Thèse de doctorat : Sciences du Vivant. Aspects Moléculaires et Cellulaires de la Biologie : Strasbourg 1 : 2008. / Thèse soutenue sur un ensemble de travaux. Titre provenant de l'écran-titre. Bibliogr. 21 p.

Résumé: Le syndrome du X fragile, première cause monogénique de déficience intellectuelle héréditaire, découle de l'expansion du nombre de répétitions CGG dans le gène FMR1 qui, accompagnée de sa méthylation, conduit à l'absence de la protéine correspondante : FMRP ou « Fragile X Mental Retardation Protein ». La fonction de cette protéine reste encore incertaine; FMRP est une protéine liant l'ARN qui serait impliqué au niveau de la synthèse protéique, mais d'autres fonctions ont également été proposées. La découverte de nouvelles observations dans un système biologique simplifié nous permettrait de mieux comprendre la contribution réelle de ces rôles. En fait, nous avons confirmé dans les plaquettes sanguines à l'état quiescent, qui sont caractérisées par un faible niveau de traduction, la présence de FMRP sous forme soluble, contrairement à la majorité des autres cellules et tissus étudiés. Puisque l'activation des plaquettes, étape incontournable de l'hémostase primaire, déclenche de nombreux processus intracellulaires telles une réorganisation du cytosquelette et une augmentation de la synthèse protéique, nous avons étudié le comportement de FMRP subséquemment à l'activation plaquettaire. Des plaquettes humaines ont été activées par l'utilisation de différents agonistes et soumises à des protocoles de fractionnement afin de déterminer la localisation subcellidaire de FMRP. Lors de l'activation plaquettaire, nous avons observé une redistribution de FMRP, de la fraction soluble à celle contenant le cytosquelette, proportionnelle au pourcentage d'agrégation des plaquettes. Cette interaction de FMRP avec certains constituants de cette fraction a également été évaluée en présence de plusieurs agents chimiques influençant différents processus cellulaires. Nous avons mis en évidence que l'utilisation de substances exerçant une influence sur la polymérisation du réseau d'actine modifie le comportement de FMRP, suggérant que cette protéine puisse interagir avec un constituant des microfilaments. Dans la mesure où certaines équipes de recherche ont rapporté que les polyribosomes plaquettaires sont une partie intégrante du cytosquelette, et d'autres que les polyribosomes avaient la possibilité de lier spécifiquement le réseau d'actine, nous avons envisagé la présence dans les plaquettes d'une interaction entre FMRP et l'appareil traductionnel en interaction avec les microfilaments. Concrètement, nous avons mis en évidence par une approche classique d'isolation des polyribosomes, la présence de FMRP dans ces fractions, et ce, uniquement postactivation. La redistribution de FMRP, bien que compatible avec d'autres modèles cellulaires, lui suggère une nouvelle fonction au sein de la réorganisation du cytosquelette et du déclenchement de la synthèse protéique survenant lors de l'activation plaquettaire. Puisque ces phénomènes peuvent facilement être modulés dans les plaquettes sanguines, ces cellules humaines ont le potentiel de devenir un modèle plus que promoteur pour l'étude de FMRP et ainsi, du syndrome du X fragile.||Abstract: Fragile X syndrome, the most common form of inherited intellectual disability, results from the expansion of CGG repeats in the FMR1 gene which, together with its methylation, leads to the absence of the corresponding protein: FMRP or Fragile X Mental Retardation Protein. The function of this protein remains uncertain; FMRP, a protein showing sequence motifs characteristic of RNA-binding proteins, seems to participate in several cellular processes related to protein synthesis. Uncovering novel observations in a simpler human biological system, will allow us to better understand the real contribution of those suggested functions. In fact, we confirm in resting blood platelets, characterized by a limited translational activity, the presence of FMRP in a soluble form, unlike most other cells and tissues studied so far. Since platelet activation, a critical step in primary hemostasis, triggers many intracellular processes including cytoskeleton's reorganization and an increase in protein synthesis, we therefore investigated the behaviour of FMRP upon platelet activation. Human platelets were activated by means of different agonists and subjected to cell fractionation protocols in order to determine the subcellular localization of FMRP. Following activation, we observed a shift of FMRP from the soluble to the cytoskeleton fraction, which was proportional to the percentage of platelet aggregation. Moreover, this interaction of FMRP with certain components of this fraction was also assessed in the presence of various chemical agents that influence different cellular processes. We showed that agents affecting actin network polymerization modified FMRP's behavior, suggesting that FMRP might interact with components of the microfilaments. Some research groups have reported that platelet polyribosomes are an integral part of the cytoskeleton, and others that polyribosomes are able to specifically bind the actin network. We thus investigated the presence of an interaction of FMRP in platelets with the microfilament's bound translational apparatus. In fact, we have demonstrated by a classical approach of polyribosome isolation, the presence of FMRP in these fractions exclusively following activation. The resultant redistribution of FMRP, although consistent with other cellular models, suggests a new function for this protein in connection with the platelet cytoskeletal reorganization and the initiation of protein synthesis occurring during platelet activation. Since these processes can easily be modulated in blood platelets, these human cells have the potential to be a very promising model for studying FMRP and thus the fragile X syndrome.

The purpose of this study was to explore what contributes to resilience in females diagnosed with Fragile X Syndrome. Fragile X Syndrome can be defined as an inherited (genetic) condition that causes mental impairment, attention deficit and hyperactivity, anxiety and unstable mood, autistic behaviours, hyper-extensible joints, and seizures. I became aware of Fragile X Syndrome during my time as a live-in caretaker to an adolescent female who was diagnosed with Fragile X Syndrome. Because she coped with her disability so resiliently, I was encouraged to explore what contributes to resilience in females diagnosed with Fragile X Syndrome. I followed a qualitative approach, anchored in the interpretivist paradigm. This means that I tried to understand the resilience of females diagnosed with Fragile X Syndrome through the meanings that the participants in my study assigned to them. Furthermore, I worked from a transformative paradigm, which meant that I was interested in changing the traditionally negative ways in which females diagnosed with Fragile X Syndrome are seen. I followed a multiple case study approach, which included four case studies. I conveniently selected the first participant, but realised that convenience sampling was not very credible for a qualitative case study. An Advisory Panel was then used to purposefully recruit three more participants. In order to explore what contributed to their resilience, I made use of interviews, observations, and visual data collection. I also interviewed adults (e.g. parents, teachers and consulting psychologists) who were significantly involved in the lives of my participants. My findings suggest that resilience in females with Fragile X Syndrome is rooted in protective processes within the individual as well as within her family and environment. Because my findings do not point to one specific resource, my study underscores newer understandings of resilience as an Eco systemic transaction. Most of the resilience-promoting resources noted by the participants in my study as contributing to their resilience have been identified as resilience-promoting in previous studies. Although the themes that emerged in my study have been reported in resilience previously, I make a contribution to theory because I link traditional resilience-promoting resources to resilience in females diagnosed with Fragile X Syndrome. Peer support was previously reported as a resilience-promoting resource, but in my study I noticed that the main source of peer support came from peers who were also disabled. Furthermore, my study transforms how we see females diagnosed with Fragile X Syndrome. This transformation encourages communities and families to work together towards resilience in females diagnosed with Fragile X Syndrome. / Ph.D, North-West University, Vaal Triangle Campus, 2011

Approximately sixty countries have been designated `Fragile States' by international development agencies. Home to two billion of the world's poorest people, these fragile states are characterized by violence, weak institutions and shattered economies. Not only do they pose a challenge to regional security, they often become the breeding grounds for terrorism. Donor agencies pour billions of dollars annually into these countries - through policy advice and conditional loans - to alleviate fragility and promote development. Development, however it is defined, involves economic, social and political transformation. Such a transformation is shaped by ideas, engages multiple interests, and proceeds within rules and norms set by political institutions. Since the structure of political institutions is influenced by human agency, leadership becomes important to study. Leadership is crucial particularly in fragile states, where institutions are weak or have been destroyed by conflict; however, a systematic effort to examine the role of leaders and coalitions in fragile states is lacking. This dissertation seeks to create a methodology to improve understanding of the role of different leadership strategies in bringing about transitions in and out of fragility. To make the scope manageable, the study focuses on: (i) leadership at the national level; and (ii) fragile states in Africa. It does so by examining: (i) evidence from country level panel data on leadership (regime) change and fragility; and (ii) in-depth analytical case studies of transitions in and out of fragility in four countries: Zimbabwe, Uganda, Rwanda, and South Africa. The analysis looks at the relationship between the change agent's leadership strategy (the independent variable: political participation and inclusion, economic growth and inclusion, and security and justice) and fragility outcomes (dependent variable: conflict and security indicators, economic indicators, and the approach to political inclusion). The results of the regression analysis exhibit a robust association between leadership change and fragility. Furthermore, the country cases show how different types of leadership strategies lead to varying trajectories of fragile states' post-transition. The case studies reveal different approaches to sequencing of political inclusion and the role of leadership exit in transitions from fragility.

WWOX (WW domain-containing oxidoreductase) is a candidate tumor suppressor gene that has been shown to be involved in various cancers including breast, lung, prostate, gastric and hepatic. The Drosophila ortholog Wwox was identified and subjected to targeted ‘loss of function’ mutagenesis. The resulting mutants were found to be viable when homozygous with no obvious defects in the adult fly. As Wwox mutant flies were found to exhibit an increased sensitivity to ionising radiation (IR), a number of Wwox proteins specifically deleted or mutated at positions consisting of conserved functional protein motifs, or regions that are highly conserved among WWOX / Wwox homologs. The Wwox variants were tested for their ability to modify the IR sensitivity phenotype. In the course of this study, it was found that background mutations introduced during the generation of the mutant flies was responsible for the IR sensitivity phenotype. As a result, proteomic alterations resulting from changes in Wwox protein levels in Drosophila were investigated in order to ascertain the possible molecular functions of the Wwox protein. 2D-DIGE analysis was conducted on a number of different fly genotypes expressing differing levels of Wwox protein in both adult and embryonic flies. The proteomic changes resulting from lack of Wwox function as well as Wwox over-expression were detected with the proteins of interest identified by mass spectrometry (MS) using both MALDI-TOF/TOF-MS and LC-ESI-MS/MS. Label free quantitative MS analysis was also performed in order to determine the most abundant protein(s) in those spots found to contain multiple proteins. These proteomic studies identified changes in a wide variety of proteins with a significant number of metabolic proteins as well as proteins involved in oxidative stress response as a result of different levels of Wwox expression. Of particular interest, consistent changes in different isoforms of superoxide dismutase 1 (Sod1) were identified. Due to the known roles these proteins play in pro and anti-apoptotic pathways, it is possible that Sod1 and Wwox may work in concert to regulate the delicate balance of defence mechanisms in response to environmental stresses, particularly oxidative stress. The protein/gene targets identified in this work therefore offer some insights into normal Wwox function. / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

The Indonesian archipelago comprises more than 17,000 islands, inhabited by ~200 million people constituting more than 350 recognizable ethnic and tribal groups which can be classified into two broad ethno-linguistic groups [the Austronesian (AN) and non-Austronesian (NAN) speaking peoples] and 3 physical anthropology groups (Deutero Malay, Proto Malay and Papuan). The origins of these groups are of considerable anthropological interest. The anthropology of Indonesia is extremely complex and still controversial. The present populations of Indonesia show very great diversity. The data presented below result from an investigation of the Fragile X A syndrome and the size and distribution of alleles at fragile sites on the X chromosome among Javanese males with developmental disability (DD) and unselected males from 10 major Indonesian ethnic groups. The Fragile X syndrome is caused by expansion of a CGG trinucleotide repeat array in the 5' untranslated region of the FMR-1 gene at Xq27.3. Normal X chromosomes have between 6-54 CGG trinucleotide repeats, whereas premutation alleles have 55-230 and full mutation alleles more than 230 repeats. In a study of predominantly Caucasian males with intellectual disability, the prevalence of Fragile X syndrome is estimated to be approximately 1:4,000. FRAXE mental retardation syndrome is caused by an expansion of a GCC trinucleotide repeat in the 5'UTR of FMR2 gene located 600 kb telomeric to FMR1. The prevalence of FMR2 is 1-2 per 100,000 live births. FMR2 common alleles consist of 11-30 GGC repeats; intermediate alleles between 31-60 GCC repeats; premutation alleles with 61-200 repeats and full mutation alleles have over 200 repeats with attendant methylation of the repeat array The first Indonesian screening program aimed at determining the presence and prevalence of fragile XA syndrome among individuals with mild DD (IQ above 50) from special schools (N=205) and isolated areas (N=50) of Java was undertaken in 1994-1996 by cytogenetic and molecular studies. In this first study 4 fragile X positive children were found among 255 males with DD. The estimated prevalence of fragile-X in males with mild DD from special schools was 1.95% (5/205) and the overall prevalence was 1.57% (4/255). The number of trinucleotide repeats in the 5' untranslated regions of the FMR1 and FMR2 genes were determined by PCR in 254 Fragile XA-negative Javanese male children with DD. The distribution of FMR1 and FMR2 trinucleotide repeat alleles was found to be significantly different in the Indonesian population with DD compared to that in equivalent Caucasian populations. The trimodal distribution of Indonesian FMR1 alleles (29, 30 and 36 repeats) is largely in agreement with findings from other Asian populations). This provides supportive evidence that the origin of Indonesians could be the same as that of the Chinese and Japanese. Sequence analysis was performed on the trinucleotide repeat arrays of the 27 individuals' FMR1 alleles in the 'grey zone' (35-52 repeats). The identification of 16 unrelated individuals with a (CGG)36 allele that also contains a (CGG)6 segment [(CGG)9AGG(CGG)9AGG(CGG)6 AGG(CGG)9 or 9A9A6A9 pattern] is in agreement with earlier observations in the Japanese population. It is proposed that this FMR1 array pattern may be specific for Asian populations and that Javanese and Japanese populations may have arisen from a single progenitor population. The presence of pure 25, 33 and 34 CGGs in FMR1 alleles with 36, 44 and 45 repeats respectively, suggests that these may represent alleles at high risk for instability and may therefore be at early stages of expansion to a premutation. The lack of the characteristic (CGG)6 in all three alleles with ?? 25 pure CGG arrays suggests that the most common Asian 36 repeat allele is not predisposed to slippage expansion. Seven of the 8 alleles with 36 CGG repeats could be sequenced. Seven of 36 CGG repeats FMR1 alleles from the Hiri population has been sequenced and 4 alleles indicated 9A9A6A9 pattern, 1 sample with 10A25 pattern Two of the remaining alleles showed 12A6A6A9 structure, which consisted of a tandem duplication of the (CGG)6 segment. The presence of a tandem duplication of (CGG)6 segments has never been reported in any other population. The other major findings of this study are that FRAXE syndrome is a rare cause of developmental disability in this predominantly-Javanese population. The most common FMR2 (GCC)20 allele in this selected Asian population is significantly longer than that previously reported for Caucasian populations. There was a weak correlation between the overall length of the FMR1 and FMR2 repeat arrays within the normal range (Spearman's Rank Correlation = 0.130, p-value=0.042) in the Indonesian population, which have been no previous associations reported for alleles within the normal range. One approach to studying the origins of the human populations is to study the genetic structure of polymorphic alleles such as those at the FMR1 locus and its linked microsatellite markers DXS548 and FRAXAC1. Length polymorphisms of the FMR1 gene (CGG)n repeat array, DXS548 and FRAXAC1 were studied in a total of 1,008 unselected males from 10 different Indonesian ethnic groups. FMR1 alleles were identified ranging from 8 to 57 CGG repeats. The most common CGG repeat allele was 29 (45.6%) followed by 30 (27.4%) and 36 repeats (8.0%). One hundred and forty four grey zone (3-52 CGG) alleles were found in the study population. Four people of the same ethnic group from an isolated island in Eastern Indonesia (Hiri, Ternate), a representative of the NAN ethnolinguistic group, had CGG repeat lengths of 55-57. The prevalence of these alleles is estimated to be 3.3% (4/120) in the population of Hiri or 0.4% (4/1008) of whole Indonesian population. Thirteen different alleles were found at the DXS548 locus, of which allele numbers 7 [194 bp] (44.1%), 6.5 [195bp] (43.5%) and 6 [196bp] (7.5%) are the most common. Seven rare alleles, some of which have not been previously found in Asian peoples were also identified (190, 191,192, 193, 197,198, 199, 202, 204 and 206) and accounted for 3.9% of the total. The odd number alleles were dominantly found in this study whereas almost none found in Caucasian. The finding of many "odd numbered" alleles DXS548 has never been found in other Asian population and has only been documented extremely rarely in Caucasians and Africans. Five different alleles of FRAXAC1 identified with alleles D [106 bp] (62.2%) and C [108bp] (35.6%) accounting for 97.8% of FRAXAC1 alleles in the population. Three rare alleles (104, 110, 112 bp = 2.2%) were identified that have not been previously found in other Asian populations (1-3). There is a striking linkage disequilibrium of FMR1 alleles with FRAXAC1 (p=0.0001), 88% of 29 (CGG)n repeats alleles associated with FRAXAC1 allele D (106bp) versus only 17% with the 30 (CGG)n repeat alleles, which is in agreement with other studies. The value of D' was calculated to be 0.7. The longer alleles of both DXS548 and FRAXAC1 were found mostly in the NAN ethnolinguistic group. Moreover the Irian Jaya people also showed a higher percentage of people with 30 CGG repeats and the 108 bp FRAXAC1. The Eastern Indonesian NAN groups demonstrate a different genetic background probably due to the contribution of Melanesian peoples. The Analysis of Molecular Variance (AMOVA) identified that the vast majority of genetic diversity occurs within, rather than between, ethnic groups. These data are consistent with a model where there is sufficient migration (~20 per generation) between populations to minimise differentiation of population through genetic drift. The results obtained are consistent with three clusters of populations that share similar allele frequencies at the fragile X locus. The most clearly defined cluster is based in the east of Indonesia and includes the two Irian populations, Minahasans and Hiri. A surprising finding was that the Minahasan who are Deutero-Malay in origin and physical appearance are genetically closer to the Irianese. This may reflect the admixture of Melanesian alleles or other eastern Indonesian alleles as a result of their geographic location in that part of Indonesia. The second major cluster is largely based in the west of the country and is composed of the following Deutero-Malay populations; Javanese, Balinese, Acehnese but which also includes people from Ternate (not including those from Hiri). Using Delta Mu and Nei's genetic distance for FMR1 locus in this study the Javanese were shown to have the closest distance to Balinese which is consistent with anthropological data and with published data. The third group is a "western and central" group composed of Bimanese, Dayak and Sundanese who share some features of the western and eastern clusters but mostly resemble the western Indonesian populations. Bima is located in the lesser Sunda in between west Indonesia and east Indonesia. The Bimanese are of mixed Deutero & Proto Malay origin that is consistent with their geographic location. The Bataks are distinctive and sit somewhat apart in this scheme. In this study, Bataks were found not to resemble the other Proto-Malay group studied (the Dayak). The Dayaks were found to have fewer alleles than the Bataks at FRAXAC1 and DXS548. In all four methods of calculating genetic distance Bataks showed a large genetic distance to almost all other ethnic groups. There are differences in allele frequency between east and west Indonesia as well as other Asian nations, but the genetic similarities between these groups are also very impressive. The findings from this study are consistent with other genetic anthropological evidence that the people of Indonesia have the same origin as North-east Asian groups. This model is referred to as the "express train from Taiwan" in which the Austronesian speakers are proposed to have radiated from Taiwan bringing the Malayo-Polynesian language group to the Philippines, Borneo and Sulawesi around 5000-4500 B.P.E. However Richards et al.(1998) have used the diversity in the mtDNA D Loop to propose an alternative to the "express train" model. The "two train7quot; model proposes that the Austronesian languages originated within eastern Indonesia during the Pleistocene era and spread through Melanesia and into the remote Pacific within the past 6,000 years. Unfortunately the high migration rates between population groups that were demonstrated in this thesis and the known migration patterns of populations through Indonesia preclude determining whether the observed allelic heterogeneity is a function of the original population or due to the admixture of several gene pools in more recent times.

Contains copies of author's previously published articles. / Includes bibliographic references. / 1 v. various foliations : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1992

The Indonesian archipelago comprises more than 17,000 islands, inhabited by ~200 million people constituting more than 350 recognizable ethnic and tribal groups which can be classified into two broad ethno-linguistic groups [the Austronesian (AN) and non-Austronesian (NAN) speaking peoples] and 3 physical anthropology groups (Deutero Malay, Proto Malay and Papuan). The origins of these groups are of considerable anthropological interest. The anthropology of Indonesia is extremely complex and still controversial. The present populations of Indonesia show very great diversity. The data presented below result from an investigation of the Fragile X A syndrome and the size and distribution of alleles at fragile sites on the X chromosome among Javanese males with developmental disability (DD) and unselected males from 10 major Indonesian ethnic groups. The Fragile X syndrome is caused by expansion of a CGG trinucleotide repeat array in the 5' untranslated region of the FMR-1 gene at Xq27.3. Normal X chromosomes have between 6-54 CGG trinucleotide repeats, whereas premutation alleles have 55-230 and full mutation alleles more than 230 repeats. In a study of predominantly Caucasian males with intellectual disability, the prevalence of Fragile X syndrome is estimated to be approximately 1:4,000. FRAXE mental retardation syndrome is caused by an expansion of a GCC trinucleotide repeat in the 5'UTR of FMR2 gene located 600 kb telomeric to FMR1. The prevalence of FMR2 is 1-2 per 100,000 live births. FMR2 common alleles consist of 11-30 GGC repeats; intermediate alleles between 31-60 GCC repeats; premutation alleles with 61-200 repeats and full mutation alleles have over 200 repeats with attendant methylation of the repeat array The first Indonesian screening program aimed at determining the presence and prevalence of fragile XA syndrome among individuals with mild DD (IQ above 50) from special schools (N=205) and isolated areas (N=50) of Java was undertaken in 1994-1996 by cytogenetic and molecular studies. In this first study 4 fragile X positive children were found among 255 males with DD. The estimated prevalence of fragile-X in males with mild DD from special schools was 1.95% (5/205) and the overall prevalence was 1.57% (4/255). The number of trinucleotide repeats in the 5' untranslated regions of the FMR1 and FMR2 genes were determined by PCR in 254 Fragile XA-negative Javanese male children with DD. The distribution of FMR1 and FMR2 trinucleotide repeat alleles was found to be significantly different in the Indonesian population with DD compared to that in equivalent Caucasian populations. The trimodal distribution of Indonesian FMR1 alleles (29, 30 and 36 repeats) is largely in agreement with findings from other Asian populations). This provides supportive evidence that the origin of Indonesians could be the same as that of the Chinese and Japanese. Sequence analysis was performed on the trinucleotide repeat arrays of the 27 individuals' FMR1 alleles in the 'grey zone' (35-52 repeats). The identification of 16 unrelated individuals with a (CGG)36 allele that also contains a (CGG)6 segment [(CGG)9AGG(CGG)9AGG(CGG)6 AGG(CGG)9 or 9A9A6A9 pattern] is in agreement with earlier observations in the Japanese population. It is proposed that this FMR1 array pattern may be specific for Asian populations and that Javanese and Japanese populations may have arisen from a single progenitor population. The presence of pure 25, 33 and 34 CGGs in FMR1 alleles with 36, 44 and 45 repeats respectively, suggests that these may represent alleles at high risk for instability and may therefore be at early stages of expansion to a premutation. The lack of the characteristic (CGG)6 in all three alleles with ?? 25 pure CGG arrays suggests that the most common Asian 36 repeat allele is not predisposed to slippage expansion. Seven of the 8 alleles with 36 CGG repeats could be sequenced. Seven of 36 CGG repeats FMR1 alleles from the Hiri population has been sequenced and 4 alleles indicated 9A9A6A9 pattern, 1 sample with 10A25 pattern Two of the remaining alleles showed 12A6A6A9 structure, which consisted of a tandem duplication of the (CGG)6 segment. The presence of a tandem duplication of (CGG)6 segments has never been reported in any other population. The other major findings of this study are that FRAXE syndrome is a rare cause of developmental disability in this predominantly-Javanese population. The most common FMR2 (GCC)20 allele in this selected Asian population is significantly longer than that previously reported for Caucasian populations. There was a weak correlation between the overall length of the FMR1 and FMR2 repeat arrays within the normal range (Spearman's Rank Correlation = 0.130, p-value=0.042) in the Indonesian population, which have been no previous associations reported for alleles within the normal range. One approach to studying the origins of the human populations is to study the genetic structure of polymorphic alleles such as those at the FMR1 locus and its linked microsatellite markers DXS548 and FRAXAC1. Length polymorphisms of the FMR1 gene (CGG)n repeat array, DXS548 and FRAXAC1 were studied in a total of 1,008 unselected males from 10 different Indonesian ethnic groups. FMR1 alleles were identified ranging from 8 to 57 CGG repeats. The most common CGG repeat allele was 29 (45.6%) followed by 30 (27.4%) and 36 repeats (8.0%). One hundred and forty four grey zone (3-52 CGG) alleles were found in the study population. Four people of the same ethnic group from an isolated island in Eastern Indonesia (Hiri, Ternate), a representative of the NAN ethnolinguistic group, had CGG repeat lengths of 55-57. The prevalence of these alleles is estimated to be 3.3% (4/120) in the population of Hiri or 0.4% (4/1008) of whole Indonesian population. Thirteen different alleles were found at the DXS548 locus, of which allele numbers 7 [194 bp] (44.1%), 6.5 [195bp] (43.5%) and 6 [196bp] (7.5%) are the most common. Seven rare alleles, some of which have not been previously found in Asian peoples were also identified (190, 191,192, 193, 197,198, 199, 202, 204 and 206) and accounted for 3.9% of the total. The odd number alleles were dominantly found in this study whereas almost none found in Caucasian. The finding of many "odd numbered" alleles DXS548 has never been found in other Asian population and has only been documented extremely rarely in Caucasians and Africans. Five different alleles of FRAXAC1 identified with alleles D [106 bp] (62.2%) and C [108bp] (35.6%) accounting for 97.8% of FRAXAC1 alleles in the population. Three rare alleles (104, 110, 112 bp = 2.2%) were identified that have not been previously found in other Asian populations (1-3). There is a striking linkage disequilibrium of FMR1 alleles with FRAXAC1 (p=0.0001), 88% of 29 (CGG)n repeats alleles associated with FRAXAC1 allele D (106bp) versus only 17% with the 30 (CGG)n repeat alleles, which is in agreement with other studies. The value of D' was calculated to be 0.7. The longer alleles of both DXS548 and FRAXAC1 were found mostly in the NAN ethnolinguistic group. Moreover the Irian Jaya people also showed a higher percentage of people with 30 CGG repeats and the 108 bp FRAXAC1. The Eastern Indonesian NAN groups demonstrate a different genetic background probably due to the contribution of Melanesian peoples. The Analysis of Molecular Variance (AMOVA) identified that the vast majority of genetic diversity occurs within, rather than between, ethnic groups. These data are consistent with a model where there is sufficient migration (~20 per generation) between populations to minimise differentiation of population through genetic drift. The results obtained are consistent with three clusters of populations that share similar allele frequencies at the fragile X locus. The most clearly defined cluster is based in the east of Indonesia and includes the two Irian populations, Minahasans and Hiri. A surprising finding was that the Minahasan who are Deutero-Malay in origin and physical appearance are genetically closer to the Irianese. This may reflect the admixture of Melanesian alleles or other eastern Indonesian alleles as a result of their geographic location in that part of Indonesia. The second major cluster is largely based in the west of the country and is composed of the following Deutero-Malay populations; Javanese, Balinese, Acehnese but which also includes people from Ternate (not including those from Hiri). Using Delta Mu and Nei's genetic distance for FMR1 locus in this study the Javanese were shown to have the closest distance to Balinese which is consistent with anthropological data and with published data. The third group is a "western and central" group composed of Bimanese, Dayak and Sundanese who share some features of the western and eastern clusters but mostly resemble the western Indonesian populations. Bima is located in the lesser Sunda in between west Indonesia and east Indonesia. The Bimanese are of mixed Deutero & Proto Malay origin that is consistent with their geographic location. The Bataks are distinctive and sit somewhat apart in this scheme. In this study, Bataks were found not to resemble the other Proto-Malay group studied (the Dayak). The Dayaks were found to have fewer alleles than the Bataks at FRAXAC1 and DXS548. In all four methods of calculating genetic distance Bataks showed a large genetic distance to almost all other ethnic groups. There are differences in allele frequency between east and west Indonesia as well as other Asian nations, but the genetic similarities between these groups are also very impressive. The findings from this study are consistent with other genetic anthropological evidence that the people of Indonesia have the same origin as North-east Asian groups. This model is referred to as the "express train from Taiwan" in which the Austronesian speakers are proposed to have radiated from Taiwan bringing the Malayo-Polynesian language group to the Philippines, Borneo and Sulawesi around 5000-4500 B.P.E. However Richards et al.(1998) have used the diversity in the mtDNA D Loop to propose an alternative to the "express train" model. The "two train7quot; model proposes that the Austronesian languages originated within eastern Indonesia during the Pleistocene era and spread through Melanesia and into the remote Pacific within the past 6,000 years. Unfortunately the high migration rates between population groups that were demonstrated in this thesis and the known migration patterns of populations through Indonesia preclude determining whether the observed allelic heterogeneity is a function of the original population or due to the admixture of several gene pools in more recent times.

Thesis (Ph. D.)--Dept. of Paediatrics, Faculty of Medicine, University of Adelaide, 1991. / Typescript (Photocopy). Includes published papers co-authored by the author at the end of volume 2. Includes bibliographical references (leaves 195-237 of vol. 1).

Thesis (Ph. D.)--University of New South Wales, 1998. / Also available online.