene function. Mammalian cloning by somatic cell nuclear transfer (SCNT) often results in gestational or neonatal failure with only a small proportion of manipulated embryos producing live births. Many of the embryos that survive to term later succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. Aberrant methylation patterns of imprinted genes in cloned cattle and mice have been elucidated, but few reports have analyzed the cloned pig genome. Four surviving cloned sows that were created by ear fibroblast nuclear transfer, each with a different life span and multiple organ defects, such as heart defects and bone growth delay, were used as epigenetic study materials. First, we identified four putative differential methylation regions (DMR) of imprinted genes in the wild-type pig genome, including two maternally imprinted loci (INS and IGF2) and two paternally imprinted loci (H19 and IGF2R). Aberrant DNA methylation, either hypermethylation or hypomethylation, commonly appeared in H19 (45% of imprinted loci hypermethylated vs. 30% hypomethylated), IGF2 (40% vs. 0%), INS (50% vs. 5%), and IGF2R (15% vs. 45%) in multiple tissues from these four cloned sows compared with wild-type pigs. Our data suggest that aberrant epigenetic modifications occur frequently in the genome of cloned swine. Even with successful production of cloned swine that avoid prenatal or postnatal death, the perturbation of methylation in imprinted genes still exists, which may be one of reason for their adult pathologies and short life. Understanding the aberrant pattern of gene imprinting would permit improvements in future cloning techniques.     

Processes of genome evolution reflected by base frequency differences among Serratia marcescens genes

The G + C content of silent sites in codons varies greatly among Serratia marcescens genes; the value in any one gene seems to reflect a balance between mutation pressure towards high G + C content and natural selection constraining choice among synonymous codons. Interestingly, non-coding sequences have substantially lower G + C content than silent sites thought to be under little selective constraint.     

Cross-correlation of bilateral differences in fatigue during sustained maximal voluntary contraction

Maximal isometric force and electromyograph (EMG) activity of biceps brachii muscle during bilateral sustained elbow flexion were followed in 25 right-handed oarsmen. The percentage decline in force was greater for the left than for the right arm. Also, the mean power frequency (MPF) and the root mean square (rms) value of the EMG amplitude decreased more for the left than for the right arm. It was hypothesized that a common drive would indicate that the two forces curves would be highly correlated during the nonfatigued period, but the level of cross-correlation would decline during muscle fatigue. For the first 4 s of the contraction, the cross-correlation between the right and left force was high (r = 0.99), but thereafter it declined rapidly to a constant level. The decline of the cross-correlation was accompanied by a similar decrease in the correlation between the right and left EMG activations (MPF and rms). Thus, the decline in the cross-correlation level of force accompanied by a similar decrease in the correlation level of EMG would suggest a fatigue-induced neural derangement of the common drive.     

Mental stress induces sustained elevation of blood pressure and lipid peroxidation in postmenopausal women

Mental stress is thought to underlie cardiovascular events, but there is information on oxidative stress induced by mental stress in association with cardiovascular responses in women. Using a sensitive assay for plasma 4-hydroxy-2-nonenal (HNE), as a marker for oxidative stress, we addressed the relation between pressor responses and oxidative stress induced by mental or physical stress in premenopausal and postmenopausal women. Healthy subjects (7 postmenopausal and 8 premenopausal women, in early and late follicular phases) were subjected to mental and physical stress evoked by a Color Word Test (CWT) and isometric handgrip, respectively. The CWT induced a rapid elevation of diastolic blood pressure (DBP), at a higher level in the postmenopausal than in the premenopausal women (p<0.01), and this higher DBP was sustained during the CWT and recovery (p<0.01). The CWT induced a significant elevation in plasma noradrenaline in premenopausal women in the early follicular phase and in postmenopausal women (p<0.05). Plasma nitric oxide metabolites were higher in postmenopausal than in the premenopausal women in the late follicular phase (p<0.05), but did not change during exposure to the two types of stress in either group. Plasma HNE was increased during recovery from the CWT, but not the handgrip, in postmenopausal women (2.4 times, p<0.05). There was a significant difference in the time course of the CWT-induced HNE response between the postmenopausal and premenopausal women (p<0.05). These findings suggest that mental, but not physical, stress causes sustained diastolic blood pressure elevation in postmenopausal women, accompanied by heightened oxidative stress.     

Phagocytosis of melanized Aspergillus conidia by macrophages exerts cytoprotective effects by sustained PI3K/Akt signalling

Host cell death is a critical component of innate immunity and often determines the progression and outcome of infections. The opportunistic human pathogen Aspergillus fumigatus can manipulate the immune system either by inducing or by inhibiting host cell apoptosis dependent on its distinct morphological form. Here, we show that conidia of Aspergillus ssp. inhibit apoptosis of macrophages induced via the intrinsic (staurosporine) and extrinsic (Fas ligand) pathway. Hence, mitochondrial cytochrome c release and caspase activation were prevented. We further found that the anti-apoptotic effect depends on both host cell de novo protein synthesis and phagocytosis of conidia by macrophages. Moreover, sustained PI3K/Akt signalling in infected cells is an important determinant to resist apoptosis. We demonstrate that pigmentless pksP mutant conidia of A. fumigatus failed to trigger protection against apoptosis and provide evidence that the sustained survival of infected macrophages depends on the presence of the grey-green conidial pigment consisting of dihydroxynaphthalene-melanin. In conclusion, we revealed a novel potential function of melanin in the pathogenesis of A. fumigatus. For the first time, we show that melanin itself is a crucial component to inhibit macrophage apoptosis which may contribute to dissemination of the fungus within the host.     

Effect of sustained serum prolactin elevation on breast epithelial and myoepithelial cell proliferation

Abstract.
Oral administration of the dopamine antagonist perphenazine (0·01% in drinking water) to adult female Sprague-Dawley rats led to a three- to fourfold increase in serum prolactin by the first time point sampled (day 2) and a sustained fourfold elevation from day 4 of treatment to the end of the experiment (day 54). In response, five- to sixfold (day 7) and three- to fourfold (day 4) peak elevations in the epithelial cell metaphase indices were seen in the breast lobular and ductular compartments respectively. Both indices fell to basal levels on day 14 but returned to a second, but diminished, peak on day 27. By day 54, the mitotic activity of the epithelium had fallen to just above basal levels in both compartments. A similar mitotic response occurred in the myoepithelial cells, clearly indicating that these must be considered an important cell kinetic component during breast stimulation. Breast epithelial cell number increased 13-14 fold in the lobular but only two- to threefold in the ductular compartments in response to perphenazine administration. Again, similar responses were seen in the myoepithelial cell population. The major proliferative response therefore occurred within the lobular as opposed to the ductular compartment. A considerable discrepancy was shown between the cell number at each time point and that predicted on the assumption of constant cell death rate. We conclude that a growth desensitizing mechanism exists in the rat breast which limits breast growth in the presence of a sustained trophic hormone stimulation. Furthermore, we suggest that this limitation in breast growth is brought about by a mechanism which involves increased cell death in addition to decreased mitotic activity.     

Effect of sustained serum prolactin elevation on breast epithelial and myoepithelial cell proliferation

Oral administration of the dopamine antagonist perphenazine (0.01% in drinking water) to adult female Sprague-Dawley rats led to a three- to fourfold increase in serum prolactin by the first time point sampled (day 2) and a sustained fourfold elevation from day 4 of treatment to the end of the experiment (day 54). In response, five- to sixfold (day 7) and three- to fourfold (day 4) peak elevations in the epithelial cell metaphase indices were seen in the breast lobular and ductular compartments respectively. Both indices fell to basal levels on day 14 but returned to a second, but diminished, peak on day 27. By day 54, the mitotic activity of the epithelium had fallen to just above basal levels in both compartments. A similar mitotic response occurred in the myoepithelial cells, clearly indicating that these must be considered an important cell kinetic component during breast stimulation. Breast epithelial cell number increased 13-14 fold in the lobular but only two- to threefold in the ductular compartments in response to perphenazine administration. Again, similar responses were seen in the myoepithelial cell population. The major proliferative response therefore occurred within the lobular as opposed to the ductular compartment. A considerable discrepancy was shown between the cell number at each time point and that predicted on the assumption of constant cell death rate. We conclude that a growth desensitizing mechanism exists in the rat breast which limits breast growth in the presence of a sustained trophic hormone stimulation. Furthermore, we suggest that this limitation in breast growth is brought about by a mechanism which involves increased cell death in addition to decreased mitotic activity.     

Serological differences among the dermatophytes.

Antigens were prepared from young mycelial growth of 20 species of dermatophytes, and tested by double diffusion against homologous and heterologous antisera raised in rabbits. 48 distinct antigens were recognised by the procedures used. Although there were a considerable number of common reactions, there were significant differences between species and groups. Species of Microsporum, with the exception of M. gypseum and M. persicolor, form a coherent group distinct from Epidermophyton and Trichophyton. All Trichophyton species investigated with the exception of T. ajelloi, were serologically closely related. M. gypseum, T. ajelloi and M. persicolor showed affinities with both Microsporum and Trichophyton, and possibly form an intermediate group. The system used does not permit differentiation of species by serological means, but gives a new dimension to the inter-relationships of these fungi.     

Allotypic differences in murine mu genes.

We report the complete DNA sequence of a c-DNA clone of the heavy chain mu b allele of the C57BL/6 mouse. Comparisons have been made with the nucleotide sequences of the germ line BALB/c mu a and the plasmacytoma TEPC-183 mu a alleles reported elsewhere over the entire length of the coding and the 3' untranslated region. In contrast to the extensive differences between the gamma 2a a and b alleles we have reported earlier we see a very high degree of homology between the mu alleles. Only one of the nucleotide differences between C57BL/6 mu b and BALB/c mu a leads to an amino acid substitution. This single amino acid exchange must form the allotypic determinant of the mu b allele. A comparison of four different DNA sequences indicates that they are all distinct IgM alleles.     

Major differences in the responses of primary human leukocyte subsets to IFN-beta

Treatment of cell lines with type I IFNs activates the formation of IFN-stimulated gene factor 3 (STAT1/STAT2/IFN regulatory factor-9), which induces the expression of many genes. To study this response in primary cells, we treated fresh human blood with IFN-β and used flow cytometry to analyze phosphorylated STAT1, STAT3, and STAT5 in CD4(+) and CD8(+) T cells, B cells, and monocytes. The activation of STAT1 was remarkably different among these leukocyte subsets. In contrast to monocytes and CD4(+) and CD8(+) T cells, few B cells activated STAT1 in response to IFN-β, a finding that could not be explained by decreased levels of IFNAR2 or STAT1 or enhanced levels of suppressor of cytokine signaling 1 or relevant protein tyrosine phosphatases in B cells. Microarray and real-time PCR analyses revealed the induction of STAT1-dependent proapoptotic mRNAs in monocytes but not in B cells. These data show that IFN-stimulated gene factor 3 or STAT1 homodimers are not the main activators of gene expression in primary B cells of healthy humans. Notably, in B cells and, especially in CD4(+) T cells, IFN-β activated STAT5 in addition to STAT3, with biological effects often opposite from those driven by activated STAT1. These data help to explain why IFN-β increases the survival of primary human B cells and CD4(+) T cells but enhances the apoptosis of monocytes, as well as to understand how leukocyte subsets are differentially affected by endogenous type I IFNs during viral or bacterial infections and by type I IFN treatment of patients with multiple sclerosis, hepatitis, or cancer.     

Quantitative differences among the brains of cephalopods

The relative sizes of 30 lobes of the brains of 63 species of cephalopods have been compared. Some of the observed differences could be related to the way of life of the animal and others to the taxonomic relationships. The octopods are separated from the decapods by their larger brachial and other suboesophageal lobes, larger inferior frontal systems and smaller optic lobes. Vampyroteulhis lies somewhat between these two main groups. The vertical lobe system is large in sepioids and loliginids, smaller in decapods from deeper water, but large in Vampyroteuthis. In octopods, it is large in the typical epibenthic forms but smaller in those from deeper water and very small in cirrates. The inferior frontal system is very large in epibenthic octopods and Benthoctopus and in cirrates, but smaller in epipelagic and bathypelagic forms. The optic lobes are larger in decapods than in octopods from comparable depths and are especially large in deep-sea decapods. They are larger in epipelagic octopods than in the typical benthic forms. The photosensitive vesicles vary by nearly two orders of magnitude. They are very small in squids living in surface waters, larger in mesopelagic forms and enormous in some cranchiids and in Balhyteuthis. In Histioteulhis , the side with the larger eye had an optic lobe twice as big as that on the side of the smaller eye, but with only slight differences in other parts of the brain. In the octopods, the inferior frontal system was generally large, being concerned with the tactile memory system, and tends to be inversely related to the size of the optic lobe.     

Simultaneous exposure to ATP and phenylephrine induces a sustained elevation in the intracellular calcium concentration in supraoptic neurons

Vasopressin (VP) release from the hypothalamo-neurohypophyseal system (HNS) is stimulated by ATP activation of P2X purinergic receptors and by activation of 1-adrenergic receptors by phenylephrine (PE). These responses are potentiated by simultaneous exposure to ATP+PE. Potentiation was blocked by depleting intracellular calcium stores with thapsigargin. To test the hypothesis that the synergistic response to ATP+PE reflects alterations in the intracellular calcium concentration ([Ca2+]i), [Ca2+]i was monitored in supraoptic neurons in HNS explants loaded with fura 2-AM. Both ATP and PE induced rapid, but transient, elevations in [Ca2+]i. In 0.3 mM Ca2+, the peak response to ATP was greater than to PE but did not differ from the peak response to ATP+PE. A sustained elevation in [Ca2+]i was induced by ATP+PE, that was greater than ATP or PE alone. In 2 mM Ca2+, the peak response to ATP+PE was significantly greater than to either ATP or PE alone, and the sustained response to ATP+PE was greater than to either agent alone. Responses were comparable in the presence of TTX. The sustained elevation in [Ca2+]i was also observed when ATP+PE was removed after 1 min, but it was eliminated by either thapsigargin or removing external calcium, indicating that both calcium influx and calcium release from internal stores are required. Some cells were vasopressinergic based on a VP-induced increase in [Ca2+]i. These observations support the hypothesis that simultaneous exposure to ATP+PE induces a different pattern of [Ca2+]i than either agent alone that may initiate events leading to synergistic stimulation of VP release.     

Variation in G + C-content and codon choice: differences among synonymous codon groups in vertebrate genes.

The relationship between G + C-content and codon usage in genes of human, mus, rat, bovine and chicken nuclear genomes was investigated. Correlation and lineal regression analyses were carried out on plots that related the frequency of each codon within each synonymous codon group to the G + C-content of the coding sequence as a whole. Under GC pressure, in most of the quartet codon groups there is a preferential choice of the C-ending codon, except in leucine and valine codon groups where the choice of the G-ending codon is preferred. Among ducts, the choice of codons specifying phenylalanine and glutamate shows the strongest dependence on G + C-content. The relationship found between G + C-content and codon usage in these genomes correlate with taxonomic distance.     

Major genes control hormone-induced ovulation rate in mice

The present study examined the magnitude of genetic variation, mode of inheritance and number of loci controlling major genetic differences in hormone-induced ovulation rate in mice. Mice were injected with 5 i.u. PMSG at 28 days of age and 5 i.u. hCG at 30 days, and hormone-induced ovulation rate was determined from counts of oviducal eggs in cumulus the next morning. Six-fold genetic differences in induced ovulation rate were detected amongst strains, ranging from a low mean (+/- s.e.) value of 8.8 (+/- 0.9) in A/J up to 53.5 (+/- 2.2) in C57BL/6J. The number of ova differed significantly amongst strains and amongst F1 crosses (P less than 0.0001): 70% of the variation in hormone-induced ovulation rate was amongst strains. Of 9 F1 crosses examined, 4 showed positive heterosis, 3 showed no heterosis and 2 showed negative heterosis for hormone-induced ovulation rate. Analysis of parental, F1 and F2 generations revealed that the induced ovulation rate of A/J and C57BL/6J mice differed due to the action of about 3 or 4 loci, and A.SW/SnJ and SJL/J mice differed due to the action of about 2 to 3 loci. Analysis of recombinant inbred strains formed from A/J and C57BL/6J confirmed that these strains differed due to the action of a small number of loci. This study demonstrates the existence of a small number of major genes controlling hormone-induced ovulation rate in young mice.