Membrane associated transporter protein gene (SLC45A2) and the genetic basis of normal human pigmentation variation

This work is concerned with the genetic basis of normal human pigmentation variation. Specifically, the role of polymorphisms within the solute carrier family 45 member 2 (SLC45A2 or membrane associated transporter protein; MATP) gene were investigated with respect to variation in hair, skin and eye colour ― both between and within populations. SLC45A2 is an important regulator of melanin production and mutations in the gene underly the most recently identified form of oculocutaneous albinism. There is evidence to suggest that non-synonymous polymorphisms in SLC45A2 are associated with normal pigmentation variation between populations. Therefore, the underlying hypothesis of this thesis is that polymorphisms in SLC45A2 will alter the function or regulation of the protein, thereby altering the important role it plays in melanogenesis and providing a mechanism for normal pigmentation variation. In order to investigate the role that SLC45A2 polymorphisms play in human pigmentation variation, a DNA database was established which collected pigmentation phenotypic information and blood samples of more than 700 individuals. This database was used as the foundation for two association studies outlined in this thesis, the first of which involved genotyping two previously-described non-synonymous polymorphisms, p.Glu272Lys and p.Phe374Leu, in four different population groups. For both polymorphisms, allele frequencies were significantly different between population groups and the 272Lys and 374Leu alleles were strongly associated with black hair, brown eyes and olive skin colour in Caucasians. This was the first report to show that SLC45A2 polymorphisms were associated with normal human intra-population pigmentation variation. The second association study involved genotyping several SLC45A2 promoter polymorphisms to determine if they also played a role in pigmentation variation. Firstly, the transcription start site (TSS), and hence putative proximal promoter region, was identified using 5' RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE). Two alternate TSSs were identified and the putative promoter region was screened for novel polymorphisms using denaturing high performance liquid chromatography (dHPLC). A novel duplication (c.–1176_–1174dupAAT) was identified along with other previously described single nucleotide polymorphisms (c.–1721C>G and c.–1169G>A). Strong linkage disequilibrium ensured that all three polymorphisms were associated with skin colour such that the –1721G, +dup and –1169A alleles were associated with olive skin in Caucasians. No linkage disequilibrium was observed between the promoter and coding region polymorphisms, suggesting independent effects. The association analyses were complemented with functional data, showing that the –1721G, +dup and –1169A alleles significantly decreased SLC45A2 transcriptional activity. Based on in silico bioinformatic analysis that showed these alleles remove a microphthalmia-associated transcription factor (MITF) binding site, and that MITF is a known regulator of SLC45A2 (Baxter and Pavan, 2002; Du and Fisher, 2002), it was postulated that SLC45A2 promoter polymorphisms could contribute to the regulation of pigmentation by altering MITF binding affinity. Further characterisation of the SLC45A2 promoter was carried out using luciferase reporter assays to determine the transcriptional activity of different regions of the promoter. Five constructs were designed of increasing length and their promoter activity evaluated. Constitutive promoter activity was observed within the first ~200 bp and promoter activity increased as the construct size increased. The functional impact of the –1721G, +dup and –1169A alleles, which removed a MITF consensus binding site, were assessed using electrophoretic mobility shift assays (EMSA) and expression analysis of genotyped melanoblast and melanocyte cell lines. EMSA results confirmed that the promoter polymorphisms affected DNA-protein binding. Interestingly, however, the protein/s involved were not MITF, or at least MITF was not the protein directly binding to the DNA. In an effort to more thoroughly characterise the functional consequences of SLC45A2 promoter polymorphisms, the mRNA expression levels of SLC45A2 and MITF were determined in melanocyte/melanoblast cell lines. Based on SLC45A2’s role in processing and trafficking TYRP1 from the trans-Golgi network to stage 2 melanosmes, the mRNA expression of TYRP1 was also investigated. Expression results suggested a coordinated expression of pigmentation genes. This thesis has substantially contributed to the field of pigmentation by showing that SLC45A2 polymorphisms not only show allele frequency differences between population groups, but also contribute to normal pigmentation variation within a Caucasian population. In addition, promoter polymorphisms have been shown to have functional consequences for SLC45A2 transcription and the expression of other pigmentation genes. Combined, the data presented in this work supports the notion that SLC45A2 is an important contributor to normal pigmentation variation and should be the target of further research to elucidate its role in determining pigmentation phenotypes. Understanding SLC45A2’s function may lead to the development of therapeutic interventions for oculocutaneous albinism and other disorders of pigmentation. It may also help in our understanding of skin cancer susceptibility and evolutionary adaptation to different UV environments, and contribute to the forensic application of pigmentation phenotype prediction.

Assessing the potential of inter-organisational shared services

Shared Services (SS) involves the convergence and streamlining of an organisation’s functions to ensure timely service delivery as effectively and efficiently as possible. As a management structure designed to promote value generation, cost savings and improved service delivery by leveraging on economies of scale, the idea of SS is driven by cost reduction and improvements in quality levels of service and efficiency. Current conventional wisdom is that the potential for SS is increasing due to the increasing costs of changing systems and business requirements for organisations and in implementing and running information systems. In addition, due to commoditisation of large information systems such as enterprise systems, many common, supporting functions across organisations are becoming more similar than not, leading to an increasing overlap in processes and fuelling the notion that it is possible for organisations to derive benefits from collaborating and sharing their common services through an inter-organisational shared services (IOSS) arrangement. While there is some research on traditional SS, very little research has been done on IOSS. In particular, it is unclear what are the potential drivers and inhibitors of IOSS. As the concepts of IOSS and SS are closely related to that of Outsourcing, and their distinction is sometimes blurred, this research has the first objective of seeking a clear conceptual understanding of the differences between SS and Outsourcing (in motivators, arrangements, benefits, disadvantages, etc) and based on this conceptual understanding, the second objective of this research is to develop a decision model (Shared Services Potential model) which would aid organisations in deciding which arrangement would be more appropriate for them to adopt in pursuit of process improvements for their operations. As the context of the study is on universities in higher education sharing administrative services common to or across them and with the assumption that such services were homogenous in nature, this thesis also reports on a case study. The case study involved face to face interviews from representatives of an Australian university to explore the potential for IOSS. Our key findings suggest that it is possible for universities to share services common across them as most of them were currently using the same systems although independently.

Changing the metaphor : the potential of online communities in teacher professional development

Belonging to an online community offers teachers the opportunity to exchange ideas, make connections with a wider peer group and form collaborative networks. The increasing popularity of teacher professional communities means that we need to understand how they work and determine the role they may play in teacher professional development. This chapter will map data from a doctoral study to a recentlydeveloped model of professional development to offer a new perspective of how online communities can add to a teacher’s personal and professional growth and, in so doing, add to the small number of studies in this field. This chapter will conclude with a call for a revision of the way we approach professional development in the 21st century and suggest that old models and metaphors are hindering the adoption of more effective means of professional development for teachers.

The comprehensive Australian Study of entrepreneurial emergence (CAUSEE) high potential nascent entrepreneurs : some preliminary findings

Principal Topic The Comprehensive Australian Study of Entrepreneurial Emergence (CAUSEE) represents the first Australian study to employ and extend the longitudinal and large scale systematic research developed for the Panel Study of Entrepreneurial Dynamics (PSED) in the US (Gartner, Shaver, Carter and Reynolds, 2004; Reynolds, 2007). This research approach addresses several shortcomings of other data sets including under coverage; selection bias; memory decay and hindsight bias, and lack of time separation between the assessment of causes and their assumed effects (Johnson et al 2006; Davidsson 2006). However, a remaining problem is that any a random sample of start-ups will be dominated by low potential, imitative ventures. In recognition of this issue CAUSEE supplemented PSED-type random samples with theoretically representative samples of the 'high potential' emerging ventures employing a unique methodology using novel multiple screening criteria. We define new ''high-potential'' ventures as new entrepreneurial innovative ventures with high aspirations and potential for growth. This distinguishes them from those ''lifestyle'' imitative businesses that start small and remain intentionally small (Timmons, 1986). CAUSEE is providing the opportunity to explore, for the first time, if process and outcomes of high potentials differ from those of traditional lifestyle firms. This will allows us to compare process and outcome attributes of the random sample with the high potential over sample of new firms and young firms. The attributes in which we will examine potential differences will include source of funding, and internationalisation. This is interesting both in terms of helping to explain why different outcomes occur but also in terms of assistance to future policymaking, given that high growth potential firms are increasingly becoming the focus of government intervention in economic development policies around the world. The first wave of data of a four year longitudinal study has been collected using these samples, allowing us to also provide some initial analysis on which to continue further research. The aim of this paper therefore is to present some selected preliminary results from the first wave of the data collection, with comparisons of high potential with lifestyle firms. We expect to see owing to greater resource requirements and higher risk profiles, more use of venture capital and angel investment, and more internationalisation activity to assist in recouping investment and to overcome Australia's smaller economic markets Methodology/Key Propositions In order to develop the samples of 'high potential' in the NF and YF categories a set of qualification criteria were developed. Specifically, to qualify, firms as nascent or young high potentials, we used multiple, partly compensating screening criteria related to the human capital and aspirations of the founders as well as the novelty of the venture idea, and venture high technology. A variety of techniques were also employed to develop a multi level dataset of sources to develop leads and firm details. A dataset was generated from a variety of websites including major stakeholders including the Federal and State Governments, Australian Chamber of Commerce, University Commercialisation Offices, Patent and Trademark Attorneys, Government Awards and Industry Awards in Entrepreneurship and Innovation, Industry lead associations, Venture Capital Association, Innovation directories including Australian Technology Showcase, Business and Entrepreneurs Magazines including BRW and Anthill. In total, over 480 industry, association, government and award sources were generated in this process. Of these, 74 discrete sources generated high potentials that fufilled the criteria. 1116 firms were contacted as high potential cases. 331 cases agreed to participate in the screener, with 279 firms (134 nascents, and 140 young firms) successfully passing the high potential criteria. 222 Firms (108 Nascents and 113 Young firms) completed the full interview. For the general sample CAUSEE conducts screening phone interviews with a very large number of adult members of households randomly selected through random digit dialing using screening questions which determine whether respondents qualify as 'nascent entrepreneurs'. CAUSEE additionally targets 'young firms' those that commenced trading from 2004 or later. This process yielded 977 Nascent Firms (3.4%) and 1,011 Young Firms (3.6%). These were directed to the full length interview (40-60 minutes) either directly following the screener or later by appointment. The full length interviews were completed by 594 NF and 514 YF cases. These are the cases we will use in the comparative analysis in this report. Results and Implications The results for this paper are based on Wave one of the survey which has been completed and the data obtained. It is expected that the findings will assist in beginning to develop an understanding of high potential nascent and young firms in Australia, how they differ from the larger lifestyle entrepreneur group that makes up the vast majority of the new firms created each year, and the elements that may contribute to turning high potential growth status into high growth realities. The results have implications for Government in the design of better conditions for the creation of new business, firms who assist high potentials in developing better advice programs in line with a better understanding of their needs and requirements, individuals who may be considering becoming entrepreneurs in high potential arenas and existing entrepreneurs make better decisions.