 Swn i ydydd i fyneud cyflym i per�awwyr hwnnw, y gwneud o'r saffwyr o ydydd cyflym o ffordd dweud. Felly, mae wir yn mynd i weld bod mae'r saffwyr ydydd cael y dydydd o saffwyr o'r saffwyr ac mae'r saffwyr o ddydd, rym ni'n gwneud o'r saffwyr hwnnw, a'r ystod o'r ddeilig gyda'r dweud. Ystod y maen nhw'n siarad yn ysgolb gyda'r ddeilig gyda'r ddeilig gyda'r ddeilig. Dyna dweud yr ystod bydd ydych yn dweud yn fy môl yn y ddeilig. Ddeilig yn ystod y ddeilig gyda'r materiwn, gyda ddim yn y ddeilig gyda'r ddeilig, ac yn cyfathu'r cymrydau ymlaen nhw'n ddeilig. Mae'n ddweud yn ddeilig gyda'r ddeilig gyda'r ddeilig. Rwy'n credu rhywbeth fel gymhannu gymhannu dyma arall yn gyfysgol genedig o gwahanol, fe allan ddau o bobl gyda'r cyfen nhw, oherwydd mae'r cyflwyll penderfyniau sydd wedi cyffredin direct â'r gyflwyno. Rydyn ni wedi'i holl y gwahanol gyda'r cyflwyn sydd yn yr Unedig continent yw hyffredin resistant. Ym Lyfr i gymryd o'r cyflwyno gymhannu genedig. Rwy'n cymorth i'r bobl yw'n gweld cyffredin gyda genau o'r lle i'r cyfrannu gael. Felly byddech chi'n meddwl, mae yna yn tro unig sy'n ffamilio am gyda'r hynny, yn hynny, mae'n cyd-aeth sy'n hollol cynnwys, ac yn cael ei wedi'u cyfeithio, maen nhw'n ceisio wirthdoch chi'n ceisio srach o genio mynd i'rdiogel. Mae'w mynd i fawr a fanyaid, mae'n 10 i 1200 ddim yn gwneud yn meddwl i'w mynd i'r syffredin cyfredin Cymru To look for common genes in people that are susceptible to things like obesity, diabetes. One of the drawbacks in using humans in these massive genetic studies is that, as individuals, we are all combinations, a mass combination of many different genes, but obviously these different combinations of genes make the analysis much more complicated. B ρt an魚w fath y my beschwyl ni, weíve got a problem, weíre just using the human gene pool because of these many different combinations and these many different environmental effects. So where did human genetic analysis, Mammalian genetic analysis go next? Well, there were two big revolutions in the last few years. One of them has been with the human genome project and this was a complete sequencing of the human genome. We now know the codes for 20,000-plus genes in the human genome. Unfortunately, we don't know what all of them do and we don't know what quite a big majority of them do ond we do not know what which variations of them cause diseases in some cases. So the other big revolution has been the use of a mouse as a model organism for looking at genetics and for looking at what these genes do, what human genes do and what the mouse version of those genes do. And there's really three things that I want to tell you about that are the basis of where Paul's going to come and give you an active example of the research we do. And there are really three major things that make mice really key in a technical order and really key to being a model organism. The first of them is that we're able to produce groups of mice that are genetically identical. And in doing this, this is really important. If you have a genetically identical set of mice and you alter one gene and you see a characteristic, you know that characteristic is because of that one gene that's being altered, not because they've been brought up differently, not because they've got a different combination of genes in their background, not because they've eaten different things and not because they've had a much different infection. During the process of the last 100 years where mouse genetics has really come to the forefront in biological research, during this time there have been a number of genetic variants that have come up. So during the selective breeding there have been a number of animals that have arisen that haven't looked like their parents and we've been able to look at what mutation has occurred in them and what variation has occurred in them and track the cause of the disease or the characteristic that they're showing. But really the big revolution has been since the 1980s in genetic engineering where the mouse genome we've been able to actively modify and manipulate the mouse genome to actively change genes that we select ourselves. All of the mice in laboratories in the whole of the world come actually from three species and a subspecies and all of them are derived as a combination of these. And actually all of the animals in laboratories at the moment are derived purely from the fancy mice or the people who kept pet mice and this lady called Abby Lathrop in Illinois at the turn of the 20th century. She supplied these fancy mice to pet shops and she got talking to some people in laboratories and was really started breeding for laboratory purposes and she's kind of seen as the forerunner of a lot of the laboratory mouse strains. And what came of the work she did and the work that somebody called Clarence Little did in the States in the States at the sort of 1910 onwards was that they produced these things called inbred strains and at the moment there's about 520 but it goes up every year. Different strains of mice that are described as being inbred and these are strains that are genetically identical so every mouse in that family is exactly the same so they're like identical twins and that allows us to manipulate single or multiple genes but on a background where everything is exactly the same so it's not a sort of confusing background that you would have with some of the human studies. On top of that during this 100 years of fairly intensive mouse breeding many mouse variants have been written spontaneously and this occurs in the human population as well. Somebody's DNA will mutate spontaneously either because of a normal biological process that's gone wrong or as a result of, in humans as a result of radiation damage and chemical damage but these have been used quite widely in research and the sort of thing they've been used for are things like congenital deafness and there's a mouse strain that was noticed that it nodded its head and when they cloned the gene they found out that it was one of the genes that's really important for your vestibular balance in your rear which meant that they could clone and that there's a lot of work being done on congenital deafness on the back of this gene. But also some of the diabetes and obesity mice that spontaneously became very fat and we've managed to clone some of the important genes that are involved in people getting extremely fat. But really the revolution and the revolution at Harwell and at the Sangren are a number of places in the UK and especially throughout the world has been the ability to genetically engineer mice. And this really has come from the ability to manipulate pre-implantation embryos and so these are fertilised embryos from a mouse that are two and a half days into gestation so they haven't yet implanted into the uterus before that stage, they're four to eight cells but basically embryos anything up to three and a half or four days can be manipulated genetically and so we can alter, at a very early stage of development, we can alter the DNA and in the 1980s there was the beginning of this whole genetic revolution in making transgenic mice. And there's a number of ways and there's a number of different techniques in modifying mice genetically and one of them is that you could add information to them and actually it's very simple technically it's quite difficult but it's a very simple concept. So this is a single fertilised embryo and the process just involves injecting DNA into the nucleus of the sperm and then we transfer this embryo back into a female mouse. So this injection needle, this injection pipette here is injecting these cells which are embryonic stem cells and these have been modified and the genes have been removed from these and you actually do this in a cell culture dish and you can remove genes from it, you can add genes to it but it's a much more targeted way so you know specifically what you're doing with this cell type. Again we inject these into an embryo, this embryo gets transferred into a female mouse and when they litter down there are mice that are lacking the gene in question. We use them for looking for gene expression so if you're not sure where a gene is made if you're not sure the cell type of gene is made then you can tag that gene with something that will show it up and this is a picture of an embryonic lung and there are specific cell types here that nobody was sure where this gene was expressed properly and also that they weren't sure when there was disease models for this how that was affecting the gene expression so you can use these animals to kind of really highlight and show up specific cells. You can use it for gene function so we have a look and see what genes are doing and this is something called an optokinetic drum and the mouse sits on this little platform and the lines rotate around it and the mouse follows it through its head and then the lines decrease and decrease until the mouse no longer follows it and that's the level of the mouse's eyesight so this is a way of measuring how much mice can see or not. You can also measure disease progression and that's something that's very difficult in human studies this is a special kind of x-ray machine that's measuring bone density so if we know that an animal is likely to get osteoporosis then we can measure that from a very early age whereas humans you only know when they have osteoporosis so it's very difficult to work out what early indicators are or what early indicators are for early intervention of the medicines and also ultimately and Paul's going to talk to you a bit about we're striving towards treatments and we can use some of these disease models for doing proof of concept and for testing potential drug therapies and so just a summary before I hand you over to Paul to give you some real examples mice is a model organism and are important because we can control the things that we can't control in humans so we can control their genetic backgrounds we can control the environment they're bred in and they're kept in and also we can specifically alter individual genes and this has been the revolution in transgenic mice or genetically modified mice so I'm now going to hand you over to Paul who's going to give you some more laboratory examples of how we use these