Genetic structure and evolution of the Vps25 family, a yeast ESCRT-II component

BACKGROUND: Vps25p is the product of yeast gene VPS25 and is found in an endosomal sorting complex required for transport (ESCRT)-II, along with Vps22p and Vps36p. This complex is essential for sorting of ubiquitinated biosynthetic and endosomal cargoes into endosomes. RESULTS: We found that VPS25 is a highly conserved and widely expressed eukaryotic gene, with single orthologs in chromalveolate, excavate, amoebozoan, plant, fungal and metazoan species. Two paralogs were found in Trichomonas vaginalis. An ortholog was strikingly absent from the Encephalitozoon cuniculi genome. Intron positions were analyzed in VPS25 from 36 species. We found evidence for five ancestral VPS25 introns, intron loss, and single instances of intron gain (a Paramecium species) and intron slippage (Theileria species). Processed pseudogenes were identified in four mammalian genomes, with a notable absence in the mouse genome. Two retropseudogenes were found in the chimpanzee genome, one more recently inserted, and one evolving from a common primate ancestor. The amino acid sequences of 119 Vps25 orthologs are aligned, compared with the known secondary structure of yeast Vps25p, and used to carry out phylogenetic analysis. Residues in two amino-terminal PPXY motifs (motif I and II), involved in dimerization of Vps25p and interaction with Vps22p and Vps36p, were closely, but not absolutely conserved. Specifically, motif I was absent in Vps25 homologs of chromalveolates, euglenozoa, and diplomonads. A highly conserved carboxy-terminal lysine was identified, which suggests Vps25 is ubiquitinated. Arginine-83 of yeast Vps25p involved in Vps22p interaction was highly, but not absolutely, conserved. Human tissue expression analysis showed universal expression. CONCLUSION: We have identified 119 orthologs of yeast Vps25p. Expression of mammalian VPS25 in a wide range of tissues, and the presence in a broad range of eukaryotic species, indicates a basic role in eukaryotic cell function. Intron splice site positions were highly conserved across all major eukaryotic species, suggesting an ancestral origin. Amino acid sequence analysis showed the consensus for the amino-terminal proline-rich motifs is P- [WP]-X-[YF] for motif I (when present) and P-P-[FYL]-[FY] for motif II, and that Vps25 may be ubiquitinated

Characterization of the Deleted in Autism 1 Protein Family: Implications for Studying Cognitive Disorders

Autism spectrum disorders (ASDs) are a group of commonly occurring, highly-heritable developmental disabilities. Human genes c3orf58 or Deleted In Autism-1 (DIA1) and cXorf36 or Deleted in Autism-1 Related (DIA1R) are implicated in ASD and mental retardation. Both gene products encode signal peptides for targeting to the secretory pathway. As evolutionary medicine has emerged as a key tool for understanding increasing numbers of human diseases, we have used an evolutionary approach to study DIA1 and DIA1R. We found DIA1 conserved from cnidarians to humans, indicating DIA1 evolution coincided with the development of the first primitive synapses. Nematodes lack a DIA1 homologue, indicating Caenorhabditis elegans is not suitable for studying all aspects of ASD etiology, while zebrafish encode two DIA1 paralogues. By contrast to DIA1, DIA1R was found exclusively in vertebrates, with an origin coinciding with the whole-genome duplication events occurring early in the vertebrate lineage, and the evolution of the more complex vertebrate nervous system. Strikingly, DIA1R was present in schooling fish but absent in fish that have adopted a more solitary lifestyle. An additional DIA1-related gene we named DIA1-Like (DIA1L), lacks a signal peptide and is restricted to the genomes of the echinoderm Strongylocentrotus purpuratus and cephalochordate Branchiostoma floridae. Evidence for remarkable DIA1L gene expansion was found in B. floridae. Amino acid alignments of DIA1 family gene products revealed a potential Golgi-retention motif and a number of conserved motifs with unknown function. Furthermore, a glycine and three cysteine residues were absolutely conserved in all DIA1-family proteins, indicating a critical role in protein structure and/or function. We have therefore identified a new metazoan protein family, the DIA1-family, and understanding the biological roles of DIA1-family members will have implications for our understanding of autism and mental retardation

Distance-based emission factors from vehicle emission remote sensing measurements

Vehicle emission remote sensing has the potential to provide detailed emissions information at a highly disaggregated level owing to the ability to measure thousands of vehicles in a single day. Fundamentally, vehicle emission remote sensing provides a direct measure of the molar volume ratio of a pollutant to carbon dioxide, from which fuel-based emissions factors can readily be calculated. However, vehicle emissions are more commonly expressed in emission per unit distance travelled e.g. grams per km or mile. To express vehicle emission remote sensing data in this way requires an estimate of the fuel consumption at the time of the emission measurement. In this paper, an approach is developed based on vehicle specific power that uses commonly measured or easily obtainable vehicle information such as vehicle speed, acceleration and mass. We test the approach against 55 independent comprehensive PEMS measurements for Euro 5 and 6 gasoline and diesel vehicles over a wide range of driving conditions and find good agreement between the method and PEMS data. The method is applied to individual vehicle model types to quantify distance-based emission factors. The method will be appropriate for application to larger vehicle emission remote sensing databases, thus extending real-world distance-based vehicle emissions information

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population

Stable isotopic composition of fossil mammal teeth and environmental change in southwestern South Africa during the Pliocene and Pleistocene

The past 5 million years mark a global change from the warmer, more stable climate of the Pliocene to the initiation of glacial-interglacial cycles during the Pleistocene. Marine core sediment records located off the coast of southwestern Africa indicate aridification and intensified upwelling in the Benguela Current over the Pliocene and Pleistocene. However, few terrestrial records document environmental change in southwestern Africa over this time interval. Here we synthesize new and published carbon and oxygen isotope data of the teeth from large mammals (>6 kg) at Langebaanweg (~5 million years ago, Ma), Elandsfontein (1.0 – 0.6 Ma), and Hoedjiespunt (0.35 – 0.20 Ma), to evaluate environmental change in southwestern Africa between the Pliocene and Pleistocene. The majority of browsing and grazing herbivores from these sites yield enamel 13 C values within the range expected for animals with a pure C3 diet, however some taxa have enamel 13C values that suggest the presence of small amounts C4 grasses at times during the Pleistocene. Considering that significant amounts of C4 grasses require a warm growing season, these results indicate that the winter rainfall zone, characteristic of the region today, could have been in place for the past 5 million years. The average 18O value of the herbivore teeth increases ~4.4‰ between Langebaanweg and Elandsfontein for all taxa except suids. This increase may solely be a function of a change in hydrology between the fluvial system at Langebaanweg and the spring-fed environments at Elandsfontein, or a combination of factors that include depositional context, regional circulation and global climate. However, an increase in regional aridity or global cooling between the early Pliocene and mid-Pleistocene cannot explain the entire increase in enamel 18O values. Spring-fed environments like those at Elandsfontein may have 75 provided critical resources for mammalian fauna in the mid-Pleistocene within an increasingly arid southwestern Africa ecosystem

Stable isotope ecology of Cape dune mole-rats (Bathyergus suillus) from Elandsfontein, South Africa: implications for C4 vegetation and hominin paleobiology in the Cape Floral Region

The archaeological and paleontological records from the west coast of South Africa have potential to provide insights into ecosystem dynamics in the region during the mid Pleistocene. Although the fossil record suggests an ecosystem quite different than that of the region today, we understand little about the ecological factors that contributed to this disparity. The site of Elandsfontein (EFT) dates to between 1.0 and 0.6 million years ago (Ma), preserves in situ lithic and faunal materials found in direct association with each other, and provides the rare opportunity to examine the relationship between hominin behavioural variability and landscape heterogeneity in a winter rainfall ecosystem. In this study, we examine the stable carbon isotopic composition of a large sample (n = 81) of Cape dune mole-rats (Bathyergus suillus) and contemporaneous large mammals (> 6 kg; n = 194) from EFT. We find that δ13C values of B. suillus are significantly different to those of contemporaneous large mammals from EFT indicating a significant presence of plants utilizing the C4 photosynthetic pathway during the mid-Pleistocene, in contrast to present C3 dominated ecosystems along the west coast of South Africa. Additionally, we find that artifact density at EFT localities is positively correlated with δ13C values in B. suillus enamel suggesting that evidence of more intense hominin occupation may be associated with the presence of more C4 vegetation. Lastly, we hypothesize that this unique distribution of vegetation 1) provided abundant resources for both hominin and non-hominin taxa and 2) may have concentrated hominin and animal behavior in certain places on the ancient landscape