 So the next speaker is Cahill Malkhan and Cahill is a molecular biologist and he works as an industrial principal scientist in London with expertise in sample preparation, I have it written down here sample preparation, assay design and development, amplification technologies and bioinformatics. Now with somebody with that amount of expertise you can be guaranteed that what he's going to tell you today is probably going to blow your mind. So can you please give a big welcome to Cahill Malkhan. Thank you very much Morris for your kind introduction. Now how many of you have done DNA testing? Okay how many of you have downloaded your data and uploaded it elsewhere? Now how many of you have actually clicked into the file and looked at your data? Wow quite a number, I'm impressed. So what I'm going to tell you about today is what you can do in terms of health with your direct-to-consumer company raw data. I'm going to give you some basic genetic definitions from a layperson's perspective to let you understand the data you're getting from other third party sites. I'm going to tell you about those providers and the third party sites that can give you health information and then I'm going to go into illustrate this, illustrate the genetics by a couple of very key Irish genetic traits and after that I'm going to show you what the third party output looks like so that using the information you've learned in the definitions you can try to interpret it for yourself and then I'm going to give you an explanation of how you might calculate genetic risk but it's a very simple level that's not as complex as the companies would use and then I'll conclude with a discussion on the pros and cons of this methodology. So Don has already showed you this and what you can see here is the SMP ID which is an RS number. It's chromosome one it's the start of the five it starts with the first chromosome and it shows you the position and it shows you the basis. Now you've got one base from presumably your father and one base from presumably your mother. Now it's not possible to tell here which one's which and you can say adenine, thiamine, cytosine, guine and occasionally you can see a no-call where there was no data for that site from the company or you can see an insertion or a deletion. Now these files continue for 700,000 more SNPs so they're very big files but these SNPs quite a few of them are relevant for your health so you can use them with these third party sites to figure out what is going on with your health in now or in the future. So a couple of basic definitions and genetics which will help you to interpret the information you're getting back from these sites. An allele, that is one of two or more alternative forms of a gene that arise by mutation and are found at the same place in the chromosome. Heterozygous, this is a person where two copies of a gene do not match and homozygous is right so heterozygous is the blue, the big blue and the red are different and homozygous is where the two reds are exactly the same and they're identical. Right the SNP stands for single nucleotide polymorphism and that is a variation of a single letter in our DNA. The RS number which I've already shown you is a unique identifier for an SNP in the SNP database and SNPs are submitted by scientists to DB database SNP are clustered into reference SNP IDs on a letter by other basis and the RS stands for the first letter's reference and first letter is SNP. A genotype is the combination of allele situated on corresponding chromosomes that determine a specific trait. So the genotype is the bit basically the letters in your DNA for a particular SNP and the phenotype is the physical manifestation of that genotype and wild type you will hear lots of scientists in talking about wild type that basically means the prevalent or normal type which is distinct from the mutant. Now dominant that an individual with one dominant and one recessive allele for a gene will have a dominant phenotype so the dominant gene is the blue it's big it's dominant and that phenotype then physical expression is blue. Now recessive for a recessive allele to produce a recessive phenotype the individual must have two copies one from each parent so only R and R together will produce red if you have an R and a B you will get a B. Now a carrier that is an individual having a single recessive disease gene that doesn't exhibit the disease but can pass the recessive gene on to their progeny who can present with the disease if they inherit two recessive alleles from both parents. So like I said before for the recessive if you have the dominant blue you may well have the R but you still get the blue phenotype. Now here I've taken you back to the raw data so you can see what we have here in the light of what I've told you but we don't have to think too much about this. Now the genetic data providers and the third-party sites along here we have the directly direct to consumer testing providers I'm sure many of you recognize all of these 23 in the ancestry and family 3 in DNA living DNA and my heritage are all quite famous. GenCoV and WeGene are less famous but you can equally well use them. Now these on the top here are the third-party testing sites some of which look at health. CodeGene, CodeGen, Promethias, Morris mentioned yesterday, DNA land, gene plaza, WeGene, Xcode and sequencing.com. Now each of these have a subset of the direct to consumer datasets that they take. CodeGen takes all these ones here. Promethias takes these and so on. I'm not sure about sequencing.com I wasn't sure whether they did talk gene CoV and WeGene but they do take all these other ones. Now here's a summary of the information that these third-party health sites will provide you. CodeGen will give you health, nutrition, fitness and heritable traits and is free. Promethias costs about $12, DNA land is free and has lifestyle traits. Gene plaza gives predispositions, weight, sleep, intelligence, coffee, neuroticism, coriander and taste. That's free. Some of their calculations are free and others they charge about five dollars per test. WeGene is free but it's in Chinese. What I tend to do here is some of the Chinese I can actually read it and some of it I use Google Translate to figure out what's going on. Xcode I haven't used myself but this is what they claim to do. Now CodeGen and the other companies they tell you what they can and they cannot do. It's for informational purposes only and this is a direct quote from the CodeGen site. The information here may be inaccurate, incomplete and has not been curated by any doctors but this will not do a diagnosis for you. You should go to a doctor for that. And important we do not offer any medical advice. This is a search engine like service. This is limiting. You may take your own interpretation. You can take it to your doctor and they can finish it off for you. Now there's some additional comments for me. It cannot identify any variations not covered by the dataset or the chip that's been used to take the data. It cannot identify the novel mutations. And what I mean by this is we know that cancer has for example cancer has a multi-stage process and there's a new mutation of each stage in a different gene. Now these mutations will occur specifically in the tissue where the cancer is happening and you won't get it in your saliva sample and you won't get it in your bucket swab. So that's not going to work. So don't get scared. It's not going to happen. And it cannot identify a copy number variations. There are a number of genetic diseases which are inherited where there's an increase in the copy number or decrease in the copy number and they have a manifestation on health but this won't do that. Now some Irish genetic traits. Laura yesterday was talking about some of these and we were discussing some of these last night. And the three that I'm going to talk about are lactase persistence into adulthood, which is encoded by this SMP. We have these alleles, these two enable the digestion of lactose in the stomach and this one here, these pair here, can't get adulthood. The other one is the red hair not being able to time thing that's very common in the Irish, which is encoded by the Meleno-Cortin-1 receptor gene with this SMP. These two can time and this one here burns. And last but not least, the alcohol tolerance gene, which is aldehyde dehydrogenase 2, which is encoded by this SMP and the GG shows efficient alcohol breakdown and the GA and the AA and especially the AA turn is red and stops drinking. Now here's some more details about the lactose persistence. So we, Homo sapiens, we are the only mammal to continue drinking into adulthood. No other animal does this, no mammal does this. This week the other mammals switch off lactase when they finish weaning. Well what did they need it for? Okay, not bothering to do this anymore, turn it off. And it's a beneficial mutation actually that we can still make the lactase. This is the SMP here, the AA variant, it occurs in the promoter of the lactase gene. Now the promoter is the sequence of the gene just before where the protein is encoded that controls how it's produced. So this essentially, this mutation here essentially switches off the control of stopping lactose production when you finish being a baby. So it's switched off by this mutation. Now lactase tolerance is highest in the Irish population and lowest in the East Asian population and it provides a selective advantage in milk producing dairy farming populations. And it allows you to get heavier, have a higher body mass index. It also allows you to drink more milk and you get more calcium from that and you get taller. And then this whole lactase gene and the mutation was associated with positive selection during the domestication of cattle and the advent of farming. And this is ermatrut, which is a cartoon cow because we're talking about lactose here, which is originally a French cartoon that was very popular in the UK back in the 70s. Now, Donald has already told you about getting 50% of your genes from your mother and 50% of your genes from your father. So that means that from your father he's had two genes and if they're both Irish, he's had, probably he's had two genes that can continue lactose, lactase into adulthood. And the mother would be the same. Now how it works is, child one gets this one and this one. Child two gets this one and this one. Child three, this one and this one. And child four, this one and this one. Like so. But in the case of the Irish, they end up all being able to drink milk into adulthood. The Japanese, on the other hand, neither parent is able to drink lactose into adulthood, which means that all the children won't be able to drink lactose into adulthood. Of course, you may get some European genetics entering in there historically from say the Spanish or the Dutch, so you might get the odd person that is able to drink it quite well. Likewise, you might get some Chinese genetics in the Irish population, so it may not always be like this. Now, when you mix an Irish and a Japanese, that here's the Irish chappy here, he can drink milk. His wife can't. So you've got a whole set of children who can drink milk because they've got one normal gene from the father. When you've got Iberians who are, unlike the Irish, not fully having lactose in every person, lactase in every person. So you get a mixture of the parents are both able to drink because they've won functional gene each, and one child is fully functional, and the rest are a mixture, and this one here actually can't drink it at all. So if you mix the Iberians and the Japanese, you've got one here who was able to drink but has one elite copy that doesn't work. You've got two here that don't work, and so you get a couple of heterozygotes that can digest milk, and you get two homozygotes that can't because of the way the genes recombine. And if you mix the Iberians and the Irish, everybody can drink milk, but you get a couple of people that may pass on the gene that doesn't work to their next generation. Now, alcohol metabolism. I think we're all familiar with this character here who symbolizes the Irish ability to drink lots of alcohol. This is Father Jack, those of you who don't know from the program Father Ted. The phenotype in the East Asians is called the alcohol flush reaction. Now, the body breaks down alcohol in two steps. At first, the enzyme alcohol dehydrogenase converts alcohol to acetaldehyde, which is a bit on the toxic side. And then aldehyde dehydrogenase converts the acetaldehyde to acetate, which is harmless. Now, the acetaldehyde accumulation causes blushing due to the dilation of facial blood vessels, nausea and sleepiness. Now, this is not found in native European, African American or South Asian populations. This is the map of the distribution of the lactase inability to drink milk in adulthood. And you do find that the mutation, which occurred in aldehyde dehydrogenase, it happened in the Han Chinese and Haka and Min Nam ethnicities in southern Fujian and East Guangdong provinces. And then it spread to the rest of the region. The mutation results in a change in the protein for lactase of glutamine to lysine at position 504. And that results in an inefficient conversion of acetaldehyde to acetate, such that the acetaldehyde builds up in the bloodstream and causes all these effects. It's dominant negative. So heterozygous person shows reduced activity and the homozygote has no activity at all. The mutation is associated with alcohol liver disease, late all onset Alzheimer's disease, colorectal cancer and esophageal cancer. But it protects against alcoholism. If you can't drink, you're not going to become an alcoholic. And it has had cultural benefits in East Asia. And if I go back a little bit, this paper from Yale University by two kids has said that it's actually had a cultural benefit and therefore has proliferated throughout East Asia. Right. And this is the the inheritance map of the alcohol breakdown. Of course, all the Irish don't have any problems. The Cantonese being from South China where the mutation first originated can't drink. If you mix an Irish and a Cantonese, you get everybody can drink, but don't push it. If you look at Jillianese, which is in the area where some of the Chinese in that area can actually drink, you get a slightly better situation in the Cantonese in that you've got this person can probably drink a little bit so can that. But occasionally you get one person that can't drink at all. And if you mix up the Jillianese and the Irish, well, basically everybody can drink, except him. I wouldn't overdo it, but he can actually he won't he won't turn red. Right. Red hair. Very famous. And timing. Let's not forget the time. People with Celtic red hair have and this is the distribution. And for some reason here, there's a whole pile of them over there as well, which is the Volga region of Russia. But people with red hair have so the sulfur containing pigment, pheomelon in their hair and in their skin. And they have pale skin. But the benefit of that is in our wonderful, not very sunny climate, we're able to make more vitamin D. And they have karate or straw red hair, freckles, lots of moles, blue eyes, and a high tendency to sunburn. Of course, that's because they have an inability to turn. I thought I'd put this up considering all the forensic conversations of yesterday. This is Horatio King from CSI Miami, played by David Caruso, who probably has some Irish ancestry, unless he's from that Russian area. Right. So melanin cells in melanocytes, melasin cells in the skin, secret melanocytes stimulating hormone in response to UV exposure. Now, that hormone binds to the melanocortin run receptor, which is the gene in which we have the polymorphisms, the mutations. That signals them to produce black and brown new melanins. Now, these black and brown new melanins can absorb UV light in the skin and hair. So they have no problems. But the mutations result in impaired function of melanocortin one receptor, which results in the melanocytes producing pheomelanin rather than eumelanin. The pheomelanin absorbs UV poorly compared to eumelanin. But even worse than this, it's phototoxic, amplifying the UV damage and giving rise to melanoma cases in some cases, which is why I always wear a hat when I go out in the summer, especially in East Asia. Now, this is the hereditary thing for this particular melanocortin receptor one mutations. So if you're typically Irish, you're both homozygous mutants, nobody can tan, we only burn and you might have red hair. For the homozygous wild type, this is the normal. We Irish were not normal, we burn, we don't tan, we have the mutant, you have the mutant, then everybody tans, everybody's fine and nobody's got red hair anywhere. Now, if you've got a mixture of homozygous for mixture and the wild type, you get a couple of people, everybody will be able to tan because it's recessive. And everybody's tanning. And nobody's got red hair. If you've got heterozygous, then you've got one case of a child where he won't be able to tan and you probably might have red hair. And then it goes on homozygous mutant and heterozygous, you get a couple of non-tanners and red hairs, and you get a couple of people that can tan. And then if you mix up the homozygous wild type and heterozygous, it's a better situation, everybody can tan and nobody is red hair. Now, haemochromatosis, which is a classic hereditary Irish disease. Now, what is it? Hereditary haemochromatosis type one. It results in an accumulation of iron in the body, due to excess absorption from the gut. And this excess iron results in depositions that can result in damage to the liver, the joints, the pancreas, the heart, etc. But carriers have improved blood iron levels. Patients over 40 start to show symptoms. It's relatively simple to diagnose and treat. And the gene responsible is HFE, which stands for high iron with the atomic symbol for iron being FE. It's also called Celtic Curse, Irish illness, British gene, and Scottish sickness. And it's caused by mostly a mutation at position 845 from a G to an A in the gene. And it's believed to have occurred in the neolithic farming as they spread from Europe through Europe from Middle East. Now, there's arguments in the literature as to how long this mutation occurred. So I just made it vague in terms of the farming spread. Now, the mutation has the highest frequency along the Northwestern European coastline, and especially in Ireland, you see some here in Brittany as well. And so highest in Ireland, spread around the Europe by the Northmen by the Northmen, I mean the Vikings. It has the lowest frequency in the regions where the Vikings didn't go. So basically, what happened is the Vikings came to Ireland, picked it up, went elsewhere, and wherever they went, they left it. So this has formed the Viking hypothesis in the sense that the disease is associated with areas of Viking sediment, which probably, I think Dublin has it probably because of the Irish rather than Vikings. All right. So the primary disease is resulting in an amino acid change in the HFE protein, which is this SMP, and it's a change from the normal cysteine at position 282 to a tyrosine at that position. And what it does, the dysfunctional, the functional protein inhibits the uptake of iron from the gut because your body can't get rid of it. So they stop taking too much of it in. That's what essentially it does. And the mutation, it stops that control. So you take in everything you can get your hands on. It's recessive in that the carriers don't show the disease, but they did have improved iron levels. Now, it conferred a benefit in the low iron farming diet, which had chemicals called phytates, which were coming from the surface of the grain and lactate from the milk, both of which hinder iron absorption by binding to it. Now, low iron hinders thyroid stimulation, stimulated metabolic heat generation and colder climates. So when these people moved from the Middle East into Europe, and then they moved up to Ireland, they were having to deal with colder weather than they had to do previously. And so this mutation helped them. So it's benefited them in our cold climate, and it actually enabled an increase in progeny, progeny, because if a woman was menstruating, she would be losing iron. If she didn't have the ability to retain iron in her diet, because she had a poor iron diet, then she was going to suffer. And the people that had the mutation were able to retain the iron, and therefore they had a benefit. Now, this is the hereditary situation. If you have a normal, a needle, everybody's fine. If you have a carrier, everybody's fine because it's recessive. But if you're both carriers, you have the chance that one of the children is going to be a disease case. And a normal and a patient. Well, if it's totally normal, then all of the children are going to have a normal allele and one disease allele, which is going to be absolutely fine. And the patient in the carrier has a higher chance of children with the actual disease. Now, I'm going to go on now and use the Code Gen site to see how they implement, how they show you the various patterns of genes, the normal, the carrier and the disease data. And I'm going to use spoof data sets for that, which I've went into the data, and I've changed the basis in that position to make it the normal, the disease state in the carrier. Now, this is the carrier. And you can see this red here, which is just warning you that you're your carrier. And it says that you have one copy of this, your carrier, and you're unlikely to be affected unless you have the other mutation as well. So you're fine. This is the patient. It tells you you have two copies of the mutation is telling you it's bad and you're going likely to be affected by hemochromatosis, which may be serious if male or post menopausal. Now, the reason for post menopausal is if you're a female and you're menstruating, you're losing that iron, and it's not going to affect you until you reach menopause when you stop losing that iron. And it builds up if you don't take care. Now, this is the normal, which is green. And it's telling you you're not a hemochromatosis carrier. You're absolutely fine. So this is the actual text from SNP dia. So what they do is code gen cross checks your genotype information from your raw data, and runs it against SNP dia, and then outputs the data in a digestible format. That's essentially what this is. And the key things are this is the SNP. And this SNP is responsible for 85% of all cases of hemochromatosis. And it can give rise to liver cancer, which is responsible for about a third of deaths of the homozygotes. And it's a preventable cancer because it's easily treated. Now, here it says it defines the mutation, it shows you the amino acids. And then it goes on to say that early identification can prevent complications. You know how to treat it, deal with it, problem solved. You can read all this at your leisure. If you if you go on to the website for SNP dia, you can actually type in any SNP, any disease state that will feed back to you without even importing your own DNA, what these things do. And 30% of the males had iron overload related diseases, versus 1% of the females, that's due to menstruation. Women are less homozygotes are less affected to menstruation may become after menopause. So it's, you see, it's accessible. You may not have a background in genetics, but you can actually take this information and do something with it. Now they talk about the spread. This is a west east decline from Ireland through the north of Europe, Vikings may have been involved in the spread, and so on. Now, risk calculation. This is very basic. What I've done is devised spoof data sets for Crohn's disease. I was inspired by a paper in 2007, which started to look in its infancy at genetic risk. Now genetic risk is quite complicated. What I've done here is a massive exaggeration. And these individuals are probably impossible. Because what we have here, we have the RS number, the SNP, we have the gene. This one is the interleukin 23 receptor. Not that I would worry about that mind you, but this seems to be quite prevalent in Crohn's. These are the bases involved. That's the risk for this base and the risk for that base. And this is the normal. And this is the odds ratio that this SNP type, or combination of bases gives. So in a normal, there's a lot of ones. So if you multiply one by one, you get ones, that's normal. But there's also a couple of fractionals. And what they do is they reduce your risk relative to the risk type, which is just a one, which is somehow normal. But the risk type has numbers greater than one, which will multiply up to give you a much bigger figure. Now, I don't think this is what companies or academics are doing. I've made this very simple to make it easy to understand. And it's pretty clear that this person here has a greater chance of getting or not getting the disease than this person here. But these are completely artificial because I've contrived them using a data set. So to conclude, we have a set of pros and cons. Doing this gives us actionable results, preventing disease before it happens. It allows you to change lifestyle and diet to prevent disease. You can identify it early and that would give rise to the ability to monitor it and to look for therapeutic development in an early stage to enhance drug development and personalized medicine. It also allows early screening for more effective and early treatment. And there may also be forensic applications because if a suspect DNA sample is showing that they have this disease, that disease and the other disease, you can identify them more easily. Now the cons are, if you are going to be upset by what you see in this data, don't look at it. That would be my suggestion. It also allows people to do homebrew eugenics by parents not having children or by stopping marriages due to the genetic risk of having children. However, do note that in history, hematromatosis was an advantage. If we do this, we lose the advantage of having this gene in the population. Another example is sickle cell anemia, where in the Sub-Saharan African population they have the disease. Here it's a disadvantage at the present time, but in Sub-Saharan Africa where there's malaria, the malaria parasite does not survive very easily in the red blood cell of the sickle cell anemia patient and they live better. So we want to keep some of these so called bad genes because they're useful and our environment may change and something that's useful now, or not useful now, may be useful in the future. So something to think about. So what I'm essentially saying here, we could result in the loss of disadvantageous mutations that could become advantageous in a changed environment. Now the other thing that has been discussed yesterday and tomorrow as well is the security of genetic information. There are privacy considerations with this and there's also the impact of health insurance from the health insurer knowing that you have this predisposition and deciding I'm not going to insure you or I'm going to insure you but I'm going to insure you at this rate. So that's that. So I'd like to acknowledge my family in Cambridge. Dr. Buyan in Lausanne, who's a clinical molecular geneticist. Professor Marilla in Cambridge, who's a historian. Tom Murphy in Newmarket, who's a lay person. Francois sitting there who works in London and Claire Slatter who works in London as well. I'd also like to thank Mark on the train the morning who also had a look at it. And Morris and Gerard and the ISOG volunteers for organizing the event and having we speak today. Thank you very much for your attention. Any questions? Thanks very much. Has anybody uploaded their data to Code Gen? Or Prometheus? Prometheus? A few people. Yeah. So any questions for Kahla rising out of that? We'll have one from Debbie, one from Gerard. Gerard to go first. Thank you very much. I've been to over 60 cities in China and I very rarely end up in the banquet with Chinese government officials whose sole job is to get the wakeware in or the foreigner drunk. And it usually ends up with all them slumped over their chairs. So thanks very much for explaining that. Well you do have to be careful Gerard because I have times in Japan where the Japanese professor has drunk me onto the table or at least tried to. So you can't always guarantee that. Debbie. I've got one observation and one question. In the, there was an ancient DNA paper published by Dan Bradley's lab about a year ago, two years ago, and they actually found heme chromatosis in an ancient Irish sample. I think that was the Bronze Age sample several thousand years ago. So it's clearly been Ireland a long time before the Vikings. The question I was going to ask was about penetrance because I went to a tall cup in Manchester from someone who was part of the heme chromatosis society and he was saying that he was actually concerned because they were getting reports of people coming with their 23 and me results who thought they had heme chromatosis but we don't actually have any information about the penetrance of these conditions. And it's the same with lactase persistence. I'm double G but I don't actually have any symptoms of lactase persistence. So we know these genes are associated but we don't actually know how many people have them and don't actually express the, don't actually have the trait. So I just wondered if you had any thoughts on that? Well I have a family member myself who should be totally fine for milk through me but thinks he can't drink it. So that's my, one of my responses to you. It all depends on how you, what your life is. If you're not taking too much iron then you're not going to be affected by it. I suppose does that answer your question? There are also other factors involved that we don't get to know about but if you have another mutation elsewhere it may be protective because a lot of these things seem to be much more complicated. That's what we thought and now that we've decided to do these polygenic risk scores and it seems there's lots of little genes that have little effects and you have to put them all together to create the big picture. That's absolutely possible. The understanding is probably still in its relative infancy and will await a whole genome sequencing relating it to the phenotype to understand what all these things are. I don't think we understand them all at the present time. I was at a meeting in London organised by the Progressive Educational Trust, PET and one of the professors presenting said that a lot of these GWAS studies, the genome-wide association studies, are picking up false signals and they're giving us incorrect signal, incorrect pointing towards a particular disease condition associated with SNP that isn't there. So there's still a lot of work that needs to be done because they're looking for signals that are generally very, very weak. There's very few conditions that are really monogenic in the sense that if you have this gene you will get this disease and like Debbie says, there's a lot of other genes out there that are probably protecting against those diseases that we don't know about. About health insurance though, I mean how real is this risk that our DNA is going to be used by insurance companies to put up our premiums? Because when you go for your interview with the insurance company they ask you, what did your mother-up die of, what did your father die of, what about your grandparents and does anybody in your family have this long list of diseases? Please tick the ones that you're aware of. Hemochromatosis, tick, Alzheimer's disease, tick, heart disease, tick, cancer, tick. So we're actually giving them inadvertently or indirectly the genetic information that we carry around in our genes. So what do you think about the actual risk of insurance companies using our DNA to inflate the premiums? Is it going to happen anyway because we're giving them more family information? Well we did hear yesterday about a law in the United States that would prohibit that happening. But if you're applying for health insurance and you're asked a question, do you know about any disease that you might have and you have tested with one of these companies and you know you have this disease it hasn't manifested. If you click or tick, I don't know, then you're not entirely telling the truth and when you manifest the situation they might decide, oh, did you know? But do you actually know, because you're not going to know of any protective measures that have yet to be discovered. That's true. You know, so it just comes back to what you were saying, this is a lot that we have identified as there is an increased risk of Alzheimer's disease if you are E4, E4 and the risk goes from 6% up to 42%. But just because you have a 42% risk of developing Alzheimer's disease, you have a 58% risk of not developing Alzheimer's disease. So you have to look at the other side of the equation as well. Certainly. Has anybody got any thoughts or ideas about insurance companies and insurance premiums? Has anybody been in that kind of situation where it's become a little bit of an issue? Cliona? No, I haven't Mars, but it's just a point of information. In Ireland they don't ask you anything as far as I'm aware. I've never been asked about any conditions. There are about 2,000 different policies on sale and regardless of whether you're 22 or 82, they are obliged to give you the same price. But that's probably not the situation in other countries. Very egalitarian approach, just overcharging everybody. I would like to give a different interpretation of the Genetic Information and Non-Discrimination Act. It's actually the Genetic Information Discrimination Act because if you have good genes, the insurance companies are obliged to discriminate against you by not giving you lower premiums. And if you've bad genes, they're obliged to discriminate against you or discriminate in your favour by not giving you a higher premium. That's a nice way of putting it. We have Pat Kennedy here. Just a question. I don't know whether it's really relevant to your situation, but recently identical twins were sent out into space. They had the same DNA, but when they arrived back on Earth, the DNAs were substantial in their variance. Did you hear about that, Cahill? I didn't hear about that. I believe it was a twin US astronaut that went out into outer space and his twin brother obviously did not. And what they did is they analyzed the difference from mutations caused by being in outer space after extended duration. They were more significant than they thought they were. Well, that was a good control test for them. I don't send a question. I guess question, comment, I guess. On the beneficiary of the human chromatosis, I was diagnosed with it about 30 years ago. I feel very fortunate I was diagnosed with it because, you know, my ancestors, going back probably prior to the 1950s, died prematurely from this normally liver disease. Age 50 or 60 or heart disease would kill you. So it's an immanageable, simple disease that you can live your whole life with. My parents were obviously autosomal carriers, autosomal recessive disease. I have five siblings, five of us have it, three of us have it, and three of us do not. In the U.S., life insurance does come into play with hemochromatosis. If you have hemochromatosis, you probably can get either, in the best-case scenario, read it as a standard, as opposed to preferred or super preferred. So it can come into play in certain, I'd say, life insurance situations more than health insurance. There's a lot of movement in the world on health insurance when it comes to pre-existing conditions not being allowed any longer to be factored into things. But life insurance, absolutely, is a, it's a, to term it. We have a final question here. It's more kind of two comments. So thank you, Kahal, for the talk. It was great. As usual, so first about the twins, I think it's fascinating students, especially because they are supposed to have the same DNA, but actually if they are raised in different families, they are quite different in the end. And all this is coming from epigenetics, so we don't talk too much about that here, but with the same book, you're not obliged to read the same sentences, so motivation got a huge importance here. We are just discovering this and I think it's really going to be a big field in the future, including gene averaging. So just first comment. So DNA is not all. We are just like, to be really involved about that, because it's really complicated, the biology behind regaining insurance company. So I know some people which are doing the mathematics behind, and they are always doing the same. So basically they are taking our history, all the information they can find about us, and they populate some big tables in which they say, for instance, for my car insurance, so in France. So I know for sure if I have a red car, I'm going to be charged more, because they discovered that in most, if you have a red car, you are more likely to have an accident. So if tomorrow you put your genetic data on Facebook in a public place, well please don't do it, because they will aggregate the data, they will do it. They are really good at it. So just don't do it and be sure that your privacy is always respected at the level you expect. That's a really good comment. So if you did want to use any of these third-party tools, you might upload your data, do the analysis, and then down-delete the data. Yeah, the last comment is just about this deal, about 23 million and cheese case, so for 400 million dollars, they send data that don't belong to them. It's your data. I mean, I don't want to see a photo of me naked on Facebook. They are doing something worse. It's way worse. It's your DNA data. I mean, can you realize that? So it's quite serious. So we should take this into consideration when ordering tests. Make sure that you have the right to erase your data and destroy your cell phone. Great. Okay, a quick comment from Debbie, and that would be the end. I disagree with what Francoise said there, because I think everyone has the right to do what they want with their own DNA. I want my DNA to be used at 23 million. I want my DNA to be used to help make any discoveries about drugs or anything else. So it's up to the individuals to how their DNA to be used. No disagreement on that. Great. Well, thank you for a fantastic presentation. Thank you for inspiring the conversation afterwards. You've got a comment, a couple as well? Just one last comment on the twin in space and the twin on the ground. It doesn't surprise me that mutations were found. We know very well that coming over here from London, we do experience more than a dose of an x-ray in order to come here. So it's not surprising at all. Great. Okay, ladies and gentlemen, please show your appreciation for Francoise and Ida. You're off. Good. Thank you very much, though. It's great. It was fun. Absolutely. Off. That's off. Hi, how are you? I'm on that subject. My sister's a doctor.