Effects of Common Polymorphisms rs11614913 in miR-196a2 and rs2910164 in miR-146a on Cancer Susceptibility: A Meta-Analysis

BACKGROUND: MicroRNAs regulate gene expression at the post-transcriptional level and involved in diverse biological and pathological processes, including tumorigenesis. Rs11614913 in miR-196a2 and rs2910164 in miR-146a are shown to associate with increased/decreased cancer risk. We performed a meta-analysis to systematically summarize the possible association. METHODOLOGY/PRINCIPAL FINDINGS: We assessed published studies of the association between these microRNA polymorphisms and cancer risk from eleven studies with 16,771 subjects for miR-196a2 and from ten studies with 15,126 subjects for miR-146a. As for rs11614913, the contrast of homozygote (TT vs CC: OR = 0.92, 95% CI = 0.85-0.99, P(heterogeneity) = 0.45), allele (T vs C: OR = 0.96, 95% CI = 0.92-0.99, P(heterogeneity) = 0.61) and recessive model (OR = 0.90, 95% CI = 0.84-0.97, P(heterogeneity) = 0.50) produced statistically association. Subgroup analysis by ethnicity, statistically significantly decreased cancer risks were found among Asians for allele contrast (OR = 0.95, 95% CI = 0.90-0.99, P(heterogeneity) = 0.74) and the recessive genetic model (OR = 0.90, 95% CI = 0.82-0.98, P(heterogeneity) = 0.85). According to subgroup analysis by tumor types, the protective effect of C/T polymorphism was only found in breast cancer under allele contrast (T vs C: OR = 0.94, 95% CI = 0.88-0.99, P(heterogeneity) = 0.26). For rs2910164, no significant associations were found among overall analysis model with relatively large heterogeneity. Through the stratified analysis, heterogeneity decreased significantly. In the subgroup analyses by cancer types, the C allele of rs2910164 was associated with protection from digestive cancer in allele contrast (C vs G: OR = 0.86, 95% CI = 0.77-0.96, P(heterogeneity) = 0.51). CONCLUSIONS/SIGNIFICANCE: Our meta-analysis suggests that the rs11614913 most likely contributes to decreased susceptibility to cancer, especially in Asians and breast cancer. Besides, the C allele of the rs2910164 might be associated with a protection from digestive cancer

Hsa-miR-196a2 Rs11614913 Polymorphism Contributes to Cancer Susceptibility: Evidence from 15 Case-Control Studies

BACKGROUND: MicroRNAs (miRNAs) are a family of endogenous, small and noncoding RNAs that negatively regulate gene expression by suppressing translation or degrading mRNAs. Recently, many studies investigated the association between hsa-miR-196a2 rs11614913 polymorphism and cancer risk, which showed inconclusive results. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a meta-analysis of 15 studies that included 9,341 cancer cases and 10,569 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, individuals with the TC/CC genotypes were associated with higher cancer risk than those with the TT genotype (OR=1.18, 95% CI=1.03-1.34, P<0.001 for heterogeneity test). In the stratified analyses, we observed that the CC genotype might modulate breast cancer risk (OR=1.11, 95%CI=1.01-1.23, Pheterogeneity=0.210) and lung cancer risk (OR=1.25, 95%CI=1.06-1.46, Pheterogeneity=0.958), comparing with the TC/TT genotype. Moreover, a significantly increased risk was found among Asian populations in a dominant model (TC/CC versus TT, OR=1.24, 95% CI=1.07-1.43, Pheterogeneity=0.006). CONCLUSIONS: These findings supported that hsa-miR-196a2 rs11614913 polymorphism may contribute to the susceptibility of cancers

α-Adducin Gly460Trp Gene Mutation and Essential Hypertension in a Chinese Population: A Meta-Analysis including 10960 Subjects

BACKGROUND: The α-adducin Gly460Trp (G460W) gene polymorphism may be associated with susceptibility to essential hypertension (EH), but this relationship remains controversial. In an attempt to resolve this issue, we conducted a meta-analysis. METHODS: Twenty-three separated studies involving 5939 EH patients and 5021 controls were retrieved and analyzed. Four ethnicities were included: Han, Kazakh, Mongolian, and She. Eighteen studies with 5087 EH patients and 4183 controls were included in the Han subgroup. Three studies with 636 EH patients and 462 controls were included in the Kazakh subgroup. The Mongolian subgroup was represented by only one study with 100 EH patients and 50 controls; similarly, only one study with 116 EH patients and 326 controls was available for the She subgroup. The pooled and ethnic group odds ratios (ORs) along with the corresponding 95% confidence intervals (95% CI) were assessed using a random effects model. RESULTS: There was a significant association between the α-adducin G460W gene polymorphism and EH in the pooled Chinese population under both an allelic genetic model (OR: 1.12, 95% CI: 1.04-1.20, P = 0.002) and a recessive genetic model (OR: 1.40, 95% CI: 1.16-1.70, P = 0.0005). In contrast, no significant association between the α-adducin G460W gene polymorphism and EH was observed in the dominant genetic model (OR: 0.88, 95% CI: 0.72-1.09, P = 0.24). In stratified analysis by ethnicity, significantly increased risk was detected in the Han subgroup under an allelic genetic model (OR: 1.13, 95% CI: 1.04-1.23, P = 0.003) and a recessive genetic model (OR: 1.43, 95% CI: 1.17-1.75, P = 0.0006). CONCLUSIONS: In a Chinese population of mixed ethnicity, the α-adducin G460W gene polymorphism was linked to EH susceptibility, most strongly in Han Chinese

Population Structure as Revealed by mtDNA and Microsatellites in Northern Fur Seals, Callorhinus ursinus, throughout Their Range

Background: The northern fur seal (Callorhinus ursinus; NFS) is a widely distributed pinniped that has been shown to exhibit a high degree of philopatry to islands, breeding areas on an island, and even to specific segments of breeding areas. This level of philopatry could conceivably lead to highly genetically divergent populations. However, northern fur seals have the potential for dispersal across large distances and have experienced repeated rapid population expansions following glacial retreat and the more recent cessation of intensive harvest pressure. Methodology/Principal Findings: Using microsatellite and mitochondrial loci, we examined population structure in NFS throughout their range. We found only weak population genetic structure among breeding islands including significant FST and W ST values between eastern and western Pacific islands. Conclusions: We conclude that insufficient time since rapid population expansion events (both post glacial and following the cessation of intense harvest pressure) mixed with low levels of contemporary migration have resulted in an absence of genetic structure across the entire northern fur seal range

PTEN/MMAC1 expression in melanoma resection specimens

PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semi-quantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas

Radiating on Oceanic Islands: Patterns and Processes of Speciation in the Land Snail Genus Theba (Risso 1826)

Island radiations have played a major role in shaping our current understanding of allopatric, sympatric and parapatric speciation. However, the fact that species divergence correlates with island size emphasizes the importance of geographic isolation (allopatry) in speciation. Based on molecular and morphological data, we investigated the diversification of the land snail genus Theba on the two Canary Islands of Lanzarote and Fuerteventura. Due to the geological history of both islands, this study system provides ideal conditions to investigate the interplay of biogeography, dispersal ability and differentiation in generating species diversity. Our analyses demonstrated extensive cryptic diversification of Theba on these islands, probably driven mainly by non-adaptive allopatric differentiation and secondary gene flow. In a few cases, we observed a complete absence of gene flow among sympatrically distributed forms suggesting an advanced stage of speciation. On the Jandía peninsula genome scans suggested genotype-environment associations and potentially adaptive diversification of two closely related Theba species to different ecological environments. We found support for the idea that genetic differentiation was enhanced by divergent selection in different environments. The diversification of Theba on both islands is therefore best explained by a mixture of non-adaptive and adaptive speciation, promoted by ecological and geomorphological factors

Exploring Demographic, Physical, and Historical Explanations for the Genetic Structure of Two Lineages of Greater Antillean Bats

Observed patterns of genetic structure result from the interactions of demographic, physical, and historical influences on gene flow. The particular strength of various factors in governing gene flow, however, may differ between species in biologically relevant ways. We investigated the role of demographic factors (population size and sex-biased dispersal) and physical features (geographic distance, island size and climatological winds) on patterns of genetic structure and gene flow for two lineages of Greater Antillean bats. We used microsatellite genetic data to estimate demographic characteristics, infer population genetic structure, and estimate gene flow among island populations of Erophylla sezekorni/E. bombifrons and Macrotus waterhousii (Chiroptera: Phyllostomidae). Using a landscape genetics approach, we asked if geographic distance, island size, or climatological winds mediate historical gene flow in this system. Samples from 13 islands spanning Erophylla's range clustered into five genetically distinct populations. Samples of M. waterhousii from eight islands represented eight genetically distinct populations. While we found evidence that a majority of historical gene flow between genetic populations was asymmetric for both lineages, we were not able to entirely rule out incomplete lineage sorting in generating this pattern. We found no evidence of contemporary gene flow except between two genetic populations of Erophylla. Both lineages exhibited significant isolation by geographic distance. Patterns of genetic structure and gene flow, however, were not explained by differences in relative effective population sizes, island area, sex-biased dispersal (tested only for Erophylla), or surface-level climatological winds. Gene flow among islands appears to be highly restricted, particularly for M. waterhousii, and we suggest that this species deserves increased taxonomic attention and conservation concern

Signatures of Environmental Genetic Adaptation Pinpoint Pathogens as the Main Selective Pressure through Human Evolution

Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes