Spatial and temporal diversity of positive selection on shared haplotypes at the PSCA locus among worldwide human populations.

Selection on standing genetic variation is important for rapid local genetic adaptation when the environment changes. We report that, for the prostate stem cell antigen (PSCA) gene, different populations have different target haplotypes, even though haplotypes are shared among populations. The C-C-A haplotype, whereby the first C is located at rs2294008 of PSCA and is a low risk allele for gastric cancer, has become a target of positive selection in Asia. Conversely, the C-A-G haplotype carrying the same C allele has become a selection target mainly in Africa. However, Asian and African share both haplotypes, consistent with the haplotype divergence time (170 kya) prior to the out-of-Africa dispersal. The frequency of C-C-A/C-A-G is 0.344/0.278 in Asia and 0.209/0.416 in Africa. Two-dimensional site frequency spectrum analysis revealed that the extent of intra-allelic variability of the target haplotype is extremely small in each local population, suggesting that C-C-A or C-A-G is under ongoing hard sweeps in local populations. From the time to the most recent common ancestor (TMRCA) of selected haplotypes, the onset times of positive selection were recent (3-55 kya), concurrently with population subdivision from a common ancestor. Additionally, estimated selection coefficients from ABC analysis were up to ~3%, similar to those at other loci under recent positive selection. Phylogeny of local populations and TMRCA of selected haplotypes revealed that spatial and temporal switching of positive selection targets is a unique and novel feature of ongoing selection at PSCA. This switching may reflect the potential of rapid adaptability to distinct environments.

Evolutionary History of the Risk of SNPs for Diffuse-Type Gastric Cancer in the Japanese Population.

A genome wide association study reported that the T allele of rs2294008 in a cancer-related gene, PSCA, is a risk allele for diffuse-type gastric cancer. This allele has the highest frequency (0.63) in Japanese in Tokyo (JPT) among 26 populations in the 1000 Genomes Project database. FST ≈ 0.26 at this single nucleotide polymorphism is one of the highest between JPT and the genetically close Han Chinese in Beijing (CHB). To understand the evolutionary history of the alleles in PSCA, we addressed: (i) whether the C non-risk allele at rs2294008 is under positive selection, and (ii) why the mainland Japanese population has a higher T allele frequency than other populations. We found that haplotypes harboring the C allele are composed of two subhaplotypes. We detected that positive selection on both subhaplotypes has occurred in the East Asian lineage. However, the selection on one of the subhaplotypes in JPT seems to have been relaxed or ceased after divergence from the continental population; this may have caused the elevation of T allele frequency. Based on simulations under the dual structure model (a specific demography for the Japanese) and phylogenetic analysis with ancient DNA, the T allele at rs2294008 might have had high frequency in the Jomon people (one of the ancestral populations of the modern Japanese); this may explain the high T allele frequency in the extant Japanese.

Two-dimensional site frequency spectrum for detecting, classifying and dating incomplete selective sweeps.

The two-dimensional site frequency spectrum (2D SFS) was investigated to describe the intra-allelic variability (IAV) maintained within a derived allele (D) group that has undergone an incomplete selective sweep against an ancestral allele group. We observed that recombination certainly muddles the ancestral relationships of allelic lineages between the two allele groups; however, the 2D SFS reveals intriguing signatures of recombination as well as the genealogical structure of the D group, particularly the size of a mutation and the time to the most recent common ancestor (TMRCA). Coalescent simulations were performed to achieve powerful and robust 2D SFS-based statistics with special reference to accurate evaluation of IAV, significance of recombination effects, and distinction between hard and soft selective sweeps. These studies were extended to a case wherein an incomplete selective sweep is no longer in progress and ceased in the recent past. The 2D SFS-based method was applied to 100 intronic linkage disequilibrium regions randomly chosen from the East Asian population of modern humans to examine the P value distributions of the summary statistics under the null hypothesis of neutrality in a nonequilibrium demographic model. We argue that about 96% of intronic variants are non-adaptive with a 10% false discovery rate. Furthermore, this method was applied to six genomic regions in Eurasian populations that were claimed to have experienced recent selective sweeps. We found that two of these genomic regions did not have significant signals of selective sweeps, but the remaining four had undergone hard and soft sweeps and were dated, in terms of TMRCA, after the major out-of-Africa dispersal of modern humans.

In silico chemical screening identifies epidermal growth factor receptor as a therapeutic target of drug-tolerant CD44v9-positive gastric cancer cells.

BACKGROUND: Tumours consist of heterogeneous cancer cells and are likely to contain drug-tolerant cell subpopulations, causing early relapse. However, treatment strategies to eliminate these cells have not been established. METHODS: We established gastric cancer patient-derived cells (PDCs) to examine the contribution of CD44 splicing variant 9 (CD44v9)-positive cells in gastric cancer drug tolerance. We performed gene expression signature-based in silico screening using JFCR_LinCAGE, our anticancer compound gene expression database and subsequent validation in BALB/c-nu/nu mouse xenograft to identify agents targeting the drug-tolerant cancer cells. RESULTS: CD44v9-positive cancer cells were enriched among residual cancer cells after treatment with SN-38, an active metabolic of irinotecan. CD44v9 protein was responsible for this drug resistance. We identified epidermal growth factor receptor (EGFR) inhibitors as agents that can target CD44v9-positive cell populations in gastric cancer PDCs. CD44v9 promoted cell proliferation, and EGFR inhibition attenuated CD44v9 protein expression through downregulation of the AKT and the ERK signalling pathways, leading to preferential suppression of CD44v9-positive cells. Importantly, EGFR inhibitors significantly reduced the number of residual cancer cells after cytotoxic anticancer drug treatment and enhanced the antitumor effect of irinotecan in vivo. CONCLUSIONS: EGFR inhibitors could be potential agents to eradicate cytotoxic anticancer drug-tolerant gastric cancer cell populations.

Neurophysiological Analysis of Intermanual Transfer in Motor Learning.

The purpose of this study was to examine the effect of motor training on motor imagery (MI), by comparing motor performance and motor cortex excitability changes with and without intermanual transfer of motor learning. Intermanual transfer was investigated in terms of excitability changes in the motor cortex and motor performance from right hand training to left hand performance. Participants were assigned to a transfer training group and a control group. We recorded motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS), applied to the left extensor carpi radialis (ECR) both with and without intermanual transfer. The results showed that after learning by the right hand, MEPs decreased during left hand MI. MEPs during MI were significantly decreased by unilateral training in the transfer training group. Since intermanual transfer plays an important role in stabilizing performance by the contralateral side, this result suggests that unilateral training decreases MEPs during MI on the contralateral side. In the control group, without right hand training, MEPs significantly increased after left hand training during MI. In the trained side, we found increased excitability in the agonist muscle area of the primary motor cortex. However, in the untrained side, excitability decreased in the homonymous muscle area of the primary motor cortex. This constitutes an increase in inhibitory effects and suggests that excitability changes in the respective neural circuit contribute to skilled performance by the ipsilateral and contralateral sides in the same motor task.

Lumbar Extension during Stoop Lifting is Delayed by the Load and Hamstring Tightness.

[Purpose] This study investigated the relationship between lumbar pelvic rhythm and the physical characteristics of stoop lifting. [Subjects and Methods] Participants performed a stoop lifting task under two conditions: with and without load. We assessed the lumbar kyphosis and sacral inclination angles using the SpinalMouse(®) system, as well as hamstring flexibility. During stoop lifting, surface electromyograms and the lumbar and sacral motions were recorded using a multi-channel telemetry system and flexible electrogoniometers. [Results] In the initial phase of lifting, lumbar extension was delayed by load; the delay showed a negative correlation with sacral inclination angle at trunk flexion, whereas a positive correlation was observed with electromyogram activity of the lumbar multifidus. Additionally, a positive correlation was observed between sacral inclination angle and hip flexion range of motion during the straight leg raise test. [Conclusion] We found that a disorder of the lumbar pelvic rhythm can be caused by both load and hamstring tightness. In the initial phase of stoop lifting, delayed lumbar extension is likely to lead to an increase in spinal instability and stress on the posterior ligamentous system. This mechanism shows that stoop lifting of a load may be harmful to the lower back of people with hamstring tightness.