Exploiting Sexual Differences In Germline Biology To Resolve The Causes Of Germline Mutation
Funder
National Health and Medical Research Council
Funding Amount
$315,914.00
Summary
Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating dis ....Mutagenesis during the production of sex cells is a fundamental biological process and the cause of inherited human disorders. These disorders span the entire spectrum of diseases that have a genetic component, such as autoimmune diseases and cancers, therefore influencing all age groups. A better understanding of the mechanisms underlying this process is a priority since it is the essential knowledge required for understanding all of the factors that contribute to this array of debilitating diseases, and for devising effective preventative and diagnostic measures. To attain this understanding necessitates establishing the mechanistic origins of germline mutagenesis. Two basic approaches are employed to understand this process. The first assesses the incidence of mutation in pedigrees. This identifies the spectrum of risk mutations underlying the specific disease surveyed. Because other biological processes also influence these observations, the results from this approach do not reflect the underlying germline mutation spectra and are therefore not translatable between diseases. As mutations are rare events, it is prohibitive to obtain sufficient observations to resolve the underlying mechanisms. The second approach employs comparative genomic data, and uses differences in germline biology to estimate sex-biased effects. This comparative approach benefits from the accumulation of mutations over vast periods of time. The approach has not, however, been applied to diagnose the mechanistic origins of mutations. In this project, we will apply the enormous volume of comparative sequencing data to relate components of the mutagenic spectrum with sexual differences in germline biology. The project will differentiate between different types of mutations, and their association with specific processes will be established. The results will be a determination of the relative contributions of different mechanisms of mutation to germline mutagenesis.Read moreRead less
Evolution in microsatellite DNA: testing models of mutation in an Australian marsupial. We aim to compare mutational events between microsatellite loci that vary in their exposure to recombination. We are able to do this because of a remarkable finding that Australian brushtail possums have multiple occurrences of a single microsatellite repeat element within the Y-chromosome and among autosomal loci. We will compare variation between the Y-linked and non Y-linked loci within and among individu ....Evolution in microsatellite DNA: testing models of mutation in an Australian marsupial. We aim to compare mutational events between microsatellite loci that vary in their exposure to recombination. We are able to do this because of a remarkable finding that Australian brushtail possums have multiple occurrences of a single microsatellite repeat element within the Y-chromosome and among autosomal loci. We will compare variation between the Y-linked and non Y-linked loci within and among individual possums and use those comparisons to distinguish between recombinant and non- recombinant mutational mechanisms. These data will provide new insights into the mutational mechanisms that drive variation in these most important molecular markers.Read moreRead less
Sex in Dragons: Evolution of sex determination in reptiles. Australia is a leader in sex determination research with major advances in our understanding attributable to Australian researchers and laboratories. This project will contribute to our prestige as a nation capable of contributing cutting edge research directions and stimulating ideas in human sex determination. Moreover, many reptiles have temperature-dependent sex determination, and so would appear appallingly vulnerable to climate ch ....Sex in Dragons: Evolution of sex determination in reptiles. Australia is a leader in sex determination research with major advances in our understanding attributable to Australian researchers and laboratories. This project will contribute to our prestige as a nation capable of contributing cutting edge research directions and stimulating ideas in human sex determination. Moreover, many reptiles have temperature-dependent sex determination, and so would appear appallingly vulnerable to climate change. Our project, will bring improved understanding of sex determination in reptiles, identify evolutionary responses of reptiles to climate change, and assist by informing society on how we might manage this issue into the future conservation of these unique Australian reptiles. Read moreRead less
Sex in Dragons: The molecular basis of genetic and environmental sex determination. How animals determine sex has been debated over decades. Particularly mysterious is that sex is determined by genes in some animals, and by temperature in others. We will study closely related dragon lizards which determine sex via genes (GSD) or temperature (TSD). We will use novel genetic, molecular and cytological aproaches to discover genes and chromosomes that control sex determination in the GSD species, an ....Sex in Dragons: The molecular basis of genetic and environmental sex determination. How animals determine sex has been debated over decades. Particularly mysterious is that sex is determined by genes in some animals, and by temperature in others. We will study closely related dragon lizards which determine sex via genes (GSD) or temperature (TSD). We will use novel genetic, molecular and cytological aproaches to discover genes and chromosomes that control sex determination in the GSD species, and explore their homologues in the TSD species. We expect this study will provide new insights to mechanisms of sex determination in all vertebrates, and demonstrate how genes and the environment interact to control the process.Read moreRead less
Organization, function and evolution of marsupial Y chromosomes. The Y chromosome of humans and other mammals contains only a few genes, most specialized for male sex and reproduction. How the Y chromosome evolved to be so peculiar has been debated for 90 years. It began as an ordinary chromosome, but has degraded until there is almost nothing left, and it is likely to disappear in about 13 million years. Molecular characterization of the Y chromosomes of distantly related mammals could serve to ....Organization, function and evolution of marsupial Y chromosomes. The Y chromosome of humans and other mammals contains only a few genes, most specialized for male sex and reproduction. How the Y chromosome evolved to be so peculiar has been debated for 90 years. It began as an ordinary chromosome, but has degraded until there is almost nothing left, and it is likely to disappear in about 13 million years. Molecular characterization of the Y chromosomes of distantly related mammals could serve to 're-run the evolutionary tape', but the Y chromosome has been left out of whole genome sequencing because it is hard to do efficiently. We developed a novel technique to isolate DNA sequences and genes on the Y chromosome in three species of marsupials, which are especially valuable because they are so different from human and mouse.Read moreRead less
Sex in Dragons: Probing the genotype-phenotype interaction in sex determination. Reptiles have two modes of sex determination: genetic (GSD) and temperature dependent (TSD). We will determine if there is an underlying mechanism of sex determination common to TSD and GSD reptiles by comparing the genomes of two sister species of dragon lizard that differ in their mode of sex determination. This study will provide new insights to the mechanism of sex determination in vertebrates and will test the ....Sex in Dragons: Probing the genotype-phenotype interaction in sex determination. Reptiles have two modes of sex determination: genetic (GSD) and temperature dependent (TSD). We will determine if there is an underlying mechanism of sex determination common to TSD and GSD reptiles by comparing the genomes of two sister species of dragon lizard that differ in their mode of sex determination. This study will provide new insights to the mechanism of sex determination in vertebrates and will test the proposition that sex determination results from the interaction between environmental influences and an underlying genetic component.Read moreRead less
Rnomics - The Role of Introns and Other Noncoding RNAs in the Evolution and Development of Complex Organisms. Approximately 98% of the transcriptional output of the human genome is noncoding RNA. The aims of the project are to (a) provide direct evidence that introns contain functional information and are part of an RNA-based regulatory network, (b) identify large numbers of new noncoding RNAs and substantiate the conclusion that noncoding RNAs genes are common in eukaryotic genomes, and (c) pr ....Rnomics - The Role of Introns and Other Noncoding RNAs in the Evolution and Development of Complex Organisms. Approximately 98% of the transcriptional output of the human genome is noncoding RNA. The aims of the project are to (a) provide direct evidence that introns contain functional information and are part of an RNA-based regulatory network, (b) identify large numbers of new noncoding RNAs and substantiate the conclusion that noncoding RNAs genes are common in eukaryotic genomes, and (c) provide supporting evidence that the higher eukaryotes have evolved a second tier of gene expression based on RNA. The project has the capacity to transform our understanding of genetic programming in the higher organisms, with considerable scientific and practical implications.Read moreRead less
Gene-environment interactions in reptile sex determination. Sex in many reptiles-crocodiles, marine and freshwater turtles, lizards, tuatara-depends on temperature in the nest. This project will examine poorly understood interactions between genes and temperature in determining sex expanding knowledge of how reptiles with temperature dependent sex determination can evolve to accommodate environmental change.
Australian Laureate Fellowships - Grant ID: FL170100008
Funder
Australian Research Council
Funding Amount
$3,248,822.00
Summary
Genes, reproduction and inheritance in a microbe. The project aims to particularly explore sexual gene inheritance in Plasmodium, a representative of a large group of human and animal parasites. Plasmodium must have a sexual exchange of genes in the mosquito for the transfer of disease to a new host. This project will investigate the fate and behaviour of Plasmodium genes during reproduction; the differing chromosome states resulting from sexual genetic processes and the asymmetrical inheritance ....Genes, reproduction and inheritance in a microbe. The project aims to particularly explore sexual gene inheritance in Plasmodium, a representative of a large group of human and animal parasites. Plasmodium must have a sexual exchange of genes in the mosquito for the transfer of disease to a new host. This project will investigate the fate and behaviour of Plasmodium genes during reproduction; the differing chromosome states resulting from sexual genetic processes and the asymmetrical inheritance of some Plasmodium genes. The project is expected to advance Australia’s ability to understand the reproduction and survival of these parasites in their mosquito vector and develop cutting-edge genetic tools that will advance the microbial genetics discipline globally. This may ultimately lead to biotechnology and biomedical outcomes.Read moreRead less
Adaptive Evolution of BRCA1 in Ancestral Mammals. This project investigates adaptive evolution of BRCA1 in the early radiation of mammals. We will test the hypothesis that the evolution of mammary glands and X chromosome inactivation has resulted in modification of the BRCA1 protein sequence as it aquired new roles in these processes. We will also investigate the importance of these changes inducing compensatory changes in other parts of the protein.