Variation And Inheritance Of Retrotransposon Epigenotype In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$355,500.00
Summary
It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way gene ....It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way genes are used. Epigenetic factors can be passed from one generation to the next like the DNA itself, and this can make it difficult to know if a trait is encoded in the DNA itself or is epigenetic. We have found that some epigenetic traits in mice are caused by retrotransposons, which are parasitic elements that reside in and among genes, and can reproduce themselves, but do not have any known function (nearly half the human genome is made up of retrotransposons). Retrotransposons are generally kept silent by epigenetic factors, but may sometimes become active; when they do they may disturb normal patterns of gene activity and cause changes in traits and even disease. Much variation in humans may thus be due to variation in the epigenetic state (epigenotype) of retrotransposons. We propose to investigate variation and inheritance of epigenotype in mice, focussing on retrotransposons. We will use simple methods to compare epigenotype of a number of retrotransposons in genetically identical mice, and we will ask if any differences we find are heritable. We will also investigate the resetting of epigenotype the point in development when epigenetic factors are cleared and reset. We suspect that this occurs in early development. These studies may reveal a system of variation and inheritance with rules completely different from those found by Mendel, which may have a pervasive influence on traits, including sporadic diseases in humans.Read moreRead less
One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number o ....One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number of chromosomes), a feature exhibited by many forms of cancer. This packaging of genomic DNA that produces a chromosome is achieved by a complex scheme of folding. At the first level, DNA is first wrapped around a mixture of proteins (called histones) to form a complete unit known as a nucleosome. About 30 million of these building blocks are required in every human cell to compact our DNA. Higher, more complicated levels of organization exist in which a linear array of nucleosomes fold to various extents to form distinct functional and structural domains. Importantly, specialised chromosomal domains, like the telomere and centromere, are assembled that keep the ends of the chromosomes stable and enable a chromosome to copy itself every time our cells divide and grow, respectively. How a chromosome is divided into these different compartments remains a mystery. This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . These histone variants control the way a linear array of nucleosomes fold into complex three-dimensional structures to perform a specialised function. This fundamental research will provide important new information on how chromosomes become unstable in cancer. It will also enable new strategies, which stabilise the chromosome, to be explored.Read moreRead less