The Genomic Signature of Crop-Wild Introgression in Maize

The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana, (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes were particularly resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly informing our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies

The Reproducibility of Blood Acid Base Responses in Male Collegiate Athletes Following Individualised Doses of Sodium Bicarbonate: A Randomised Controlled Crossover Study

Background: Current evidence suggests sodium bicarbonate (NaHCO3) should be ingested based upon the individualised alkalotic peak of either blood pH or bicarbonate (HCO3−) because of large inter-individual variations (10–180 min). If such a strategy is to be practical, the blood analyte response needs to be reproducible. Objective: This study aimed to evaluate the degree of reproducibility of both time to peak (TTP) and absolute change in blood pH, HCO3− and sodium (Na+) following acute NaHCO3 ingestion. Methods: Male participants (n = 15) with backgrounds in rugby, football or sprinting completed six randomised treatments entailing ingestion of two doses of 0.2 g·kg−1 body mass (BM) NaHCO3 (SBC2a and b), two doses of 0.3 g·kg−1 BM NaHCO3 (SBC3a and b) or two control treatments (CON1a and b) on separate days. Blood analysis included pH, HCO3− and Na+ prior to and at regular time points following NaHCO3 ingestion over a 3-h period. Results: HCO3− displayed greater reproducibility than pH in intraclass correlation coefficient (ICC) analysis for both TTP (HCO3− SBC2 r = 0.77, P = 0.003; SBC3 r = 0.94, P < 0.001; pH SBC2 r = 0.62, P = 0.044; SBC3 r = 0.71, P = 0.016) and absolute change (HCO3− SBC2 r = 0.89, P < 0.001; SBC3 r = 0.76, P = 0.008; pH SBC2 r = 0.84, P = 0.001; SBC3 r = 0.62, P = 0.041). Conclusion: Our results indicate that both TTP and absolute change in HCO3− is more reliable than pH. As such, these data provide support for an individualised NaHCO3 ingestion strategy to consistently elicit peak alkalosis before exercise. Future work should utilise an individualised NaHCO3 ingestion strategy based on HCO3− responses and evaluate effects on exercise performance

Androgen receptor footprint on the way to prostate cancer progression

The prostate gland is exquisitely sensitive to androgen receptor (AR) signaling. AR signaling is obligatory for prostate development and changes in AR levels, its ligands or shifts in AR mode of action are reflected in the physiology of the prostate. The AR is intimately linked to prostate cancer biology through the regulation of epithelial proliferation, suppression of apoptosis and the development of castration-resistant disease. Thus, AR is the primary therapeutic target in various prostate diseases such as BPH and cancer. Although some tumors lose AR expression, most retain the AR and have elevated levels and/or shifts in activity that are required for tumor progression and metastasis. New AR inhibitors currently in clinical trials with higher receptor affinity and specificity may improve prostate cancer patient outcome. Several events play an important role in initiation, primary tumor development and metastatic spread. Androgen receptor activity and promoter specificity change due to altered coregulator expression. Changes in epigenetic surveillance alter the AR cistrome. Both systemic and local inflammation increases with PCa progression affecting AR levels, activity, and requirement for ligand. Our current understanding of AR biology suggest that global androgen suppression may drive the development of castration-resistant disease and therefore the question remains: Does effective inhibition of AR activity mark the end of the road for PCa or only a sharp turn toward a different type of malignancy

Disease-associated alleles in genome-wide association studies are enriched for derived low frequency alleles relative to HapMap and neutral expectations

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies give insight into the genetic basis of common diseases. An open question is whether the allele frequency distributions and ancestral vs. derived states of disease-associated alleles differ from the rest of the genome. Characteristics of disease-associated alleles can be used to increase the yield of future studies.</p> <p>Methods</p> <p>The set of all common disease-associated alleles found in genome-wide association studies prior to January 2010 was analyzed and compared with HapMap and theoretical null expectations. In addition, allele frequency distributions of different disease classes were assessed. Ages of HapMap and disease-associated alleles were also estimated.</p> <p>Results</p> <p>The allele frequency distribution of HapMap alleles was qualitatively similar to neutral expectations. However, disease-associated alleles were more likely to be low frequency derived alleles relative to null expectations. 43.7% of disease-associated alleles were ancestral alleles. The mean frequency of disease-associated alleles was less than randomly chosen CEU HapMap alleles (0.394 vs. 0.610, after accounting for probability of detection). Similar patterns were observed for the subset of disease-associated alleles that have been verified in multiple studies. SNPs implicated in genome-wide association studies were enriched for young SNPs compared to randomly selected HapMap loci. Odds ratios of disease-associated alleles tended to be less than 1.5 and varied by frequency, confirming previous studies.</p> <p>Conclusions</p> <p>Alleles associated with genetic disease differ from randomly selected HapMap alleles and neutral expectations. The evolutionary history of alleles (frequency and ancestral vs. derived state) influences whether they are implicated in genome-wide assocation studies.</p

Genome-Wide Association Study SNPs in the Human Genome Diversity Project Populations: Does Selection Affect Unlinked SNPs with Shared Trait Associations?

Genome-wide association studies (GWAS) have identified more than 2,000 trait-SNP associations, and the number continues to increase. GWAS have focused on traits with potential consequences for human fitness, including many immunological, metabolic, cardiovascular, and behavioral phenotypes. Given the polygenic nature of complex traits, selection may exert its influence on them by altering allele frequencies at many associated loci, a possibility which has yet to be explored empirically. Here we use 38 different measures of allele frequency variation and 8 iHS scores to characterize over 1,300 GWAS SNPs in 53 globally distributed human populations. We apply these same techniques to evaluate SNPs grouped by trait association. We find that groups of SNPs associated with pigmentation, blood pressure, infectious disease, and autoimmune disease traits exhibit unusual allele frequency patterns and elevated iHS scores in certain geographical locations. We also find that GWAS SNPs have generally elevated scores for measures of allele frequency variation and for iHS in Eurasia and East Asia. Overall, we believe that our results provide evidence for selection on several complex traits that has caused changes in allele frequencies and/or elevated iHS scores at a number of associated loci. Since GWAS SNPs collectively exhibit elevated allele frequency measures and iHS scores, selection on complex traits may be quite widespread. Our findings are most consistent with this selection being either positive or negative, although the relative contributions of the two are difficult to discern. Our results also suggest that trait-SNP associations identified in Eurasian samples may not be present in Africa, Oceania, and the Americas, possibly due to differences in linkage disequilibrium patterns. This observation suggests that non-Eurasian and non-East Asian sample populations should be included in future GWAS