Under-dominance constrains the evolution of negative autoregulation in diploids

Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this stiking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance - mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution

A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.

Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combined in vitro and in vivo approach, we have identified Ventral Anterior Homeobox 1 (Vax1) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts in Vax1 knock-out embryos revealed Vax1 to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects of Vax1 on fertility, we generated Vax1flox mice and crossed them with Gnrhcre mice to specifically delete Vax1 within GnRH neurons. GnRH staining in Vax1flox/flox:GnRHcre mice show a total absence of GnRH expression in the adult. We performed lineage tracing in Vax1flox/flox:GnRHcre:RosaLacZ mice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and GT1-7, we show that VAX1 is a direct regulator of Gnrh1 transcription by binding key ATTA sites within the Gnrh1 promoter. This study identifies VAX1 as a key transcription factor regulating GnRH expression and establishes VAX1 as a novel candidate gene implicated in heritable infertility

Sex-related differences in chromatic sensitivity

Generally women are believed to be more discriminating than men in the use of colour names and this is often taken to imply superior colour vision. However, if both X-chromosome linked colour deficient males (~8%) and females (<1%) as well as heterozygote female carriers (~15%) are excluded from comparisons, then differences between men and women in red-green colour discrimination have been reported as not being significant (e.g., Pickford, 1944; Hood et al., 2006). We re-examined this question by assessing the performance of 150 males and 150 females on the Colour Assessment and Diagnosis (CAD) test (Rodriguez-Carmona, 2005). This is a sensitive test that yields small colour detection thresholds. The test employs direction-specific, moving, chromatic stimuli embedded in a background of random, dynamic, luminance contrast noise. A four-alternative, forced-choice procedure is employed to measure the subject’s thresholds for detection of colour signals in 16 directions in colour space, while ensuring that the subject cannot make use of any residual luminance contrast signals. In addition, we measured the Rayleigh anomaloscope matches in a subgroup of 111 males and 114 females. All the age-matched males (30.8 ± 9.7) and females (26.7 ± 8.8) had normal colour vision as diagnosed by a battery of conventional colour vision tests. Females with known colour deficient relatives were excluded from the study. Comparisons between the male and female groups revealed no significant differences in anomaloscope midpoints (p=0.709), but a significant difference in matching ranges (p=0.040); females on average tended to have a larger mean range (4.11) than males (3.75). Females also had significantly higher CAD thresholds than males along the red-green (p=0.0004), but not along the yellow-blue discrimination axis. The differences between males and females in red-green discrimination may be related to the heterozygosity in X-linked cone photopigment expression common among females

Gene dynamics of toll-like receptor 4 through a population bottleneck in an insular population of water voles (Arvicola amphibius)

Acknowledgments We would like to thank all colleagues who have contributed to fieldwork and sampling during this study. We would especially like to thank Marius Wenzel and Sandra Telfer for collaboration with different aspects of the study, and Dave Jones and Nat Jones for Bartonella PCR assays. This work was supported by the BBSRC studentship to MKG (BB/J01446X/1) and a NERC studentship to MKO. The research was carried out under project license PPL 40/1813.Peer reviewedPublisher PD

Reliability assessment of null allele detection: inconsistencies between and within different methods

Microsatellite loci are widely used in population genetic studies, but the presence of null alleles may lead to biased results. Here we assessed five methods that indirectly detect null alleles, and found large inconsistencies among them. Our analysis was based on 20 microsatellite loci genotyped in a natural population of Microtus oeconomus sampled during 8 years, together with 1200 simulated populations without null alleles, but experiencing bottlenecks of varying duration and intensity, and 120 simulated populations with known null alleles. In the natural population, 29% of positive results were consistent between the methods in pairwise comparisons, and in the simulated dataset this proportion was 14%. The positive results were also inconsistent between different years in the natural population. In the null-allele-free simulated dataset, the number of false positives increased with increased bottleneck intensity and duration. We also found a low concordance in null allele detection between the original simulated populations and their 20% random subsets. In the populations simulated to include null alleles, between 22% and 42% of true null alleles remained undetected, which highlighted that detection errors are not restricted to false positives. None of the evaluated methods clearly outperformed the others when both false positive and false negative rates were considered. Accepting only the positive results consistent between at least two methods should considerably reduce the false positive rate, but this approach may increase the false negative rate. Our study demonstrates the need for novel null allele detection methods that could be reliably applied to natural population

Autosegregation of enzyme loci Me1 and Gpi2 in agamospermous progenies of triploid sugarbeet plants

Ratios of malic-enzyme (ME1) and glucosephosphate isomerase (GPI2) phenotypic classes were studied in agamospermous progenies of triploid sugar beet plants. It was shown that the ratio of enzymes phenotypic classes quite well accords with the calculations based on the supposition about reduplication of chromosome sites carrying alleles of enzyme loci accompanied by a loss of excessive allelic copies in the first cell division under embryogenesis. Polyteny &#x2013; conditioned allelic dose increase leads to the occurrence of alleles &#x2013; absent in the initial parent &#x2013; at a certain frequency in the developing progeny. The notions of &#x201c;meiotic autosegregation&#x201d; and &#x201c;mitotic autosegregation&#x201d; &#x2013; typical of meiotic and mitotic agamospermy, respectively, &#x2013; were introduced; the term locus &#x201c;polygenotype&#x201d; characterizing the allelic composition of locus, number of chromosomes and a copies number of chromatides sites carrying marker-locus alleles in the cell before entering embryogenesis was also introduced

Evolutionary ecology of opsin gene sequence, expression and repertoire.

Linking molecular evolution to biological function is a long-standing challenge in evolutionary biology. Some of the best examples of this involve opsins, the genes that encode the molecular basis of light reception. In this issue of Molecular Ecology, three studies examine opsin gene sequence, expression and repertoire to determine how natural selection has shaped the visual system. First, Escobar-Camacho et al. () use opsin repertoire and expression in three Amazonian cichlid species to show that a shift in sensitivity towards longer wavelengths is coincident with the long-wavelength-dominated Amazon basin. Second, Stieb et al. () explore opsin sequence and expression in reef-dwelling damselfish and find that UV- and long-wavelength vision are both important, but likely for different ecological functions. Lastly, Suvorov et al. () study an expansive opsin repertoire in the insect order Odonata and find evidence that copy number expansion is consistent with the permanent heterozygote model of gene duplication. Together these studies emphasize the utility of opsin genes for studying both the local adaptation of sensory systems and, more generally, gene family evolution

Preliminary genetic evidence of two different populations of Opisthorchis viverrini in Lao PDR

Opisthorchis viverrini is a major public health concern in Southeast Asia. Various reports have suggested that this parasite may represent a species complex, with genetic structure in the region perhaps being dictated by geographical factors and different species of intermediate hosts. We used four microsatellite loci to analyze O. viverrini adult worms originating from six species of cyprinid fish in Thailand and Lao PDR. Two distinct O. viverrini populations were observed. In Ban Phai, Thailand, only one subgroup occurred, hosted by two different fish species. Both subgroups occurred in fish from That Luang, Lao PDR, but were represented to very different degrees among the fish hosts there. Our data suggest that, although geographical separation is more important than fish host specificity in influencing genetic structure, it is possible that two species of Opisthorchis, with little interbreeding, are present near Vientiane in Lao PDR