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Much of modern population genetics revolves around neutral genetic differences among individuals, populations, and species. In this dissertation, I study how sex-specific life history traits affects neutral diversity levels within populations (polymorphism) and between species (divergence) on autosomes and sex chromosomes. In chapter 1, I consider the effects of sex specific life histories, and particularly generation times, on substitution rates along the great ape phylogeny. Using a model that approximates features of the mutational process in most mammals, and fitting the model on data from pedigree-studies in humans, I predict the effects of life history traits on specific great ape lineages. As I show, my model can account for a number of seemingly disparate observations: notably, the puzzlingly low X-to-autosome ratios of substitution rates in humans and chimpanzees and differences in rates of autosomal substitutions among great ape lineages. The model further suggests how to translate pedigree-based estimates of human mutation rates into split times among extant apes, given sex-specific life histories. In so doing, it largely bridges the gap reported traditional fossil-based estimates of mutation rates, and recent pedigree-based estimates. In chapter 2, I consider the effects of sex- and age- dependent mortalities, fecundities, reproductive variances and mutation rates on polymorphism levels in humans. Using a coalescence framework, I provide closed formulas for the expected polymorphism rate, accounting for life history effects. These formulas generalize and simplify previous models. Applying the model to humans, my results suggest that the effects of life history – and of sex differences in generation times in particular – attenuate how changes in historical population sizes affect X to autosome polymorphism ratios. Applying these results to observations across human populations, I find that life history effects and demographic histories can largely explain the reduction in X to autosome polymorphism ratios outside Africa. More generally, my work elucidates the major role of sex-specific life history traits – and male and female generation times in particular – in shaping patterns of neutral genetic diversity within and between species.

Chan Ching Yin. / Thesis submitted in: October 2003. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 197-221). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.iii / Abstract in Chinese --- p.vi / List of abbreviations --- p.ix / List of tables --- p.xv / List of figures --- p.xvi / Contents --- p.xviii / Chapter 1. --- Introduction --- p.1 / Chapter 1.1. --- What are astrocytic tumors? --- p.1 / Chapter 1.1.1. --- Histological characteristics and classification --- p.2 / Chapter 1.1.2. --- Epidemiology --- p.2 / Chapter 1.1.3. --- Treatment and patient survival --- p.4 / Chapter 1.2. --- "Cytogenetics, molecular genetics and epigenetics of astrocytic tumors" --- p.6 / Chapter 1.2.1. --- Cytogenetics --- p.6 / Chapter 1.2.2. --- Genetic imbalances --- p.7 / Chapter 1.2.3. --- Tumor suppressor genes --- p.13 / Chapter 1.2.4. --- Oncogenes --- p.22 / Chapter 1.2.5. --- Primary and secondary GBMs --- p.26 / Chapter 1.3. --- Major pathways involved in astrocytic tumorigenesis --- p.30 / Chapter 1.3.1. --- Cell cycle dysregulation and suppression of apoptosis --- p.30 / Chapter 1.3.2. --- Promotion of proliferation and survival --- p.33 / Chapter 1.4. --- BRAF mutation in human cancers --- p.38 / Chapter 1.5. --- Other CNS tumors included in the current study --- p.52 / Chapter 2. --- Aims of study --- p.61 / Chapter 3. --- Materials and methods --- p.64 / Chapter 3.1. --- Clinical materials --- p.64 / Chapter 3.2. --- Cell lines --- p.75 / Chapter 3.3. --- Cell culture --- p.77 / Chapter 3.4. --- DNA extraction --- p.78 / Chapter 3.4.1. --- Pre-treatment of samples --- p.78 / Chapter 3.4.2. --- Cell lysis and protein removal --- p.80 / Chapter 3.4.3. --- Precipitation of DNA --- p.81 / Chapter 3.4.4. --- Determination of DNA concentration --- p.81 / Chapter 3.5. --- Mutation analysis of BRAF by cycle sequencing --- p.83 / Chapter 3.5.1. --- Amplification of BRAF exons --- p.83 / Chapter 3.5.2. --- Cycle sequencing and automated gel electrophoresis --- p.84 / Chapter 3.6. --- Immunohistochemistry of B-Raf and GFAP --- p.87 / Chapter 3.6.1. --- Pre-treatment of samples --- p.87 / Chapter 3.6.2. --- Detection of B-Raf and GFAP antigens by ABC method --- p.88 / Chapter 3.6.3. --- Controls --- p.90 / Chapter 3.7. --- Quantification of EGFR gene dosage by TaqMan based real-time PCR --- p.91 / Chapter 3.7.1. --- Preparation of gene constructs --- p.92 / Chapter 3.7.2. --- Primers and TaqMan probes --- p.93 / Chapter 3.7.3. --- Experimental condition and PCR program --- p.95 / Chapter 3.7.4. --- DNA standards --- p.95 / Chapter 3.7.5. --- Controls --- p.96 / Chapter 3.7.6. --- Experimental layout --- p.96 / Chapter 3.8. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.97 / Chapter 4. --- Results --- p.101 / Chapter 4.1. --- Mutation analysis of BRAF --- p.101 / Chapter 4.2. --- Immunohistochemistry of B-Raf protein --- p.107 / Chapter 4.3. --- Quantification of EGFR gene dosage --- p.117 / Chapter 4.4. --- Correlation between EGFR dosage and BRAF mutation --- p.128 / Chapter 4.5. --- Correlation between EGFR dosage and B-Raf expression --- p.129 / Chapter 4.6. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.131 / Chapter 5. --- Discussions --- p.149 / Chapter 5.1. --- BRAF mutations as common events in human cancers --- p.149 / Chapter 5.2. --- BRAF mutation in CNS tumor specimens --- p.150 / Chapter 5.2.1. --- Tumorigenic effect of the V599E substitution --- p.153 / Chapter 5.2.2. --- V599E B-Raf mutant activation independent of Ras activation --- p.155 / Chapter 5.2.3. --- Autocrine stimulation of Ras signaling in V599E B-Raf mutant --- p.156 / Chapter 5.3. --- BRAF expression in astrocytic tumors --- p.159 / Chapter 5.4. --- Mutually exclusive pattern between EGFR amplification and BRAF expression --- p.161 / Chapter 5.4.1. --- Similar effect of EGFR activation and B-Raf activation --- p.163 / Chapter 5.4.2. --- Mutual effects between Ras/Raf/Mek/Erk and Akt signaling --- p.164 / Chapter 5.5. --- Microsatellite analysis of chromosome 14q in human cancers --- p.167 / Chapter 5.6. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.170 / Chapter 5.6.1. --- Finer mapping of common regions of deletion --- p.170 / Chapter 5.6.2. --- Genes within the common regions of deletion --- p.173 / Chapter 5.6.3. --- Overlapping deletion regions in astrocytic and non-CNS tumors --- p.186 / Chapter 6. --- Further studies --- p.190 / Chapter 6.1. --- Role of BRAF alterations in astrocytic tumors --- p.190 / Chapter 6.2. --- B-Raf expression in astrocytic tumors and correlation with EGFR overexpression --- p.193 / Chapter 6.3. --- Microsatellite analysis of 14q in astrocytic tumors --- p.194 / Chapter 7. --- Conclusions --- p.195 / Chapter 8. --- References --- p.198

When cells divide, a series of events must proceed in a timely and co-ordinated manner to ensure that all DNA is replicated and partitioned equally between the two daughter cells. A central component of this process is the kinetochore, a large proteinaceous complex (>100 proteins) found within the centromere of all chromosomes. During the dynamic process of cell division, this machinery must be able to capture microtubules, promote chromosome movements towards the spindle midzone and ensure that segregration only occurs once this alignment has been successfully completed. This requires intricate mechanical and regulatory co-ordination between components and it is therefore no surprise that the structures responsible are structurally and functionally varied. It has, however, become clear that many kinetochore proteins assemble into distinct sub-complexes and despite the fact that their specific contributions are well studied, the way the many unique sub-assemblies come together to form a fully operational kinetochore is still poorly understood. Here, chromosome isolation techniques from chicken DT40 cells combined with mass spectrometry employing Stable Isotope Labeling by Amino acids in Cell culture (SILAC), is used to compare the proteome of mitotic chromosomes from different conditional kinetochore knockout (KO) cell lines. This includes components of the inner kinetochore; CENP-C, CENP-T and CENP-W, and a sub-unit of the Ndc80 complex that is important for microtubule attachment. With these large data sets I have focused on the impact these depletions have on the architecture of the holo-kinetochore by measuring the SILAC ratios of individual proteins. From these measurements I can define whether specific components are decreased, increased or unchanged in terms of their abundance on chromosomes in response to the various deletions. I have found that proteins within the same complex typically behave in a similar manner across the different KO conditions. By integrating all of the data sets, dependency networks are revealed, as well as highlighting potential novel kinetochore proteins worthy of further study.

Thesis--University of Turku, 1984. / At head of title: From the Institute of Dentistry and the Institute of Biomedicine, University of Turku. Extra t.p. with thesis statement inserted. Also published in: Proceedings of the Finnish Dental Society, Vol. 80, 1984, Suppl. V. Includes bibliographical references.

Thesis--University of the Witwatersrand. / Bibliography: p. [363]-384.

Thesis--University of the Witwatersrand. / Bibliography: p. [363]-384.

6 Abstract Scincoidean lizards, i.e. cordylids, gerrhosaurids, skinks and xantusiids, are known for their remarkable ecological and morphological variability. It was hypothesized that, at least in skinks, sex determining systems are highly variable as well. In the other three families, evidence for presence or absence of sex chromosomes has been scarce, with two species of night lizards with ZZ/ZW sex chromosomes being the exception. In this thesis, conventional and molecular cytogenetic methods, including C-banding, fluorescence in situ hybridization (FISH) with probes for telomeric motifs and rDNA loci and comparative genomic hybridization (CGH) were used to identify cytogenetically distinguishable sex chromosomes. Although most studied species showed no sex-specific differences by cytogenetic examination, some did. Tracheloptychus petersi has accumulations of rDNA loci on a pair of macrochromosomes and a pair of microchromosomes in males, while again on a pair of macrochromosomes and a single microchromosome in females. This distribution suggests a ZZ/ZW system in this species, which is the first report of sex chromosomes in any gerrhosaurid lizard. In Zonosaurus madagascariensis, CGH was able to identify the W chromosome in females, which is the second report of sex chromosomes in this family....

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu). / The distribution of variants of fourteen genetic and fourteen cytogenetic markers is investigated in samples from two Bedouin tribes, the Ajman (n = 52) and the Suluba (n = 52) and from the general population of Kuwait (n = 89). Typical of the many tribal populations in the Arabian peninsula, both Ajman and Suluba are socially isolated from each other. There is little documentation on the ancestral descent of both tribes. However, oral tradition regards Ajman as a deep-rooted Arabian tribe, while the Suluba is thought by some to have originated from the followers of the Crusade camps. The validity of the history of ancestral descent of both tribes is substantiated by a comparison of the distribution of several genetic markers with those of other peninsular communities, and by genetic distance measures between them, the peninsula Arabs of the South-West, and a European population (Italians). Distance measures were calculated by two different methods. Both genetic and cytogenetic marker data obtained from the three Kuwaiti communities contribute significantly to the sparse genetic information on the peninsular populations, and illustrate the degree of genetic microheterogeniety between these communities which was brought about by some social factors that caused their isolation. Gene flow from the neighboring East African populations is evident from the allelic distribution of certain systems such as the Duffy and the Rhesus. Evidence is presented which supports the speculation regarding the prevalence of K of the Kell system and M and S of the MNSs system in the indigeneous peninsular populations. A new salivary amylase isozyrne, Amy K1, was detected in a subject of probable Asiatic Indian descent sampled in Kuwait. Q-band chromosomal heteromorphisms were scored in the three sampled Kuwaiti communities. There was no statistical significance in the differences in frequencies of these heteromorphisms between the three samples. Genetic distances between the Kuwaiti communities and others from the literature were calculated on the basis of Q-band heteromorphic loci. The distances demonstrate the pitfalls in using absolute frequencies of chromosomal variants scored by different research groups for comparative studies. Large Y chromosome was present at high frequencies in the three Kuwaiti communities and was highest among members of the Ajman tribe. This finding suggests that the prevalance of large Y may be a distinguishing cytogenetic feature of the indigenous peninsular populations. Small Y was present in the sample from the general population, but not detected in either sample from the tribal communities. The differences in frequencies of Y chromosome variants between the three sampled communities was found to be statistically significant. Investigation of the 9qh region with the G-11 technique has shown an absence of inversions, partial and complete, of this heteromorphic region in the sample from the general population of Kuwait.

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