William Rice - US grants

The proposed research will experimentally test predictions from recent theory, concerning the mechanisms that lead to the evolution of dimorphic sex chromosomes. Most animal species, and a smaller percentage of plant species, have a special pair of chromosomes, the X and Y sex chromosomes, that determine gender. The typical pattern is for males to carry two types of sex chromosomes, and X and a Y, and for females to carry two of the same type (X) of sex chromosome. Several lines of evidence now indicate that sex chromosomes are derived from a pair of chromosomes which formerly were not associated with the determination of gender. This transition first involves the evolution of a major sex determining gene, followed by the evolution of a sex-determining chromosomal segment, and finally in the evolution of sex-determining chromosomes. During the evolution of sex chromosomes, one chromosome, the X, evolves enhanced biochemical activity (dosage compensation) while the partner chromosome, the Y, is degraded and loses virtually all genetic activity. The sex chromosomes also lose their ability to exchange genetic material during this transition. An understanding of the genetic mechanisms responsible for the formation of sex chromosomes is the focus of the proposed research. The investigator will use a Drosophila melanogaster (common fruit fly) model system to experimentally create a new pair of sex- determining genes and chromosomes. The investigator will then use this model system to explore the mechanisms that lead to the breakdown in genetic exchange between the sex chromosomes, and to the mechanisms that lead to the deterioration (accumulation of mutations) of the genetic activity of the Y sex chromosome. An understanding of the evolution of dimorphic sex chromosomes has many practical applications. First, the presence of sex chromosomes causes males (more generally the heterogametic sex) to be far more susceptible to hereditary disease. Dimorphic sex chromosomes are the physical basis for sex-linked inheritance and cause males to inherit many hereditary diseases thousands of times more frequently than females. The evolution of dimorphic sex chromosomes also results in the phenomena of dosage compensation (a modified level of gene expression for the hereditary material located on the sex chromosomes). Biochemical irregularities with dosage compensation are responsible for some forms of hereditary disease. The proposed experiments will also monitor the accumulation of deleterious mutations on both the sex chromosomes and on ordinary chromosomes. An understanding of this accumulation process is important in understanding the risk to human populations of increasing levels of exposure to radiation (e.g. that produced from nuclear waste and the thinning of the ozone layer of the atmosphere). Recent applied theoretical work by the investigator also suggests that data from the experiments will be useful in determining the genetic risk (due to inbreeding depression and natural levels of background radiation) to wildlife populations that are maintained to small effective population size, such as occurs in parks and game refuges.

The human immunodeficiency virus type 1 (HIV-1) has been defined as the etiologic agent of he acquired immune deficiency syndrome (AIDS). Although intensive research has been directed toward management of this lethal disease, to date no facile means of prevention and treatment has been identified. Recently, human saliva was found to inhibit the infectivity of HIV-1 into human peripheral blood lymphocytes, suggesting that saliva and possibly other secretory fluids contain human-derived products having anti- HIV-1 activity. The objective of the proposed study is to isolate and identify the inhibitory factors in human secretory fluids and to then study the modes of action of these factors, with the ultimate goal of developing therapeutic interventions against HIV-1 infection. Preliminary results indicate that perchloric acid-stable factors(s) in human whole saliva inhibit the infectivity of HIV-1, as judged by the inhibition of expression of reverse transcriptase activity released into the extracellular milieu of HIV-1 infected CEM cells. Proposed studies will include screening of various secretory fluids (milk, tears, whole saliva, parotid saliva, and submandibular/sublingual saliva) and of a number of purified secretory components (lactoferrin, IgA, lactoferrin-IgA complexes, lysozyme, peroxidase, agglutinins and secretory leukocyte protease inhibitor) for anti-HIV-1 activity. Concomitantly, native secretory fluids will be fractionated by a number of currently used chromatographic procedures, with the exact sequence of procedures dependent upon the fractionation patterns of the anti-HIV-1 activities. Further characterization of the anti-HIV-1 activities will include determination of the specificities of the activities toward different virus isolates and different target cells, and determination if the factors can prevent syncytia formation by HIV-1- infected cells. Together, these studies should provide valuable information regarding the nature of human-derived weapons against HIV-1 and may lead to effective therapeutic intervention of HIV-1 infections.

9307735 Recent theory predicts that some forms of hereditary disease may accumulate in humans and other animals due to opposing selection in the two sexes. Positions on chromosomes (the physical units of hereditary information) where such opposing selection occurs are called sexually antagonistic genes. Males and females of the same species are superficially very similar, yet when examined more carefully they differ in many ways. In a very broad sense, the sexes are designed by natural selection to do different things: males to produce and disseminate microgametes (sperm) and females to produce macrogametes (eggs) and frequently nurture their offspring. The optimal phenotype (i.e. the sum of all characteristics of an organism) for males and females frequently may differ between the sexes leading to adaptation in each sex being compromised via counter selection in the other sex. Recent experiments in my laboratory indicate that sex specific selection leads to a major genetic "tug of war". between the sexes potentially resulting in the build upon of hereditary diseases that produce sex specific dysfunction. %%% The proposed experiments use a Drosophila melanogaster (common fruit fly) model system to confirm and extend these earlier findings. Fruit flies are used because they are so well known genetically and for purely pragmatic reasons (inexpensive culturing, short generation time, etc.). Entire haplotype (one half of the hereditary material carried by an individual) will be transmitted father to son for 50 generations. This protocol eliminates female specific selection. Periodically over the course of the experiment the haplotype will be place in both males and females and each sex's life time fitness will be assayed. If sex specific selection is a major contributor to hereditary disease then these haplotype will substantially increase the fitness in males while reducing the fitness of females.

9509101 RICE Genetic recombination is a prominent feature of virtually all complex, multicellular organisms. Yet some species of plants and animals lack this genetic feature, including many agriculturally important species like fruit trees, grape varieties, etc. The proposed research tests one of the prevailing theories about the importance of genetic recombination, i.e., it accelerates the rate of beneficial adaptation in response to environmental change. The common fruit fly (Drosophila melanogaster) is used as a model system owing to its inexpensive culturing, short generation time, and availability of numerous genetic tools critical for the operation of multi-generation experiments. Using a new strain recently developed in Dr. Rice's laboratory, he will experimentally vary the amount of genetic recombination in different populations. He will then challenge these populations with a new environment (low grade thermal stress), as it might occur during a period of rapid global warming. Next he will measure the rate of adaptation and relate this to the experimentally controlled level of genetic recombination. Current theory predicts that genetic recombination will greatly enhance the capacity of the populations to adapt to the new environment. The capacity for rapid adaptation is becoming increasingly important owing to the rapid environmental change induced by human activities. Results from these experiments will contribute to basic understanding of plant and animal breeding programs, and will help to predict the capacity of different life forms to adapt to human-induced environmental change.

9623479 Rice The Dissertation Research funded by this award will test basic theory on adaptive evolution. Natural selection can be divided into two components - sexual selection (competition by males to fertilize eggs) and non-sexual selection (survival of both sexes and egg production by females). Theory predicts that these two forms of selection can be either reinforcing or antagonistic. If the latter case is common, sexual selection will slow a population's adaptation to a changing environment. Research funded by this award will establish how these two forms of natural selection interact in nature. To do this, a laboratory population of Drosophila melanogaster will be challenged with a new environmental factor, heat stress. The rate of adaptation by the population to the new environment will then be determined with and without sexual selection imposed, providing a direct measure of the regime under which adaptation accrues most rapidly. The relationship between sexual selection and non-sexual selection is of practical concern in all breeding enterprises involving animals or plants (e.g. agriculture, zoological parks, and conservation biology). This research will also shed light on how fast can populations adapt to thermally changing environments. Findings will provide practical information for predicting the ability of insect populations to respond to a protracted and substantial increase in temperature, as anticipated under global climate change.

Abstract

This project will examine the origin and dynamics of turbulence in the interplanetary medium. Turbulence will be incorporated into mean-field models of the solar wind and the role of turbulence on shock waves and the acceleration of particles at shocks will be investigated. The role of turbulence in the modulation of cosmic rays will also be investigated. The coupling of turbulence to the mean-field models of the solar wind will be accomplished by introducing source terms for the dissipation of turbulence into the large-scale solar wind model. To investigate the role of turbulence in shocks, coupled microscopic and macroscopic models of the shock waves will be used to generalize the Rankine-Hugoniot conditions. The influence of turbulence on cosmic ray modulation will be accomplished by adding turbulent scattering to existing cosmic ray transport codes.

Abstract

This project will examine the origin and dynamics of turbulence in the interplanetary medium. Turbulence will be incorporated into mean-field models of the solar wind and the role of turbulence on shock waves and the acceleration of particles at shocks will be investigated. The role of turbulence in the modulation of cosmic rays will also be investigated. The coupling of turbulence to the mean-field models of the solar wind will be accomplished by introducing source terms for the dissipation of turbulence into the large-scale solar wind model. To investigate the role of turbulence in shocks, coupled microscopic and macroscopic models of the shock waves will be used to generalize the Rankine-Hugoniot conditions. The influence of turbulence on cosmic ray modulation will be accomplished by adding turbulent scattering to existing cosmic ray transport codes.

This research investigates a process by which natural selection can lead to gender-specific dysfunction. Males and females need to accomplish different biological functions, yet nearly 90% of the genome is expressed in both sexes. In a recent pilot experiment the entire genome of the common fruit fly (Drosophila melanogaster) was cloned and then identical copies of the same genomes were expressed in both males and females. Genomes that produced the highest Darwinian fitness in females produced low fitness in males, and visa versa. This intersexual reversal suggests that genes that are favored in one sex and disfavored in the other sex are common in the genome of the fruit fly. Because all animals express many of the same genes, the observed intersexual genetic conflict may be widespread. In the proposed research cytogenetic cloning will be used to measure: i) the functional significance of sexually antagonistic genetic variation, ii) its distribution among chromosomes, iii) its transmission dynamics between generations, and iv) the traits that mediate intersexual genetic conflict.
The experiments are relevant to hereditary factors that mediate gender-specific impairment (e.g., sterility). In the past it has been assumed that harmful genetic variation was maintained solely by recurrent mutation or genetic drift. This research evaluates a new source for the genetic polymorphisms that are responsible for gender-specific dysfunction.