Balinese Y-chromosome perspective on the peopling of Indonesia: genetic contributions from pre-neolithic hunter-gatherers, Austronesian farmers, and Indian traders

The island of Bali lies near the center of the southern chain of islands in the Indonesian archipelago, which served as a stepping-stone for early migrations of hunter-gatherers to Melanesia and Australia and for more recent migrations of Austronesian farmers from mainland Southeast Asia to the Pacific. Bali is the only Indonesian island with a population that currently practices the Hindu religion and preserves various other Indian cultural, linguistic, and artistic traditions (Lansing 1983). Here, we examine genetic variation on the Y chromosomes of 551 Balinese men to investigate the relative contributions of Austronesian farmers and pre-Neolithic hunter-gatherers to the contemporary Balinese paternal gene pool and to test the hypothesis of recent paternal gene flow from the Indian subcontinent. Seventy-one Y-chromosome binary polymorphisms (single nucleotide polymorphisms, SNPs) and 10 Y-chromosome-linked short tandem repeats (STRs) were genotyped on a sample of 1,989 Y chromosomes from 20 populations representing Indonesia (including Bali), southern China, Southeast Asia, South Asia, the Near East, and Oceania. SNP genotyping revealed 22 Balinese lineages, 3 of which (O-M95, O-M119, and O-M122) account for nearly 83.7% of Balinese Y chromosomes. Phylogeographic analyses suggest that all three major Y-chromosome haplogroups migrated to Bali with the arrival of Austronesian speakers; however, STR diversity patterns associated with these haplogroups are complex and may be explained by multiple waves of Austronesian expansion to Indonesia by different routes. Approximately 2.2% of contemporary Balinese Y chromosomes (i.e., K-M9*, K-M230, and M lineages) may represent the pre-Neolithic component of the Indonesian paternal gene pool. In contrast, eight other haplogroups (e.g., within H, J, L, and R), making up approximately 12% of the Balinese paternal gene pool, appear to have migrated to Bali from India. These results indicate that the Austronesian expansion had a profound effect on the composition of the Balinese paternal gene pool and that cultural transmission from India to Bali was accompanied by substantial levels of gene flow.     

Two quantitative trait loci for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains

Prepulse inhibition (PPI) of acoustic startle is a genetically complex quantitative phenotype of considerable medical interest due to its impairment in psychiatric disorders such as schizophrenia. To identify quantitative trait loci (QTL) involved in mouse PPI, we studied mouse chromosome substitution strains (CSS) that each carry a homologous chromosome pair from the A/J inbred strain on a host C57BL/6J inbred strain background. We determined that the chromosome 16 substitution strain has elevated PPI compared to C57BL/6J (P = 1.6 x 10(-11)), indicating that chromosome 16 carries one or more PPI genes. QTL mapping using 87 F(2) intercross progeny identified two significant chromosome 16 loci with LODs of 3.9 and 4.7 (significance threshold LOD is 2.3). The QTL were each highly significant independently and do not appear to interact. Sequence variation between B6 and A/J was used to identify strong candidate genes in the QTL regions, some of which have known neuronal functions. In conclusion, we used mouse CSS to rapidly and efficiently identify two significant QTL for PPI on mouse chromosome 16. The regions contain a limited number of strong biological candidate genes that are potential risk genes for psychiatric disorders in which patients have PPI impairments.     

Nucleotide variation at Msn and Alas2, two genes flanking the centromere of the X chromosome in humans

The centromeric region of the X chromosome in humans experiences low rates of recombination over a considerable physical distance. In such a region, the effects of selection may extend to linked sites that are far away. To investigate the effects of this recombinational environment on patterns of nucleotide variability, we sequenced 4581 bp at Msn and 4697 bp at Alas2, two genes situated on either side of the X chromosome centromere, in a worldwide sample of 41 men, as well as in one common chimpanzee and one orangutan. To investigate patterns of linkage disequilibrium (LD) across the centromere, we also genotyped several informative sites from each gene in 120 men from sub-Saharan Africa. By studying X-linked loci in males, we were able to recover haplotypes and study long-range patterns of LD directly. Overall patterns of variability were remarkably similar at these two loci. Both loci exhibited (i) very low levels of nucleotide diversity (among the lowest seen in the human genome); (ii) a strong skew in the distribution of allele frequencies, with an excess of both very-low and very-high-frequency derived alleles in non-African populations; (iii) much less variation in the non-African than in the African samples; (iv) very high levels of population differentiation; and (v) complete LD among all sites within loci. We also observed significant LD between Msn and Alas2 in Africa, despite the fact that they are separated by approximately 10 Mb. These observations are difficult to reconcile with a simple demographic model but may be consistent with positive and/or purifying selection acting on loci within this large region of low recombination.     

The genetic or mythical ancestry of descent groups: lessons from the Y chromosome

Traditional societies are often organized into descent groups called "lineages," "clans," and "tribes." Each of these descent groups claims to have a common ancestor, and this ancestry distinguishes the group's members from the rest of the population. To test the hypothesis of common ancestry within these groups, we compared ethnological and genetic data from five Central Asian populations. We show that, although people from the same lineage and clan share generally a recent common ancestor, no such common ancestry is observed at the tribal level. Thus, a tribe might be a conglomerate of clans who subsequently invented a mythical ancestor to strengthen group unity.     

Regulation of tillering in sorghum: genotypic effects

MethodsFive sorghum hybrids, derived from inbred lines with a common genetic background and with similar phenology and plant height but contrasting tillering, were grown in five experiments. The experiments covered a wide range in radiation and temperature conditions, so that number of tillers produced varied significantly. Data on leaf area, tiller number, and biomass accumulation and partitioning were collected at regular intervals. To quantify internal plant competition for carbohydrates, a carbohydrate supply–demand index (S/D_index) was developed and related to variation in tillering.ConclusionsThe results support the hypothesis that genotypic differences in tillering were associated with differences in plant carbon S/D balance, associated with differences in leaf size and in the threshold at which tillers grow out. The results provide avenues for phenotyping of mapping populations to identify genomic regions regulating tillering. Incorporating the results in crop growth simulation models could provide insight into the complex genotype-by-management-by-environment interactions associated with drought adaptation.     

Optimization of ultrasound contrast agents with computational models to improve selection of ligands and binding strength

Diagnosis of cardiovascular disease is currently limited by the testing modality. Serum tests for biomarkers can provide quantification of severity but lack the ability to localize the source of the cardiovascular disease, while imaging technology such as angiography and ultrasound can only determine areas of reduced flow but not the severity of tissue ischemia. Targeted imaging with ultrasound contrast agents offers the ability to locally image as well as determine the degree of ischemia by utilizing agents that will cause the contrast agent to home to the affected tissue. Ultrasound molecular imaging via targeted microbubbles (MB) is currently limited by its sensitivity to molecular markers of disease relative to other techniques (e.g., radiolabeling). We hypothesize that computational modeling may provide a useful first approach to maximize microbubble binding by defining key parameters governing adhesion. Adhesive dynamics (AD) was used to simulate the fluid dynamic and stochastic molecular binding of microbubbles to inflamed endothelial cells. Sialyl Lewis^X (sLe^x), P‐selectin aptamer (PSA), and ICAM‐1 antibody (abICAM) were modeled as the targeting receptors on the microbubble surface in both single‐ and dual‐targeted arrangements. Microbubble properties (radius [R_c], kinetics [k_f, k_r], and densities of targeting receptors) and the physical environment (shear rate and target ligand densities) were modeled. The kinetics for sLe^x and PSA were measured with surface plasmon resonance. R_c, shear rate, and densities of sLe^x, PSA, or abICAM were varied independently to assess model sensitivity. Firm adhesion was defined as MB velocity <2% of the free stream velocity. AD simulations revealed an optimal microbubble radius of 1–2 µm and thresholds for (>10² s^?1) and (<10^?3 s^?1) for firm adhesion in a multi‐targeted system. State diagrams for multi‐targeted microbubbles suggest sLe^x and abICAM microbubbles may require 10‐fold more ligand to achieve firm adhesion at higher shear rates than sLe^x and PSA microbubbles. The AD model gives useful insight into the key parameters for stable microbubble binding, and may allow flexible, prospective design, and optimization of microbubbles to enhance clinical translation of ultrasound molecular imaging. Biotechnol. Bioeng. 2010;107: 854–864. © 2010 Wiley Periodicals, Inc.     

RIC-3 Exclusively Enhances the Surface Expression of Human Homomeric 5-Hydroxytryptamine Type 3A (5-HT3A) Receptors Despite Direct Interactions with 5-HT3A, -C, -D, and -E Subunits

Although five 5-hydroxytryptamine type 3 (5-HT3) subunits (A–E) have been cloned, knowledge on the regulation of their assembly is limited. RIC-3 has been identified as a chaperone specific for the pentameric ligand-gated nicotinic acetylcholine and 5-HT₃ receptors. Therefore, we examined the impact of RIC-3 on differently composed 5-HT₃ receptors with the focus on 5-HT3C, -D, and -E subunits. The influence of RIC-3 on these receptor subtypes is supported by the presence of RIC3 mRNA in tissues expressing at least one of the subunits 5-HT3C, -D, and -E. Furthermore, immunocytochemical studies on transfected mammalian cells revealed co-localization in the endoplasmic reticulum and direct interaction of RIC-3 with 5-HT3A, -C, -D, and -E. Functional and pharmacological characterization was performed using HEK293 cells expressing 5-HT3A or 5-HT3A + 5-HT3B (or -C, -D, or -E) in the presence or absence of RIC-3. Ca²⁺ influx analyses revealed that RIC-3 does not influence the 5-HT concentration-response relationship on 5-HT₃A receptors but leads to differential increases of 5-HT-induced maximum response (E_max) on cells expressing different subunits. Increases of E_max were due to analogously enhanced B_max values for binding of the 5-HT₃ receptor antagonist [³H]GR65630. The observed enhanced cell surface expression of the tested 5-HT3 subunit combinations correlated with the increased surface expression of 5-HT3A as determined by flow cytometry. In conclusion, we showed that RIC-3 can interact with 5-HT3A, -C, -D, and -E subunits and predominantly enhances the surface expression of homomeric 5-HT₃A receptors in HEK293 cells. These data implicate a possible role of RIC-3 in determining 5-HT₃ receptor composition in vivo.     

Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells

The blood-brain barrier contributes to maintain brain cholesterol metabolism and protects this uniquely balanced system from exchange with plasma lipoprotein cholesterol. Brain capillary endothelial cells, representing a physiological barrier to the central nervous system, express apolipoprotein A-I (apoA-I, the major high-density lipoprotein (HDL)-associated apolipoprotein), ATP-binding cassette transporter A1 (ABCA1), and scavenger receptor, class B, type I (SR-BI), proteins that promote cellular cholesterol mobilization. Liver X receptors (LXRs) and peroxisome-proliferator activated receptors (PPARs) are regulators of cholesterol transport, and activation of LXRs and PPARs has potential therapeutic implications for lipid-related neurodegenerative diseases. To clarify the functional impact of LXR/PPAR activation, sterol transport along the: (i) ABCA1/apoA-I and (ii) SR-BI/HDL pathway was investigated in primary, polarized brain capillary endothelial cells, an in vitro model of the blood-brain barrier. Activation of LXR (24(S)OH-cholesterol, TO901317), PPARalpha (bezafibrate, fenofibrate), and PPARgamma (troglitazone, pioglitazone) modulated expression of apoA-I, ABCA1, and SR-BI on mRNA and/or protein levels without compromising transendothelial electrical resistance or tight junction protein expression. LXR-agonists and troglitazone enhanced basolateral-to-apical cholesterol mobilization in the absence of exogenous sterol acceptors. Along with the induction of cell surface-located ABCA1, several agonists enhanced cholesterol mobilization in the presence of exogenous apoA-I, while efflux of 24(S)OH-cholesterol (the major brain cholesterol metabolite) in the presence of exogenous HDL remained unaffected. Summarizing, in cerebrovascular endothelial cells apoA-I, ABCA1, and SR-BI represent drug targets for LXR and PPAR-agonists to interfere with cholesterol homeostasis at the periphery of the central nervous system.