Summary Marine stickleback fish have colonized and adapted to innumerable streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of 20 additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results suggest that reuse of globally-shared standing genetic variation, including chromosomal inversions, plays an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, with regulatory changes likely predominating in this classic example of repeated adaptive evolution in nature.
Estrogens are known to be important in the growth of breast cancers in both pre- and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also on innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs.
BackgroundDorsal spine reduction in threespine sticklebacks (Gasterosteus aculeatus) is a classic example of recurrent skeletal evolution in nature. Sticklebacks in marine environments typically have long spines that form part of their skeletal armor. Many derived freshwater populations have evolved shorter spines. Changes in spine length are controlled in part by a quantitative trait locus (QTL) previously mapped to chromosome 4, but the causative gene and mutations underlying the repeated evolution of this interesting skeletal trait have not been identified.ResultsRefined mapping of the spine length QTL shows that it lies near the MSX2A transcription factor gene. MSX2A is expressed in developing spines. In F1 marine × freshwater fish, the marine allele is preferentially expressed.Differences in expression can be attributed to splicing regulation. Due to the use of an alternative 5 ′ splice site within the first exon, the freshwater allele produces greater amounts of a shortened, non-functional transcript and makes less of the full-length transcript. Sequence changes in the MSX2A region are shared by many freshwater fish, suggesting that repeated evolution occurs by reuse of a spine-reduction variant.To demonstrate the effect of full-length MSX2A on spine length, we produced transgenic freshwater fish expressing a copy of marine MSX2A. The spines of the transgenic fish were significantly longer on average than those of their non-transgenic siblings, partially reversing the reduced spine lengths that have evolved in freshwater populations.Conclusions MSX2A is a major gene underlying dorsal spine reduction in freshwater sticklebacks. The gene is linked to a separate gene controlling bony plate loss, helping explain the concerted effects of chromosome 4 on multiple armor-reduction traits. The nature of the molecular changes provides an interesting example of morphological evolution occurring not through a simple amino acid change, nor through a change only in gene expression levels, but through a change in the ratio of splice products encoding both normal and truncated proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0456-5) contains supplementary material, which is available to authorized users.
Multiple DNA ligation events are required to join the Okazaki fragments generated during lagging strand DNA synthesis. In eukaryotes, this is primarily carried out by members of the DNA ligase I family. The C-terminal catalytic region of these enzymes is composed of three domains: a DNA binding domain, an adenylation domain and an OB-fold domain. In the absence of DNA, these domains adopt an extended structure but transition into a compact ring structure when they engage a DNA nick, with each of the domains contacting the DNA. The non-catalytic N-terminal region of eukaryotic DNA ligase I is responsible for the specific participation of these enzymes in DNA replication. This proline-rich unstructured region contains the nuclear localization signal and a PCNA interaction motif that is critical for localization to replication foci and efficient joining of Okazaki fragments. DNA ligase I initially engages the PCNA trimer via this interaction motif which is located at the extreme N-terminus of this flexible region. It is likely that this facilitates an additional interaction between the DNA binding domain and the PCNA ring. The similar size and shape of the rings formed by the PCNA trimer and the DNA ligase I catalytic region when it engages a DNA nick suggest that these proteins interact to form a double-ring structure during the joining of Okazaki fragments. DNA ligase I also interacts with replication factor C, the factor that loads the PCNA trimeric ring onto DNA. This interaction, which is regulated by phosphorylation of the non-catalytic N-terminus of DNA ligase I, also appears to be critical for DNA replication.
We present a method to detect copy number variants (CNVs) that are differentially present between two groups of sequenced samples. We use a finite-state transducer where the emitted read depth is conditioned on the mappability and GC-content of all reads that occur at a given base position. In this model, the read depth within a region is a mixture of binomials, which in simulations matches the read depth more closely than the often-used negative binomial distribution. The method analyzes all samples simultaneously, preserving uncertainty as to the breakpoints and magnitude of CNVs present in an individual when it identifies CNVs differentially present between the two groups. We apply this method to identify CNVs that are recurrently associated with postglacial adaptation of marine threespine stickleback () to freshwater. We identify 6664 regions of the stickleback genome, totaling 1.7 Mbp, which show consistent copy number differences between marine and freshwater populations. These deletions and duplications affect both protein-coding genes and -regulatory elements, including a noncoding intronic telencephalon enhancer of The functions of the genes near or included within the 6664 CNVs are enriched for immunity and muscle development, as well as head and limb morphology. Although freshwater stickleback have repeatedly evolved from marine populations, we show that freshwater stickleback also act as reservoirs for ancient ancestral sequences that are highly conserved among distantly related teleosts, but largely missing from marine stickleback due to recent selective sweeps in marine populations.
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