MicroRNAs (miRNAs) regulate gene output by targeting degenerate elements in mRNAs and have undergone drastic expansions in higher metazoan genomes. The evolutionary advantage of maintaining copies of highly similar miRNAs is not well understood, nor is it clear what unique functions, if any, miRNA family members possess. Here, we study evolutionary patterns of metazoan miRNAs, focusing on the targeting preferences of the let-7 and miR-10 families. These studies reveal hotspots for sequence evolution with implications for targeting and secondary structure. High-throughput screening for functional targets reveals that each miRNA represses sites with distinct features and regulates a large number of genes with cooperative function in regulatory networks. Unexpectedly, given the high degree of similarity, single-nucleotide changes grant miRNA family members with distinct targeting preferences. Together, our data suggest complex functional relationships among miRNA duplications, novel expression patterns, sequence change, and the acquisition of new targets.
It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta-analysis to assess whether this ‘evolutionary mismatch hypothesis’ can explain susceptibility to both estrogen receptor positive (ER-positive) and estrogen receptor negative (ER-negative) cancer. Our meta-analysis includes a total of 33 studies and examines parity, age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer.
In a meta-analysis published by myself and co-authors, we report differences in the life history risk factors for estrogen receptor negative (ER−) and estrogen receptor positive (ER+) breast cancers. Our meta-analysis did not find the association of ER− breast cancer risk with fast life history characteristics that Hidaka and Boddy suggest in their response to our article. There are a number of possible explanations for the differences between their conclusions and the conclusions we drew from our meta-analysis, including limitations of our meta-analysis and methodological challenges in measuring and categorizing estrogen receptor status. These challenges, along with the association of ER+ breast cancer with slow life history characteristics, may make it challenging to find a clear signal of ER− breast cancer with fast life history characteristics, even if that relationship does exist. The contradictory results regarding breast cancer risk and life history characteristics illustrate a more general challenge in evolutionary medicine: often different sub-theories in evolutionary biology make contradictory predictions about disease risk. In this case, life history models predict that breast cancer risk should increase with faster life history characteristics, while the evolutionary mismatch hypothesis predicts that breast cancer risk should increase with delayed reproduction. Whether life history tradeoffs contribute to ER− breast cancer is still an open question, but current models and several lines of evidence suggest that it is a possibility.
Recent transcriptome data from yeast, worm, plants, and humans has shown that alternative polyadenylation (APA), a mechanism that enables expression of multiple 3′UTR isoforms for the same gene, is widespread in eukaryotic organisms. It is still poorly understood why metazoans require multiple 3′UTRs for the same gene, but accumulating evidence suggests that APA is largely regulated at a tissue-specific level. APA may direct combinatorial variation between cis-elements and microRNAs, perhaps to regulate gene expression in a tissue-specific manner. Apart from a few single gene anecdotes, this idea has not been systematically explored.
This dissertation research employs a systems biology approach to study the somatic tissue dynamics of APA and its impact on microRNA targeting networks in the small nematode C. elegans. In the first aim, tools were developed and applied to isolate and sequence mRNA from worm intestine and muscle tissues, which revealed pervasive tissue-specific APA correlated with microRNA regulation. The second aim provides genetic evidence that two worm genes use APA to escape repression by microRNAs in the body muscle. Finally, in aim three, mRNA from five additional somatic worm tissues was sequenced and their 3′ends mapped, allowing for an integrative study of APA and microRNA targeting dynamics in worms. Together, this work provides evidence that APA is a pervasive mechanism operating in somatic tissues of C. elegans with the potential to significantly rearrange their microRNA regulatory networks and precisely dose their gene expression.
The eddy covariance technique is well established to measure energy, water, and carbon fluxes and is used to quantify and compare flux measurements over different land surfaces. Results reveal that in an urban setting, paved surfaces exhibit the largest sensible and lowest latent heat fluxes in an urban environment, while a mesic landscape exhibits the largest latent heat fluxes, due to heavy irrigation. Irrigation impacts flux sensitivity to precipitation input, where latent heat fluxes increase with precipitation in xeric and parking lot landscapes, but do not impact the mesic system. In a semiarid managed rangeland, past management strategies and disturbance histories impact vegetation distribution, particularly the distribution of mesquite trees. At the site with less mesquite coverage, evapotranspiration (ET) is greater, due to greater grass cover. Both sites are generally net sinks of CO2, which is largely dependent on moisture availability, while the site with greater mesquite coverage has more respiration and generally greater gross ecosystem production (GEP). Initial impacts of brush management reveal ET and GEP decrease, due to the absence of mesquite trees. However the impact appears to be minimal by the end of the productive season. Overall, this dissertation advances the understanding of land cover change impacts on surface energy, water, and carbon fluxes in semiarid ecosystems.
Cancer therapy selects for cancer cells resistant to treatment, a process that is fundamentally evolutionary. To what extent, however, is the evolutionary perspective employed in research on therapeutic resistance and relapse? We analyzed 6,228 papers on therapeutic resistance and/or relapse in cancers and found that the use of evolution terms in abstracts has remained at about 1% since the 1980s. However, detailed coding of 22 recent papers revealed a higher proportion of papers using evolutionary methods or evolutionary theory, although this number is still less than 10%. Despite the fact that relapse and therapeutic resistance is essentially an evolutionary process, it appears that this framework has not permeated research. This represents an unrealized opportunity for advances in research on therapeutic resistance.
This study examines the spatial and temporal patterns of the surface urban heat island (SUHI) intensity in the Phoenix metropolitan area and the relationship with land use land cover (LULC) change between 2000 and 2014. The objective is to identify specific regions in Phoenix that have been increasingly heated and cooled to further understand how LULC change influences the SUHI intensity. The data employed include MODerate-resolution Imaging Spectroradiometer (MODIS) land surface temperature (LST) 8-day composite June imagery, and classified LULC maps generated using 2000 and 2014 Landsat imagery. Results show that the regions that experienced the most significant LST changes during the study period are primarily on the outskirts of the Phoenix metropolitan area for both daytime and nighttime. The conversion to urban, residential, and impervious surfaces from all other LULC types has been identified as the primary cause of the UHI effect in Phoenix. Vegetation cover has been shown to significantly lower LST for both daytime and nighttime due to its strong cooling effect by producing more latent heat flux and less sensible heat flux. We suggest that urban planners, decision-makers, and city managers formulate new policies and regulations that encourage residential, commercial, and industrial developers to include more vegetation when planning new construction.
