Origins and affinities of modern humans: a comparison of mitochondrial and nuclear genetic data

Journal ArticleTo test hypotheses about the origin of modern humans, we analyzed mtDNA sequences, 30 nuclear restriction-site polymorphisms (RSPs), and 30 tetranucleotide short tandem repeat (STR) polymorphisms in 243 Africans, Asians, and Europeans. An evolutionary tree based on mtDNA displays deep African branches, indicating greater genetic diversity for African populations. This finding, which is consistent with previous mtDNA analyses, has been interpreted as evidence for an African origin of modern humans. Both sets of nuclear polymorphisms, as well as a third set of trinucleotide polymorphisms, are highly consistent with one another but fail to show deep branches for African populations. These results, which represent the first direct comparison of mtDNA and nuclear genetic data in major continental populations, undermine the genetic evidence for an African origin of modern humans

Identification of signaling pathways in early mammary gland development by mouse genetics

The mammary gland develops as an appendage of the ectoderm. The prenatal stage of mammary development is hormone independent and is regulated by sequential and reciprocal signaling between the epithelium and the mesenchyme. A number of recent studies using human and mouse genetics, in particular targeted gene deletion and transgenic expression, have identified some of the signals that control specific steps in development. This process involves cell specification and proliferation, reciprocal tissue interactions and cell migration. Since some of these events are recapitulated during tumorigenesis, an understanding of these signaling pathways may contribute to the development of targeted therapies and novel drugs

Sheldon-Hall syndrome

Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate. Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature. Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive. SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic. Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers. The diagnosis of SHS is based on clinical criteria. Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome). Prenatal diagnosis by ultrasonography is feasible at 18–24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible. There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery. Life expectancy and cognitive abilities are normal

mtDNA Variation in Caste Populations of Andhra Pradesh, India.

Various anthropological analyses have documented extensive regional variation among populations on the subcontinent of India using morphological, protein, blood group, and nuclear DNA polymorphisms. These patterns are the product of complex population structure (genetic drift, gene flow) and a population history noted for numerous branching events. As a result, the interpretation of relationships among caste populations of South India and between Indians and continental populations remains controversial. The Hindu caste system is a general model of genetic differentiation among endogamous populations stratified by social forces (e.g., religion and occupation). The mitochondrial DNA (mtDNA) molecule has unique properties that facilitate the exploration of population structure. We analyzed 36 Hindu men born in Andhra Pradesh who were unrelated matrilineally through at least 3 generations and who represent 4 caste populations: Brahmin (9), Yadava (10), Kapu (7), and Relli (10). Individuals from Africa (36), Asia (36), and Europe (36) were sampled for comparison. A 200-base-pair segment of hypervariable segment 2 (HVS2) of the mtDNA control region was sequenced in all individuals. In the Indian castes 25 distinct haplotypes are identified. Aside from the Cambridge reference sequence, only two haplotypes are shared between caste populations. Middle castes form a highly supported cluster in a neighbor-joining network. Mean nucleotide diversity within each caste is 0.015, 0.012, 0.011, and 0.012 for the Brahmin, Yadava, Kapu, and Relli, respectively. mtDNA variation is highly structured between castes (GST = 0.17; p < 0.002). The effects of social structure on mtDNA variation are much greater than those on variation measured by traditional markers. Explanations for this discordance inelude (1) the higher resolving power of mtDNA, (2) sex-dependent gene flow, (3) differences in male and female effective population sizes, and (4) elements of the kinship structure. Thirty distinct haplotypes are found in Africans, 17 in Asians, and 13 in Europeans. Mean nucleotide diversity is 0.019, 0.014, 0.009, and 0.007 for Africans, Indians, Asians, and Europeans, respectively. These populations are highly structured geographically (GST = 0.15;p < 0.001). The caste populations of Andhra Pradesh cluster more often with Africans than with Asians or Europeans. This is suggestive of admixture with African populations.We would like to thank T. Jenkins, H. Soodyall, P. Nute, and J. Kidd for providing DNA samples and S. Austin, A. Comuzzie, R. Duggirala, R. Feldman, K. Lum, A. Rogers, and S. Watkins for technical advice, critical comments, and thoughtful discussion. This work was supported in part by the National Science Foundation through grant NSF-DBS-9211255, the Clinical Research Center at the University of Utah through grant NIH RR-00064, and the Technology Access Center of the Utah Human Genome Project

Short photoperiod-induced decrease of histamine H3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster

Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod

Relativistically rotating dust

Dust configurations play an important role in astrophysics and are the simplest models for rotating bodies. The physical properties of the general--relativistic global solution for the rigidly rotating disk of dust, which has been found recently as the solution of a boundary value problem, are discussed.Comment: 18 pages, 11 figure

Comprehensive analysis of Alu-associated diversity on the human sex chromosomes

A comprehensive analysis of the human sex chromosomes was undertaken to assess Alu-associated human genomic diversity and to identify novel Alu insertion polymorphisms for the study of human evolution. Three hundred forty-five recently integrated Alu elements from eight different Alu subfamilies were identified on the X and Y chromosomes, 225 of which were selected and analyzed by polymerase chain reaction (PCR). From a total of 225 elements analyzed, 16 were found to be polymorphic on the X chromosome and one on the Y chromosome. In line with previous research using other classes of genetic markers, our results indicate reduced Alu-associated insertion polymorphism on the human sex chromosomes, presumably reflective of the reduced recombination rates and lower effective population sizes on the sex chromosomes. The Alu insertion polymorphisms identified in this study should prove useful for the study of human population genetics. © 2003 Elsevier B.V. All rights reserved

Analysis of 6,515 exomes reveals a recent origin of most human protein-coding variants

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history1,2 and will help facilitate the development of new approaches for disease gene discovery3. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth4-6, notable for an excess of rare genetic variants, qualitatively suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European (n=4,298) and African (n=2,217) American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that ~73% of all protein-coding SNVs and ~86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs compared to other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, illustrate the profound effect recent human history has had on the burden of deleterious SNVs segregating in contemporary populations, and provides important practical information that can be used to prioritize variants in disease gene discovery

New mutations at the imprinted Gnas cluster show gene dosage effects of Gsα in postnatal growth and implicate XLαs in bone and fat metabolism, but not in suckling

The imprinted Gnas cluster is involved in obesity, energy metabolism, feeding behavior, and viability. Relative contribution of paternally expressed proteins XLαs, XLN1, and ALEX or a double dose of maternally expressed Gsα to phenotype has not been established. In this study, we have generated two new mutants (Ex1A-T-CON and Ex1A-T) at the Gnas cluster. Paternal inheritance of Ex1A-T-CON leads to loss of imprinting of Gsα, resulting in preweaning growth retardation followed by catch-up growth. Paternal inheritance of Ex1A-T leads to loss of imprinting of Gsα and loss of expression of XLαs and XLN1. These mice have severe preweaning growth retardation and incomplete catch-up growth. They are fully viable probably because suckling is unimpaired, unlike mutants in which the expression of all the known paternally expressed Gnasxl proteins (XLαs, XLN1 and ALEX) is compromised. We suggest that loss of ALEX is most likely responsible for the suckling defects previously observed. In adults, paternal inheritance of Ex1A-T results in an increased metabolic rate and reductions in fat mass, leptin, and bone mineral density attributable to loss of XLαs. This is, to our knowledge, the first report describing a role for XLαs in bone metabolism. We propose that XLαs is involved in the regulation of bone and adipocyte metabolism