Risk Factors Associated With The Expansion Of CGG Repeat Sequences In The FMR1 (fragile X) Gene: A Study In Tasmania
Funder
National Health and Medical Research Council
Funding Amount
$246,020.00
Summary
This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not unifor ....This study will identify the risk factors that lie in an individual's DNA profile for a disease called fragile X syndrome. This disease is the most common form of intellectual disability that runs in families caused by an unusual form of change in a particular gene called FMR1, whereby a very short sequence of DNA in a gene expands by repeating itself to such an extent that once it reaches a certain size the whole gene stops working and the disease occurs. The expansion in the gene is not uniform across the generations, and only occurs when passed on from the mother to her offspring. However, many females carrying only a short sequence may pass on, for unknown reasons, either a large expanded sequence leading to disease, or one similar in size to her own. This complexity in the progression of the number of CGG repeats means that there is a relatively large number of mothers, ~1 in 300, who are quite normal but at risk of having an affected offspring. The factors that trigger this expansion in the DNA are presently not well understood, but a number of genetic markers in the FMR1 gene have been implicated. This study will assess the contribution of an array of these genetic markers in determining the risk of expansion of the short repeat from mother to offspring and hence the risk of fragile X. Conducting this study in Tasmania has two advantages. First, by having access to genealogical records that permit the linking of fragile X families we shall be able to identify common predisposing factors of fragile X more accurately. Second, by testing the whole population with intellectual disability in one State of manageable size we shall obtain an unbiased estimate of the prevalence of fragile X.Read moreRead less
The Influence Of Alpha Actinins On Human Performance
Funder
National Health and Medical Research Council
Funding Amount
$542,500.00
Summary
There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to gener ....There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to generate maximal force at high speed. Similarly, the severity of muscle disease in an affected individual is influenced, in part, by other genes that affect normal muscle performance. The genes responsible for normal variations in muscle function in humans are unknown. The alpha-actinins are structural components of skeletal muscle. The two forms of alpha-actinin in skeletal muscle interact with a number of proteins involved in human muscle disease and thus likely contribute to the severity of muscle weakness in affected patients. Alpha-actinin-3 is present only in fast (type 2) fibres - the muscle fibres responsible for perfomance at high speed. We have identified a genetic change that results in absence of this protein in 1 in 5 people in the general population, without causing disease. We now have evidence that this genetic change, and hence whether or not muscle contains alpha-actinin-3, influences muscle performance in elite athletes. We will now use a variety of approaches to study the alpha-actinins in normal and diseased skeletal muscle. We will study the effect of changes (mutations) in the alpha-actinins in the muscle cells grown in the laboratory and in animal models. This work will impact on our understanding of how normal skeletal muscle functions, and the factors that influence human diversity in the general population.Read moreRead less
The Influence Of Alpha Actinins On Human Performance In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,989.00
Summary
We have identified a common genetic variation that results in absence of the fast muscle fibre protein, a-actinin-3, in over 1 billion people worldwide. Loss of a-actinin-3 influences elite athletic performance and skeletal muscle function in the general population by altering efficiency of muscle metabolism. We will now study mice and humans to determine how a-actinin-3 deficiency influences normal muscle function with age, response to exercise and the severity of human muscle disease.
Deciphering the regulatory principles of metazoan development. This proposal aims to elucidate how regulatory elements in the genome, known as enhancers, determine the identity and function of animal tissues. Currently, it is believed that enhancers cannot be traced across evolutionarily distant animals. The project uses novel concepts, computational and molecular approaches to identify deeply conserved enhancers. It further dissects the mechanism of function by proteomics and high-throughput ge ....Deciphering the regulatory principles of metazoan development. This proposal aims to elucidate how regulatory elements in the genome, known as enhancers, determine the identity and function of animal tissues. Currently, it is believed that enhancers cannot be traced across evolutionarily distant animals. The project uses novel concepts, computational and molecular approaches to identify deeply conserved enhancers. It further dissects the mechanism of function by proteomics and high-throughput genomics. The expected outcomes will overturn our current view on enhancer evolution and reposition our understanding of how enhancers are functionally encoded in the genome. The work is an important contribution to understanding cellular complexity and species evolution with wide-ranging impact in genetics.Read moreRead less
Evolution of the dermomyotome in vertebrates. The project seeks to understand how different muscle populations within the embryo form and have evolved within the vertebrate phylogeny. All amniote muscles, except that of the head, derive from a transient embryonic structure termed the dermomyotome. The formation of muscle from the dermomyotome of amniotes uses a highly conserved mechanism that is distinct from that deployed by bony fish and amphibians. How the dermomyotome evolved to generate th ....Evolution of the dermomyotome in vertebrates. The project seeks to understand how different muscle populations within the embryo form and have evolved within the vertebrate phylogeny. All amniote muscles, except that of the head, derive from a transient embryonic structure termed the dermomyotome. The formation of muscle from the dermomyotome of amniotes uses a highly conserved mechanism that is distinct from that deployed by bony fish and amphibians. How the dermomyotome evolved to generate the distinct types of locomotor systems we see deployed throughout the vertebrate phylogeny remains unresolved. This project aims to contribute to an understanding of how different locomotor strategies deployed at important evolutionary transitions were generated.Read moreRead less
How limbs evolved from fins: the role of somite cells. This project aims to investigate the developmental basis of vertebrate appendage diversity and how during evolution limbs became fins. The project expects to determine how specific populations of cells that regulate fin formation arise during development, the genetic basis of their function, and how their role in development has evolved in lineages with divergent appendage anatomy. Expected outcomes include understanding the molecular basis ....How limbs evolved from fins: the role of somite cells. This project aims to investigate the developmental basis of vertebrate appendage diversity and how during evolution limbs became fins. The project expects to determine how specific populations of cells that regulate fin formation arise during development, the genetic basis of their function, and how their role in development has evolved in lineages with divergent appendage anatomy. Expected outcomes include understanding the molecular basis of the fin-limb transition and the origin of divergent appendage patterning systems. This should provide significant benefits by advancing our knowledge of the relationship between evolution and development, and understanding limb defects, which are amongst the most common of human congenital malformations.Read moreRead less
Fins to Limbs: Investigating the Evolution of complex Limb Musculature. This application aims to investigates the basis of the fin-to-limb transition, an event that set the stage for the entire tetrapod radiation. This project expects to generate new knowledge concerning the natural history of vertebrates using a multidisciplinary approach that combines paleontology and embryology of unique Australian fauna. While the skeletal changes associated with the move from water to land have been investi ....Fins to Limbs: Investigating the Evolution of complex Limb Musculature. This application aims to investigates the basis of the fin-to-limb transition, an event that set the stage for the entire tetrapod radiation. This project expects to generate new knowledge concerning the natural history of vertebrates using a multidisciplinary approach that combines paleontology and embryology of unique Australian fauna. While the skeletal changes associated with the move from water to land have been investigated, little is known about the origin of tetrapod limb muscles. This proposal has as an expected outcome, a determination of how limb muscles arose during evolution. This knowledge should provide significant benefits by transforming our understanding of the origins of the tetrapod body plan and our own natural history.Read moreRead less