Patterns and tempo of PCSK9 pseudogenizations suggest an ancient divergence in mammalian cholesterol homeostasis mechanisms.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in cholesterol homeostasis in humans as a major regulator of LDLR levels. PCSK9 is an intriguing protease in that it does not act by proteolysis but by preventing LDLR recirculation from endosomes to the plasma membrane. This, and the inexistence of any other proteolytic substrate but itself could suggest that PCSK9 is an exquisite example of evolutionary fine-tuning. However, the gene has been lost in several mammalian species, and null alleles are present (albeit at low frequencies) in some human populations without apparently deleterious health effects, raising the possibility that the PCSK9 may have become dispensable in the mammalian lineage. To address this issue, we systematically recovered, assembled, corrected, annotated and analysed publicly available PCSK9 sequences for 420 eutherian species to determine the distribution, frequencies, mechanisms and timing of PCSK9 pseudogenization events, as well as the evolutionary pressures underlying the preservation or loss of the gene. We found a dramatic difference in the patterns of PCSK9 retention and loss between Euarchontoglires-where there is strong pressure for gene preservation-and Laurasiatheria, where multiple independent events have led to PCSK9 loss in most species. These results suggest that there is a fundamental difference in the regulation of cholesterol metabolism between Euarchontoglires and Laurasiatheria, which in turn has important implications for the use of Laurasiatheria species (e.g. pigs) as animal models of human cholesterol-related diseases.

On the possible existence of a liver LDL-ostat, and its malfunctioning in familial hypercholesterolemia.

The investigation of familial hypercholesterolemia (FH) and its relationship to atherosclerosis has led to enormous scientific and medical progress, including the identification of genetic defects underlying FH, the elucidation of molecular mechanisms crucial for cellular cholesterol homeostasis and the development of current pharmaceutical tools for FH treatment (which are directed at increasing LDL uptake). These successes also led to the establishment of a model centered on cellular rather than whole organism processes, and a view of FH as resulting from a deficiency in LDL uptake. On the other hand, whole organism fluxes of cholesterol (like those of other nutrients) are centered on the liver, LDL (ultimately derived from the liver) is the main cholesterol transporter in plasma, and there is evidence of evolutionary pressure favoring mechanisms to maintain LDL plasma concentrations. Furthermore, the alterations in cellular metabolism observed in FH are consistent with a coordinated response by the liver to increase the levels of plasma LDL, suggesting that a signaling defect (rather than an uptake deficiency) is the fundamental problem underlying hypercholesterolemia - an hypothesis that explains the occurrence of hypercholesterolemia in CESD, despite normal LDL binding and uptake. I therefore propose that the liver contains a mechanism to assess and regulate plasma levels of LDL (an "LDL-ostat"), and that hypercholesterolemia is caused by defects in it. This model has implications for future research directions, and suggests alternative therapeutic approaches, particularly centered on efforts to restore LDL measurement/signaling (rather than its uptake), some of which are in stark contrast to those currently in use.

New Mitochondrial Gene Rearrangement in Psyttalia concolor, P. humilis and P. lounsburyi (Hymenoptera: Braconidae), Three Parasitoid Species of Economic Interest.

The family Braconidae consists mostly of specialized parasitoids, some of which hold potential in biocontrol of agricultural pests. Psyttalia concolor, Psyttalia humilis and Psyttalia lounsburyi are parasitoids associated with Bactrocera oleae, a major pest of cultivated olives. The native range of Psyttalia concolor is the Mediterranean, and P. humilis and P. lounsburyi are native to sub-Saharan Africa. This study reports the mitochondrial genomes of the three species, thus laying the foundation for mitogenomic analyses in the genus Psyttalia. Comparative mitogenomics within Braconidae showed a novel gene arrangement in Psyttalia in involving translocation and inversion of transfer RNA genes. The placement of Psyttalia in the subfamily Opiinae was well-supported, and the divergence between Psyttalia and its closest relative (Diachasmimorpha longicaudata) was at ~55 MYA [95% highest posterior density (HPD): 34-83 MYA]. Psyttalia lounsburyi occupied the most basal position among the three Psyttalia, having diverged from the other two species ~11 MYA (95% HPD: 6-17 MYA). Psyttalia concolor and P. humilis were recovered as sister species diverged at ~2 MYA (95% HPD: 1.1-3.6 MYA). This phylogeny combining new sequences and a set of 31 other cyclostomes and non-cyclostomes highlights the importance of a comprehensive taxonomic coverage of Braconidae mitogenomes to overcome the lack of robustness in the placement of several subfamilies.

The complete mitochondrial genome of Bactrocera biguttula (Bezzi) (Diptera: Tephritidae) and phylogenetic relationships with other Dacini.

Bactrocera biguttula is an African olive fruit fly that does not attack cultivated olives but rather develops in the fruits of wild species of Olea and Noronhia. The complete mitochondrial genome of an individual specimen was characterized in comparison to other Bactrocera. The phylogenetic relationships of B. biguttula with other Dacini were investigated, with special focus on B. oleae, an agricultural pest known to attack cultivated and wild olives. The sequence had a total length of 15,829 bp, and included the typical features of insect mitogenomes, similarly to the other Bactrocera analysed. Start codons included ATG, ATC, ATT, and TCG (in COI). The majority of stop codons (TAA) were fully encoded, whereas in some cases only TA or T were present. The complete sequence was biased towards A + T, with a positive AT-skew and a negative GC-skew. The predicted cloverleaf structure of tRNASer1 showed absence of the DHU arm, a common feature in insects and other Metazoans. Phylogenetic reconstruction showed that B. biguttula and B. oleae are sister species, having diverged from a common ancestor < 10 Myr ago. This result warrants future genomic comparisons between these two closely related species for investigating the specific adaptations to the different hosts.

The complete mitochondrial genome of Parage aegeria (Insecta: Lepidoptera: Papilionidae).

Pararge aegeria is a palearctic butterfly used as a model organism in ecology, behavior, evolution and development, with significant geographically-correlated morphological variation and two close relatives in Macaronesia. In this study, I have determined the complete mitogenome sequence of P. aegeria. The genome is 15,240 bp long, and has the typical gene organization of other lepidopteran mitogenomes. Salient features include the IMQ order of tRNA genes, a sizable (52 bp) spacer between trnQ and nad2, a CGA start codon in cox1 and the ATAGA(T)19 motif in the control region. Interestingly, this region also contains four copies of the imperfect palindrome TAAATATWTATAWATATTTA.

Exploring and exploiting instability.

Genetic instability was postulated to be essential for tumor development almost three decades ago, and yet its exact nature in and relationship with cancer continue to be ill-understood and hotly debated subjects. In this article, we review and discuss current knowledge and thinking about the existence, characteristics, reasons for and mechanisms of genetic instability in human cancers, as well as how its study can help us better understand and fight cancer. Particular emphasis is given to chromosomal instability, the most common and least understood of the types of genetic instability found in human tumors.