Showing papers by "University of Kiel published in 2003"

Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene

Abstract: Malignant cells often display defects in autophagy, an evolutionarily conserved pathway for degrading long-lived proteins and cytoplasmic organelles. However, as yet, there is no genetic evidence for a role of autophagy genes in tumor suppression. The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer. Therefore, we used a targeted mutant mouse model to test the hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we show that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus-induced premalignant lesions. Molecular analyses of tumors in beclin 1 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation and reduced autophagy in vivo. These findings demonstrate that beclin 1 is a haplo-insufficient tumor-suppressor gene and provide genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression. Thus, mutation of beclin 1 or other autophagy genes may contribute to the pathogenesis of human cancers.

Human Gene Mutation Database (HGMD): 2003 update.

Abstract: The Human Gene Mutation Database (HGMD) constitutes a comprehensive core collection of data on germ-line mutations in nuclear genes underlying or associated with human inherited disease (www.hgmd.org). Data catalogued includes: single base-pair substitutions in coding, regulatory and splicing-relevant regions; micro-deletions and micro-insertions; indels; triplet repeat expansions as well as gross deletions; insertions; duplications; and complex rearrangements. Each mutation is entered into HGMD only once in order to avoid confusion between recurrent and identical-by-descent lesions. By March 2003, the database contained in excess of 39,415 different lesions detected in 1,516 different nuclear genes, with new entries currently accumulating at a rate exceeding 5,000 per annum. Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease-associated and functional polymorphisms, as well as links to data present in publicly available online locus-specific mutation databases. Although HGMD has recently entered into a licensing agreement with Celera Genomics (Rockville, MD), mutation data will continue to be made freely available via the Internet.

Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans

Abstract: Both dauer formation (a stage of developmental arrest) and adult life-span in Caenorhabditis elegans are negatively regulated by insulin-like signaling, but little is known about cellular pathways that mediate these processes. Autophagy, through the sequestration and delivery of cargo to the lysosomes, is the major route for degrading long-lived proteins and cytoplasmic organelles in eukaryotic cells. Using nematodes with a loss-of-function mutation in the insulin-like signaling pathway, we show that bec-1, the C. elegans ortholog of the yeast and mammalian autophagy gene APG6/VPS30/beclin1, is essential for normal dauer morphogenesis and life-span extension. Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10. Thus, autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans.

Conceptual Change: A Powerful Framework for Improving Science Teaching and Learning

Abstract: In this review, we discuss (1) how the notion of conceptual change has developed over the past three decades, (2) giving rise to alternative approaches for analysing conceptual change, (3) leading towards a multiperspective view of science learning and instruction that (4) can be used to examine scientific literacy and (5) lead to a powerful framework for improving science teaching and learning

Resin-ceramic bonding: a review of the literature.

Abstract: Current ceramic materials offer preferred optical properties for highly esthetic restorations. The inherent brittleness of some ceramic materials, specific treatment modalities, and certain clinical situations require resin bonding of the completed ceramic restoration to the supporting tooth structures for long-term clinical success. This article presents a literature review on the resin bond to dental ceramics. A PubMed database search was conducted for in vitro studies pertaining to the resin bond to ceramic materials. The search was limited to peer-reviewed articles published in English between 1966 and 2001. Although the resin bond to silica-based ceramics is well researched and documented, few in vitro studies on the resin bond to high-strength ceramic materials were identified. Available data suggest that resin bonding to these materials is less predictable and requires substantially different bonding methods than to silica-based ceramics. Further in vitro studies, as well as controlled clinical trials, are needed.

Lithium Lanthanum Titanates: A Review

Abstract: To date, the highest bulk lithium ion-conducting solid electrolyte is the perovskite (ABO3)-type lithium lanthanum titanate (LLT) Li3xLa(2/3)-x□(1/3)-2xTiO3 (0 < x < 0.16) and its related structure materials. The x ≈ 0.1 member exhibits conductivity of 1 × 10-3 S/cm at room temperature with an activation energy of 0.40 eV. The conductivity is comparable to that of commonly used polymer/liquid electrolytes. The ionic conductivity of LLT mainly depends on the size of the A-site ion cation (e.g., La or rare earth, alkali or alkaline earth), lithium and vacancy concentration, and the nature of the B−O bond. For example, replacement of La by other rare earth elements with smaller ionic radii than that of La decreases the lithium ion conductivity, while partial substitution of La by Sr (larger ionic radii than that of La) slightly increases the lithium ion conductivity. The high lithium ion conductivity of LLT is considered to be due to the large concentration of A-site vacancies, and the motion of lithium by a...

Demand for Beef from Cattle Administered Growth Hormones or Fed Genetically Modified Corn: A Comparison of Consumers in France, Germany, the United Kingdom, and the United States

Abstract: We compare consumer valuations of beef ribeye steaks from cattle produced without growth hormones or genetically modified corn in France, Germany, the United Kingdom, and the United States. Results suggest that French consumers place a higher value on beef from cattle that have not been administered added growth hormones than U.S. consumers; however, valuations of non-hormone-treated beef are statistically indistinguishable across Germany, the United Kingdom, and the United States. Results also suggest that European consumers place a much higher value on beef from cattle that have not been fed genetically modified corn than U.S. consumers. Copyright 2003, Oxford University Press.

Novel Fast Lithium Ion Conduction in Garnet-Type Li5La3M2O12 (M = Nb, Ta)

Abstract: Lithium metal oxides with the nominal composition Li5La3M2O12 (M = Nb, Ta), possessing a garnetlike structure, have been investigated with regard to their electrical properties. These compounds form a new class of solid-state lithium ion conductors with a different crystal structure compared with all those known so far. The materials are prepared by solid-state reaction and characterized by powder XRD and ac impedance to determine their lithium ionic conductivity. Both the niobium and tantalum members exhibit the same order of magnitude of bulk conductivity (∼10−6 S/cm at 25°C). The activation energies for ionic conductivity (<300°C) are 0.43 and 0.56 eV for Li5La3Nb2O12 and Li5La3Ta2O12, respectively, which are comparable to those of other solid lithium conductors, such as Lisicon, Li14ZnGe4O16. Among the investigated materials, the tantalum compound Li5La3Ta2O12 is stable against reaction with molten lithium. Further tailoring of the compositions by appropriate chemical substitutions and improved synthesizing methods, especially with regard to minimizing grain-boundary resistance, are important issues in view of the potential use of the new class of compounds as electrolytes in practical lithium ion batteries.

Deep roots of the Messinian salinity crisis

Abstract: The Messinian salinity crisis—the desiccation of the Mediterranean Sea between 5.96 and 5.33 million years (Myr) ago1—was one of the most dramatic events on Earth during the Cenozoic era2. It resulted from the closure of marine gateways between the Atlantic Ocean and the Mediterranean Sea, the causes of which remain enigmatic. Here we use the age and composition of volcanic rocks to reconstruct the geodynamic evolution of the westernmost Mediterranean from the Middle Miocene epoch to the Pleistocene epoch (about 12.1–0.65 Myr ago). Our data show that a marked shift in the geochemistry of mantle-derived volcanic rocks, reflecting a change from subduction-related to intraplate-type volcanism, occurred between 6.3 and 4.8 Myr ago, largely synchronous with the Messinian salinity crisis. Using a thermomechanical model, we show that westward roll back of subducted Tethys oceanic lithosphere and associated asthenospheric upwelling provides a plausible mechanism for producing the shift in magma chemistry and the necessary uplift (approx1 km) along the African and Iberian continental margins to close the Miocene marine gateways, thereby causing the Messinian salinity crisis.

Climate change at the 4.2 ka BP termination of the Indus valley civilization and Holocene south Asian monsoon variability

Abstract: [1] Planktonic oxygen isotope ratios off the Indus delta reveal climate changes with a multi-centennial pacing during the last 6 ka, with the most prominent change recorded at 4.2 ka BP. Opposing isotopic trends across the northern Arabian Sea surface at that time indicate a reduction in Indus river discharge and suggest that later cycles also reflect variations in total annual rainfall over south Asia. The 4.2 ka event is coherent with the termination of urban Harappan civilization in the Indus valley. Thus, drought may have initiated southeastward habitat tracking within the Harappan cultural domain. The late Holocene drought cycles following the 4.2 ka BP event vary between 200 and 800 years and are coherent with the evolution of cosmogenic 14C production rates. This suggests that solar variability is one fundamental cause behind Holocene rainfall changes over south Asia.

Transcriptional profiling identifies Id2 function in dendritic cell development

Abstract: Dendritic cells (DCs) are potent antigen-presenting cells with a pivotal role in antigen-specific immune responses. Here, we found that the helix-loop-helix transcription factor Id2 is up-regulated during DC development in vitro and crucial for the development of distinct DC subsets in vivo. Id2-/- mice lack Langerhans cells (LCs), the cutaneous contingent of DCs, and the splenic CD8alpha+ DC subset is markedly reduced. Mice deficient for transforming growth factor (TGF)-beta also lack LCs, and we demonstrate here that, in DCs, TGF-beta induces Id2 expression. We also show that Id2 represses B cell genes in DCs. These findings reveal a TGF-beta-Id2 signaling pathway in DCs and suggest a mechanism by which Id2 affects the lineage choice of B cell and DC progenitors.

Galactic-Field Initial Mass Functions of Massive Stars

Abstract: Over the past years observations of young and populous star clusters have shown that the stellar initial mass function (IMF) appears to be an invariant featureless Salpeter power law with an exponent ? = 2.35 for stars more massive than a few M?. A consensus has also emerged that most, if not all, stars form in stellar groups and star clusters and that the mass function of young star clusters in the solar neighborhood and in interacting galaxies can be described, over the mass range of a few 10 to 107 M?, as a power law with an exponent ? ? 2. These two results imply that galactic-field IMFs for early-type stars cannot, under any circumstances, be a Salpeter power law, but that they must have a steeper exponent, ?field 2.8. This has important consequences for the distribution of stellar remnants and for the chemodynamical and photometric evolution of galaxies.

The cerebral oscillatory network of parkinsonian resting tremor

Abstract: Data from experiments in MPTP monkeys as well as from invasive and non-invasive recordings in patients with Parkinson's disease suggest an abnormal synchronization of neuronal activity in the generation of resting tremor in Parkinson's disease. In six patients with tremor-dominant idiopathic Parkinson's disease, we recorded simultaneously surface electromyograms (EMGs) of hand muscles, and brain activity with a whole-head magnetoencephalography (MEG) system. Using a recently developed analysis tool (Dynamic Imaging of Coherent Sources; DICS), we determined cerebro-muscular and cerebro-cerebral coherence as well as the partial coherence between cerebral areas and muscle, and localized coherent sources within the individual MRI scans. The phase lag between the EMG and cerebral activity was determined by means of a Hilbert transform of both signals. After overnight withdrawal from medication, patients showed typical Parkinson's disease resting tremor (4-6 Hz). This tremor was associated with strong coherence between the EMG of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Phase lags between M1 activity and EMG were between 15 and 25 ms (M1 activity leading) at single, but also at double tremor frequency, corresponding well to the corticomuscular conduction time. Furthermore, significant coherence was observed between M1 and medial wall areas (cingulate/supplementary motor area; CMA/SMA), lateral premotor cortex (PM), diencephalon, secondary somatosensory cortex (SII), posterior parietal cortex (PPC) and the contralateral cerebellum at single tremor and, even stronger at double tremor frequency. Spectra of coherence between thalamic activity and cerebellum as well as several brain areas revealed additional broad peaks around 20 Hz. Power spectral analysis of activity in all central areas indicated the strongest frequency components at double tremor frequency. Partial coherence analysis and the calculation of phase shifts revealed a strong bidirectional coupling between the EMG and diencephalic activity and a direct afferent coupling between the EMG and SII and the PPC. In contrast, the cerebellum, SMA/CMA and PM show little evidence for direct coupling with the peripheral EMG but seem to be connected with the periphery via other cerebral areas (e.g. M1). In summary, our results demonstrate tremor-related oscillatory activity within a cerebral network, with abnormal coupling in a cerebello-diencephalic-cortical loop and cortical motor (M1, SMA/CMA, PM) and sensory (SII, PPC) areas contralateral to the tremor hand. The main frequency of cerebro-cerebral coupling corresponds to double the tremor frequency.

Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death.

Abstract: Pancreatic cancer is resistant to almost all cytotoxic drugs. Currently, gemcitabine appears to be the only clinically active drug but, because of pre-existing or acquired chemoresistance of most of the tumor cells, it failed to significantly improve the outcome of pancreatic carcinoma patients. The current study examined the relevance of nuclear factor kappaB (NF-kappaB) and PI3K/Akt in the resistance of five pancreatic carcinoma cell lines towards gemcitabine. Treatment for 24 h with gemcitabine (0.04-20 micro M) led to a strong induction of apoptosis in PT45-P1 and T3M4 cells but not in BxPc-3, Capan-1 and PancTu-1 cells. These resistant cell lines exhibited a high basal NF-kappaB activity in contrast to the sensitive cell lines. Furthermore, gemcitabine showed a dose-dependent induction of NF-kappaB. At a dose of 0.04 micro M, gemcitabine still induced apoptosis in the sensitive cell lines, but did not induce NF-kappaB. In addition, NF-kappaB inhibition by MG132, sulfasalazine or the IkappaBalpha super-repressor strongly diminished the resistance against gemcitabine (0.04-20 micro M). In contrast to this obvious correlation between basal NF-kappaB activity and gemcitabine resistance, PI3K/Akt seems not to be involved in gemcitabine resistance of these cell lines. Neither did the basal Akt activity correlate with the sensitivity towards gemcitabine treatment, nor did the inhibition of PI3K/Akt by LY294002 alter gemcitabine-induced apoptosis. These results indicate that constitutive NF-kappaB activity confers resistance against gemcitabine and that modulation of this activity by pharmacological or genetic approaches may have therapeutical potential when combined with gemcitabine in the treatment of pancreatic carcinoma.

Translation of symptoms and signs into mechanisms in neuropathic pain

Abstract: 1. IntroductionFor centuries, clinicians have been taught to examine andclassify patients on the basis of topographical lesion and theunderlying pathology. In most clinical specialities, such anapproach has been a key element in understanding thepathophysiology of diseases and has led to progress interms of finding disease modifying or even disease curingtherapies. Examples are multiple including bacterial menin-gitis, painful neuroborrelosis, osteoarthrosis, cancer, rheu-matoid arthritis, ischaemic heart disease etc. In most ofthese disorders, pain can be a major complaint, whichthen rapidly disappears after the relevant therapy has beengiven.But what happens when the symptom itself becomes adisease? When pain persists and becomes a chronic problemand when the underlying diseases such as diabetes, cancer,vasculitis are known, or cannot be cured? Are we thenhelped by the classical ‘Sherlock Holmes’ approach, first,to look for the ‘crime site’ (topography of lesion) andsecond, for the ‘criminal’ (the disease) that caused thispain? The short answer is: no. Clinical experience anddecades of rather discouraging systematic research mainlyrelated to therapy in chronic pain have shown that a strategydirected at examining, classifying and treating pain on basisof anatomy or underlying disease is of limited help to thesepatients and their pain. These observations have then raisedthe question whether an entirely different strategy in whichpain is analysed on the basis of underlying mechanismscould be an alternative approach to examine and classifypatients to obtain a better outcome. Our increasing under-standing of mechanisms underlying chronic pain togetherwith the discovery of new molecular targets for modifyingpain has strengthened the demand for other ways to treatpain. Woolf and other authors (Woolf et al., 1998; Woolfand Decosterd, 1999; Sindrup and Jensen, 1999) haveemphasised the rational for a treatment approach directedat mechanism(s) rather than at diseases because new treat-ments are being developed on basis of the biologicalmechanisms that underlie the pain. One area that needssuch a new approach is neuropathic pain.2. Neuropathic pain classification problemsAccording to the current International Association forthe Study of Pain (IASP) definition of neuropathic pain,these disorders are characterised by lesions or dysfunctionof the system(s) that under normal conditions transmitnoxious information to the central nervous system. Thusin theory, neuropathic pain should be easy to distinguishfrom other conditions, but in practise, they are both diffi-cult to identify and to treat and there are several reasonwhy this is the case:† There is rarely one diagnostic test that can confirm orrefute the hypothesis of nerve lesion/dysfunction.† The perception of neuropathic (and other types of) painis a pure subjective phenomenon, which despite use ofthe most sophisticated equipment can’t be measured;only correlates to the perceived content can be obtained.† The borderland between definite, probable, possible andunlikely diagnoses is not clear. Prevalent disorders suchas cancer, low back pain, traumatic injuries may containa considerable (although as yet undetermined) neuro-pathic component.† In contrast to other sensory systems, the pain system isnot static, but changes in a dynamic and somewhatunpredictable fashion whenever the system has beenactivated.

Cell-wall recovery after irreversible deformation of wood

Abstract: The remarkable mechanical properties of biological materials reside in their complex hierarchical architecture and in specific molecular mechanistic phenomena1,2,3. The fundamental importance of molecular interactions and bond recovery has been suggested by studies on deformation and fracture of bone and nacre4,5,6. Like these mineral-based materials, wood also represents a complex nanocomposite with excellent mechanical performance, despite the fact that it is mainly based on polymers. In wood, however, the mechanistic contribution of processes in the cell wall is not fully understood7,8,9. Here we have combined tensile tests on individual wood cells and on wood foils with simultaneous synchrotron X-ray diffraction analysis in order to separate deformation mechanisms inside the cell wall from those mediated by cell–cell interactions. We show that tensile deformation beyond the yield point does not deteriorate the stiffness of either individual cells or foils. This indicates that there is a dominant recovery mechanism that re-forms the amorphous matrix between the cellulose microfibrils within the cell wall, maintaining its mechanical properties. This stick–slip mechanism, rather like Velcro operating at the nanometre level, provides a 'plastic response' similar to that effected by moving dislocations in metals. We suggest that the molecular recovery mechanism in the cell matrix is a universal phenomenon dominating the tensile deformation of different wood tissue types.

Introduction to Hierarchical Matrices with Applications

Abstract: We give a short introduction to methods for the data-sparse approximation of matrices resulting from the discretisation of non-local operators occurring in boundary integral methods, as the inverses of partial differential operators or as solutions of control problems. The result of the approximation will be so-called hierarchical matrices (or short H-matrices). These matrices form a subset of the set of all matrices and have a data-sparse representation. The essential operations for these matrices (matrix-vector and matrix – matrix multiplication, addition and inversion) can be performed in, up to logarithmic factors, optimal complexity. We give a review of specialised variants of H-matrices, especially of H 2 -matrices, and finally consider applications of the different methods to problems from integral equations, partial differential equations and control theory. q 2003 Elsevier Science Ltd. All rights reserved.

Metal Lines in DA White Dwarfs

Abstract: We report Keck telescope HIRES echelle observations of DA white dwarfs in a continuation of an extensive search for metals. These spectra are supplemented with new JHK magnitudes that are used to determine improved atmospheric parameters. Of the DA white dwarfs not in binary or common proper motion systems, about 25% show Ca II lines. For these, Ca abundances are determined from comparison with theoretical equivalent widths from model atmosphere calculations; in a few cases we also obtain Mg, Fe, Si, and Al abundances. If Ca is not observed, we generally determine very stringent upper limits. We compare the data to predictions of previously published models involving the accretion/diffusion of interstellar matter and of comets. The derived abundances are not obviously compatible with the predictions of either model, which up to now could only be tested with traces of metals in helium-rich white dwarfs. By modifying certain assumptions in the published interstellar accretion model we are able to match the distribution of the elements in the white dwarf atmospheres, but, even so, tests of other expectations from this scenario are less successful. Because comet accretion appears unlikely to be the primary cause of the DAZ phenomenon, the data suggest that no more than about 20% of F-type main-sequence stars are accompanied by Oort-like comet clouds. This represents the first observational estimate of this fraction. A plausible alternative to the accretion of cometary or interstellar matter is disruption and accretion of asteroidal material, a model first suggested in 1990 to explain excess near-infrared emission from the DAZ G29-38. An asteroidal debris model to account for the general DAZ phenomenon does not presently disagree with the HIRES data, but neither is there any compelling evidence in support of such a model. The HIRES data indicate that in close red dwarf/white dwarf binaries not known to be cataclysmic variables there is, nonetheless, significant mass transfer, perhaps in the form of a wind flowing off the red dwarf. As a by-product we find from the kinematics of GD 165 a likely age of more than 2 Gyr for its probable brown dwarf companion GD 165B.

Complex regional pain syndrome: mystery explained?

Abstract: Complex regional pain syndrome (CRPS) is the result of changes to the somatosensory systems that process noxious, tactile, and thermal information; to the sympathetic systems that innervate skin (blood vessels, sweat glands); and to the somatomotor systems. The changes suggest that the CNS representations of the systems have been altered. Patients with CRPS also have peripheral changes (eg, oedema, signs of inflammation, sympathetic-afferent coupling [the basis for sympathetically maintained pain], and trophic changes) that cannot be explained by central changes. On the basis of clinical observation and research in human beings and animals, we hypothesise that CRPS is a systemic disease involving the CNS and peripheral nervous system. The most important question for future research is what causes CRPS? In this article, we suggest a change to the focus of research efforts and treatment. We also suggest there be diagnostic reclassification and redefinition of CRPS.

Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease

Abstract: Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

The Genetic Heritage of the Earliest Settlers Persists Both in Indian Tribal and Caste Populations

Abstract: Two tribal groups from southern India—the Chenchus and Koyas—were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools.