New insights into the history of the C-14010 lactase persistence variant in Eastern and Southern Africa

Lactase persistence (LP), the ability to digest lactose into adulthood, is strongly associated with the cultural traits of pastoralism and milk-drinking among human populations, and several different genetic variants are known that confer LP. Recent studies of LP variants in Southern African populations, with a focus on Khoisan-speaking groups, found high frequencies of an LP variant (the C-14010 allele) that also occurs in Eastern Africa, and concluded that the C-14010 allele was brought to Southern Africa via a migration of pastoralists from Eastern Africa. However, this conclusion was based on indirect evidence; to date no study has jointly analyzed data on the C-14010 allele from both Southern African Khoisan-speaking groups and Eastern Africa. Here, we combine and analyze published data on the C-14010 allele in Southern and Eastern African populations, consisting of haplotypes with the C-14010 allele and four closely-linked short tandem repeat loci. Our results provide direct evidence for the previously-hypothesized Eastern African origin of the C-14010 allele in Southern African Khoisan-speaking groups. In addition, we find evidence for a separate introduction of the C-14010 allele into the Bantu-speaking Xhosa. The estimated selection intensity on the C-14010 allele in Eastern Africa is lower than that in Southern Africa, which suggests that in Eastern Africa the dietary changes conferring the fitness advantage associated with LP occurred some time after the origin of the C-14010 allele. Conversely, in Southern Africa the fitness advantage was present when the allele was introduced, as would be expected if pastoralism was introduced concomitantly. Am J Phys Anthropol 156:661–664, 2015. © 2014 Wiley Periodicals, Inc.     

Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.     

Posttranslational Modifications in Type I Collagen from Different Tissues Extracted from Wild Type and Prolyl 3-Hydroxylase 1 Null Mice

Type I collagen extracted from tendon, skin, and bone of wild type and prolyl 3-hydroxylase 1 (P3H1) null mice shows distinct patterns of 3-hydroxylation and glycosylation of hydroxylysine residues. The A1 site (Pro-986) in the α1-chain of type I collagen is almost completely 3-hydroxylated in every tissue of the wild type mice. In contrast, no 3-hydroxylation of this proline residue was found in P3H1 null mice. Partial 3-hydroxylation of the A3 site (Pro-707) was present in tendon and bone, but absent in skin in both α-chains of the wild type animals. Type I collagen extracted from bone of P3H1 null mice shows a large reduction in 3-hydroxylation of the A3 site in both α-chains, whereas type I collagen extracted from tendon of P3H1 null mice shows little difference as compared with wild type. These results demonstrate that the A1 site in type I collagen is exclusively 3-hydroxylated by P3H1, and presumably, this enzyme is required for the 3-hydroxylation of the A3 site of both α-chains in bone but not in tendon. The increase in glycosylation of hydroxylysine in P3H1 null mice in bone was found to be due to an increased occupancy of normally glycosylated sites. Despite the severe disorganization of collagen fibrils in adult tissues, the D-period of the fibrils is unchanged. Tendon fibrils of newborn P3H1 null mice are well organized with only a slight increase in diameter. The absence of 3-hydroxyproline and/or the increased glycosylation of hydroxylysine in type I collagen disturbs the lateral growth of the fibrils.     

Genomic Evidence for Island Population Conversion Resolves Conflicting Theories of Polar Bear Evolution

Despite extensive genetic analysis, the evolutionary relationship between polar bears (Ursus maritimus) and brown bears (U. arctos) remains unclear. The two most recent comprehensive reports indicate a recent divergence with little subsequent admixture or a much more ancient divergence followed by extensive admixture. At the center of this controversy are the Alaskan ABC Islands brown bears that show evidence of shared ancestry with polar bears. We present an analysis of genome-wide sequence data for seven polar bears, one ABC Islands brown bear, one mainland Alaskan brown bear, and a black bear (U. americanus), plus recently published datasets from other bears. Surprisingly, we find clear evidence for gene flow from polar bears into ABC Islands brown bears but no evidence of gene flow from brown bears into polar bears. Importantly, while polar bears contributed <1% of the autosomal genome of the ABC Islands brown bear, they contributed 6.5% of the X chromosome. The magnitude of sex-biased polar bear ancestry and the clear direction of gene flow suggest a model wherein the enigmatic ABC Island brown bears are the descendants of a polar bear population that was gradually converted into brown bears via male-dominated brown bear admixture. We present a model that reconciles heretofore conflicting genetic observations. We posit that the enigmatic ABC Islands brown bears derive from a population of polar bears likely stranded by the receding ice at the end of the last glacial period. Since then, male brown bear migration onto the island has gradually converted these bears into an admixed population whose phenotype and genotype are principally brown bear, except at mtDNA and X-linked loci. This process of genome erosion and conversion may be a common outcome when climate change or other forces cause a population to become isolated and then overrun by species with which it can hybridize.     

Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease

von Willebrand factor (vWf) is a multimeric plasma glycoprotein that functions in hemostasis as the initiator of platelet adhesion to damaged blood vessels and as the carrier of Factor VIII (FVIII). Montgomery et al. (Montgomery, R.R., Hathaway, W.E., Johnson, J., Jacobsen, L., and Muntean, W. (1982) Blood 60, 201-207) reported a variant of von Willebrand disease characterized by the abnormal interaction between FVIII and a defective vWf. To identify the molecular basis of this abnormal interaction, we isolated platelet RNA from members of one of the affected families and determined the nucleotide sequence of the FVIII-binding domain encoded by the vWf mRNA. A single G to A transition at nucleotide 2561 was linked with disease expression and results in the substitution of Gln for Arg91 in mature vWf. A restriction fragment containing this mutation was introduced into a full-length vWf expression vector, and both wild type and mutant vWf were expressed in COS-7 cells. In a solid-phase binding assay, expressed vWf was captured with anti-vWf monoclonal antibody AVW1 and then incubated with 6.25-400 milliunits of recombinant FVIII. After washing, vWf-bound FVIII activity was determined with a chromogenic assay. Mutant vWf showed reduced binding of FVIII compared with wild type, suggesting that the substitution of Gln for Arg91 is the likely basis for the abnormal vWf/FVIII interaction in this von Willebrand disease variant.     

Urogenital schistosomiasis infection prevalence targets to determine elimination as a public health problem based on microhematuria prevalence in school-age children

BackgroundRecent research suggests that schistosomiasis targets for morbidity control and elimination as a public health problem could benefit from a reanalysis. These analyses would define evidence-based targets that control programs could use to confidently assert that they had controlled or eliminated schistosomiasis as a public health problem. We estimated how low Schistosoma haematobium infection levels diagnosed by urine filtration in school-age children should be decreased so that microhematuria prevalence was at, or below, a “background” level of morbidity.MethodologyData obtained from school-age children in Burkina Faso, Mali, Niger, Tanzania, and Zambia who participated in schistosomiasis monitoring and evaluation cohorts were reanalyzed before and after initiation of preventive chemotherapy. Bayesian models estimated the infection level prevalence probabilities associated with microhematuria thresholds ≤10%, 13%, or 15%.Principal findingsAn infection prevalence of 5% could be a sensible target for urogenital schistosomiasis morbidity control in children as microhematuria prevalence was highly likely to be below 10% in all surveys. Targets of 8% and 11% infection prevalence were highly likely to result in microhematuria levels less than 13% and 15%, respectively. By contrast, measuring heavy-intensity infections only achieves these thresholds at impractically low prevalence levels.Conclusions/significanceA target of 5%, 8%, or 11% urogenital schistosomiasis infection prevalence in school-age children could be used to determine whether a geographic area has controlled or eliminated schistosomiasis as a public health problem depending on the local background threshold of microhematuria.     

Collection protocol for human pancreas

This dissection and sampling procedure was developed for the Network for Pancreatic Organ Donors with Diabetes (nPOD) program to standardize preparation of pancreas recovered from cadaveric organ donors. The pancreas is divided into 3 main regions (head, body, tail) followed by serial transverse sections throughout the medial to lateral axis. Alternating sections are used for fixed paraffin and fresh frozen blocks and remnant samples are minced for snap frozen sample preparations, either with or without RNAse inhibitors, for DNA, RNA, or protein isolation. The overall goal of the pancreas dissection procedure is to sample the entire pancreas while maintaining anatomical orientation. Endocrine cell heterogeneity in terms of islet composition, size, and numbers is reported for human islets compared to rodent islets. The majority of human islets from the pancreas head, body and tail regions are composed of insulin-containing β-cells followed by lower proportions of glucagon-containing α-cells and somatostatin-containing δ-cells. Pancreatic polypeptide-containing PP cells and ghrelin-containing epsilon cells are also present but in small numbers. In contrast, the uncinate region contains islets that are primarily composed of pancreatic polypeptide-containing PP cells. These regional islet variations arise from developmental differences. The pancreas develops from the ventral and dorsal pancreatic buds in the foregut and after rotation of the stomach and duodenum, the ventral lobe moves and fuses with the dorsal. The ventral lobe forms the posterior portion of the head including the uncinate process while the dorsal lobe gives rise to the rest of the organ. Regional pancreatic variation is also reported with the tail region having higher islet density compared to other regions and the dorsal lobe-derived components undergoing selective atrophy in type 1 diabetes. Additional organs and tissues are often recovered from the organ donors and include pancreatic lymph nodes, spleen and non-pancreatic lymph nodes. These samples are recovered with similar formats as for the pancreas with the addition of isolation of cryopreserved cells. When the proximal duodenum is included with the pancreas, duodenal mucosa may be collected for paraffin and frozen blocks and minced snap frozen preparations.     

Pineal photoreceptor cells are required for maintaining the circadian rhythms of behavioral visual sensitivity in zebrafish

In non-mammalian vertebrates, the pineal gland functions as the central pacemaker that regulates the circadian rhythms of animal behavior and physiology. We generated a transgenic zebrafish line [Tg(Gnat2:gal4-VP16/UAS:nfsB-mCherry)] in which the E. coli nitroreductase is expressed in pineal photoreceptor cells. In developing embryos and young adults, the transgene is expressed in both retinal and pineal photoreceptor cells. During aging, the expression of the transgene in retinal photoreceptor cells gradually diminishes. By 8 months of age, the Gnat2 promoter-driven nitroreductase is no longer expressed in retinal photoreceptor cells, but its expression in pineal photoreceptor cells persists. This provides a tool for selective ablation of pineal photoreceptor cells, i.e., by treatments with metronidazole. In the absence of pineal photoreceptor cells, the behavioral visual sensitivity of the fish remains unchanged; however, the circadian rhythms of rod and cone sensitivity are diminished. Brief light exposures restore the circadian rhythms of behavioral visual sensitivity. Together, the data suggest that retinal photoreceptor cells respond to environmental cues and are capable of entraining the circadian rhythms of visual sensitivity; however, they are insufficient for maintaining the rhythms. Cellular signals from the pineal photoreceptor cells may be required for maintaining the circadian rhythms of visual sensitivity.     

Saltatory search in a lateral line predator

The dwarf scorpionfish Scorpaena papillosa detected the hydrodynamic signals produced by prey with the mechanosensory lateral line. This species displayed a pause and move search pattern that is consistent with a saltatory search. The pause phase of the search cycle was probably used to detect prey because pauses often ended early in order to initiate an approach at prey and prey were detected throughout the search space. The move phase of the search cycle repositioned the fish so that it moved approximately a third of the reactive distance. Move distance was found to be the most important factor in gaining novel search space. Turning was shown to be relatively unimportant in gaining novel search space with a high frequency of low turn angles made by the fish. The dwarf scorpionfish, however, exhibited a spiralling or looping pattern over a search path exhibiting a turn bias towards either the left or right. The dwarf scorpionfish adopted a search behaviour that is consistent with a saltatory search and efficient for lateral line predation.     

Cost-Benefit Analysis in a Regulatory Setting

The purpose of requiring cost-benefit analysis is to produce better out-comes from regulatory processes. If implemented well, cost-benefit analysis and risk assessment can produce improvements at several levels, by encouraging regulators to consider unintended effects of regulations and thereby avoid making things worse, to find the least burdensome approach to a goal, and to balance the pluses and minuses involved in choosing a goal. Whether these improvements will occur depends in large part on how cost-benefit analysis is implemented. Guidelines for conducting cost-benefit analysis and procedures for considering evidence on costs and benefits play an important role. This article describes how guidelines and rules of process can affect outcomes, and the issues that cost-benefit guidelines need to cover. Guidelines can affect the bias of a regulatory process toward one set of stakeholders or another, make outcomes more predictable, define the information needed for decisions, and provide a basis for legal challenges. The questions that guidelines should address include: what are costs and benefits, what constitutes good economics, what are standards of proof, how should unquantified costs and benefits be treated, how should uncertainties of cost-benefit estimates be dealt with, and how should alternatives be generated? The article concludes with recommen dations about how the adoption of cost-benefit analysis can be made most effective and beneficial in regulatory processes.