Brian Charlesworth - US grants

An exciting recent finding of genetics has been the discovery that the genomes of organisms from bacteria to humans contain families of DNA sequences that have the ability to make new copies of themselves that can insert elsewhere in the genome. These are known as transposable elements (TEs). The insertion of a TE into or near a gene may cause a mutation with a harmful effect on the survival ability or fertility of the individual. For example, in humans TE insertions have been implicated in mutations causing hemophilia and breast cancer. The discovery of TEs has led to a debate on the nature of the forces that control the distribution of TEs within populations of their host species. Previous studies in Drosophila, yeast and bacteria have shown that, although several copies of members of the same family of TE may be present within a host individual's genome, different individuals may have different numbers of copies. Furthermore, these are generally found to be inserted into different places in different host individuals, suggesting that some force of forces are preventing TE's from filling up all the sites available for occupation within the genome. The present study is designed to help identify the nature of these forces Further data on the distribution of TE's within a population of Drosophila will be collected and compared with the predictions of theoretical models. This will provide a check of the generality of the observations mentioned above. In addition, tests will be made of the tendency of TEs to accumulate in regions of the genome where genetic recombination is restricted. Such a tendency is predicted by the hypothesis that genetic exchange between homologous TE's located in different locations can produce chromosomal damage that eliminates the TEs concerned, and hence acts to prevent their spread. One such region is known as the centric heterochromatin. This region has not previously been studied in detail because of technical difficulties associated with the abundance of highly repeated DNA sequences in this region. Recent advances in DNA technology mean that it is now possible to study TE abundance in the heterochromatin, and this forms a major focus of the project.

9317683 Charlesworth Mutation of genes to alleles with deleterious effects on survival or fertility occurs in the populations of all living organisms, and the net rate of mutation summed up over all the loci in the genome of any organism is now thought to be very high. Severely deleterious mutations are the cause of many diseases in human populations, and mutations with lesser effects are probably most important in human disease, though little is known about these as they are difficult to study. In a preliminary study, the investigators found that the occurrence of deleterious mutations in a region of the genome affects the evolution of DNA sequences in the same region. They have found that genetic variability at nucleotide sites that themselves do not affect fitness can be greatly reduced in such a region. The investigators will quantify this effect in relation to distances between the genes on the genetic map, and will extend studies to sequence differences that do have slight fitness effects. It is important in interpreting such data to include such biologically important phenomena as deleterious mutations of loci nearby in the genetic map to those under study. This has not previously been done in theoretical studies. %%% Results will have implications for the interpretation of data on variability within populations and on evolutionary divergence between populations. Such divergence in DNA sequences has b een used as a "molecular clock" to date the times of origin of species, and has also been used to infer that natural selection caused the observed differences. When other loci in the genetic background are included in the models, in addition to the loci under study, the inference of natural selection may become less certain, and that the rate of the molecular clock may prove to be influenced by the locations of genes in the genetic map, and by the level of inbreeding populations.

This project will assess the nature of variation due to newly- arisen mutations in Drosophila, with respect to a number of several different life-history characteristics including age- specific female fecundity, age-specific male mating success, longevity, viability, and net fitness. Mutations will be accumulated on second chromosomes maintained free of selection. The aim is to test the theory that senescence is in part due to the accumulation of deleterious mutations with effects confined to late in life, by determining whether or not a significant fraction of mutational variation is age-specific in the way required by this theory. The nature of mutational variation will be compared with that maintained as standing variation, where earlier studies have suggested negative correlations between effects at different ages. Rates of mutation for genes controlling life-history characters will be estimated as part of this study.

9520694 Arnold Research will focus on how an individual's growth rate affects its age of maturation, its longevity and its offspring's survival. The investigators will also examine the costs to growth, costs associated with an individual's lifespan, the health of its offspring, and the environmental and genetic influences on variation among and within populations of Thamonophis elegans. Three approaches will be used: experiments in nature, experiments in the laboratory, and mathematical modeling. Ultimately, the answers to these research questions will contribute to an understanding of how the environment combines with an individual's genetic makeup to shape its growth, maturation, ald survival.

9701098 Charlesworth Sex determination in many species is controlled by a special pair of chromosomes, the X and Y chromosomes. The Y chromosome usually has few active genes. In some species, "neo-sex chromosomes" have been formed by the fusion of an X or Y chromosome to a regular chromosome, causing this chromosome to be transmitted in the same way as the true sex chromosomes. This allows study of the forces responsible for the degeneration of the Y chromosome. The fruitfly Drosophila miranda is a classic example, in which some of the genes on the neo-Y chromosome have degenerated. Different processes that might be responsible for degeneration have different consequences for the patterns of between- and within-species variation of neo-Y chromosome genes. The DNA sequences of neo-Y chromosome genes will be obtained from different individuals of D. miranda, and from its relative D. pseudoobscura, in order to find out which processes are occurring. This work will illuminate the origin of the basic features of sex chromosomes, and enhance knowledge of the genetic mechanisms controlling variation in DNA sequences. Since sex chromosomes play an important role in human genetic diseases, the results will aid our understanding of these diseases.

9701114 Charlesworth Genetic material is exchanged between maternally and paternally derived homologous chromosomes, by the process of crossing over. The level of within-species variability in the DNA sequence of a gene is related to the frequency with which the gene experiences crossing over. Chromosome four of the fruitfly Drosophila melanogaster lacks crossing over, and its genes show little variability. This provides an opportunity to test two major hypotheses about the relation between crossing over and variability. Under the first hypothesis, variability is eliminated in the absence of crossing over because a selectively favorable variant drags all genes on the chromosome along with it, as it spreads through the species. Restoration of variability depends on new mutations, which are necessarily rare. Under the second hypothesis, variability is reduced because selection continually eliminates harmful mutations all along the chromosome; the relative abundance of rare versus common variants should be little affected. These hypotheses will be tested by examining the proportions of rare versus common variants at genes on this chromosome, using DNA sequencing technology. This research will shed light on the genetic mechanisms affecting diversity levels in natural populations. This has broad implications for conservation biology and the genetics of human variation, as well as for knowledge of fundamental biological processes.