tag:blogger.com,1999:blog-1812431336777691886.post3834067200101299539..comments2024-02-29T03:57:00.088-05:00Comments on The Mermaid's Tale: Can we or can't we explain common disease?Anne Buchananhttp://www.blogger.com/profile/09212151396672651221noreply@blogger.comBlogger15125tag:blogger.com,1999:blog-1812431336777691886.post-86437352033697203282012-12-05T05:37:18.185-05:002012-12-05T05:37:18.185-05:00This is the strategy of using isolates or populati...This is the strategy of using isolates or populations with large inbred families as found in some middle east cultures, or Finland (and Iceland, etc.). It's an old and respectable idea.<br /><br />The issue is that such variants are likely to be very rare in larger more variable populations. If the variant has a strong effect size, why has it not been found elsewhere? Generally, because it's too rare to show up enough times in GWAS to generate a signal.<br /><br />Others advocate looking in families segregating the trait, even in heterogeneous societies, and to find co-segregating genes, essentially using the families as a kind of isolate. This, too, is an old idea.<br /><br />I think there is no one answer, and we need to learn what we gain from identifying very rare variants. Advocates of unrestrained omics approaches have various answers, often based on assuming that computational power can make sense of each person's assemblage of variants, etc.<br /><br />Others would argue that we should show that knowing a 'real' variant (one with substantial effect) can lead to treatment or solid new understanding of the underlying biology.<br /><br />So, to use your word, to be fruitful what is the 'fruit' one wants? And what is the most cost-effective way to do this?<br /><br />When environmental causation is far more powerful than genetics, or than a single variant, should the environmental causes be addressed first, saving the exotic genetic approaches for the remaining cases that really are genetic?<br /><br />I have my own views, but these are things that need to be decided by the community at large and the public who is paying the bill. Clearly at present technological approaches focusing on genes are ruling. How long that will last is impossible to say, I think.<br /><br />Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-90758618646594943752012-12-04T22:26:17.106-05:002012-12-04T22:26:17.106-05:00Well, speaking of rare variants of large effect, d...Well, speaking of rare variants of large effect, deCode came out with a paper in November in NEJM in which they discovered a rare non-syn SNP that has a effect size of nearly 3 to confer risk of obtaining late-onset Alzheimer's. They sequenced 2000 individuals and the variant was segregating at less than 1%. I'm not sure exactly what the demographic history of Iceland is, but would it be more fruitful to focus on sequencing homogenous population isolates around the world? Amithttps://www.blogger.com/profile/17374419504359860299noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-22081151465991079152012-12-03T08:45:50.325-05:002012-12-03T08:45:50.325-05:00Daniel, can you explain what larger samples can te...Daniel, can you explain what larger samples can tell us that we don't already know? Ok, yes, the identification of more rare variants perhaps, but we already don't know what to make of all the rare variants that have already been identified, unless they are associated with Mendelian disease. <br /><br />And when do we stop collecting data, since every new meiosis means potentially new deleterious rare variants (not to mention every mitosis)? And, of course larger samples mean increased heterogeneity; how does that help clarify things?<br /><br />What we're arguing is that the picture is already pretty clear. We already know that complex diseases are polygenic, that there are many pathways to the same phenotype, that there's gene by environment interaction, whatever that means. Given that reality, what more can larger samples tell us? They won't change the reality. <br /><br />And, will larger studies produce information that's useful for prediction at the individual level? We can be pretty sure that the answer to that is no for complex diseases (we've written a lot about that), and we've already got the statistical methods and conceptual understanding to do that for Mendelian diseases, for which we do not need larger and larger samples. <br /><br />So, until I understand what I'm missing here, I agree with Ken -- given what I think is the probability of low return from the huge investment sequencing larger samples will yield, the money could be better spent on other things. Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-32460103904945442572012-12-03T06:27:14.111-05:002012-12-03T06:27:14.111-05:00There is a long history of these issues. Ideas alo...There is a long history of these issues. Ideas alone can't solve the problem, but massive (expensive) new data gathering may not do it, either.<br /><br />Waving terms around, like 'complexity' can be just as fashionable and empty as demanding ever more data to be collected.<br /><br />The key is to have focused question and design to determine what kinds of data would be illuminating.<br /><br />But if many-to-many causal landscapes are the reality, new conceptual approaches may be needed. <br /><br />It is fair to point out, I think, the various reasons that new toys and technology and the grants that go with them are appealing, in an age where we are expected (for better or worse) to keep the mill churning out 'results'. We live in an industrial society and that culture affects (or infects) science as well.<br /><br />Look at this another way: if funds become limited, or 'translation' is really the goal, to reduce disease loads, then the funds could be better spent on other things that, perhaps without the techiness or even without understanding complex underlying mechanisms, can achieve results.<br /><br />Ken Weisshttps://www.blogger.com/profile/02049713123559138421noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-85697756460016370902012-12-03T00:16:51.404-05:002012-12-03T00:16:51.404-05:00Hi Anne,
I'm all in favor of innovative ideas...Hi Anne,<br /><br />I'm all in favor of innovative ideas, but I'm not convinced that they'll have much value without simultaneously generating "more of the same" (sequence data). Complex models will, if anything, require even larger sample sizes (along with additional information about environmental variables) than the current simple genetic models. So I just can't see how incorporating "complexity" will magically allow us to make do with less sequence data than we have currently.Danielhttps://www.blogger.com/profile/07276690118219000204noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-56129572249371618792012-11-30T15:01:26.373-05:002012-11-30T15:01:26.373-05:00I agree. What we need is innovative ideas, not ju...I agree. What we need is innovative ideas, not just more of the same.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-37370506063947397852012-11-30T12:25:57.505-05:002012-11-30T12:25:57.505-05:00Its really frustrating to hear 'We need larger...Its really frustrating to hear 'We need larger sample sizes' as the way forward. I think some of the points in this article talking about the fallacy of big data apply to genomics http://techcrunch.com/2012/11/25/the-big-data-fallacy-data-≠-information-≠-insights/Amithttps://www.blogger.com/profile/17374419504359860299noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-25960347661612980702012-11-30T12:16:21.500-05:002012-11-30T12:16:21.500-05:00In fact I’m a student in social anthropology but I...In fact I’m a student in social anthropology but I’m also strongly interested by life science and biological anthropology.<br /><br />Initially I already had an e-mail correspondence with your colleague Ken Weiss on this topic because I was “troubled” by some strange speculative assertions about rare variants on The Internet and as you said this is what you discuss here.<br /><br />And indeed I see that there is no scientifically determined about rare variants and even distribution of rare variants between populations and their possible consequences. And I also see that I have a lot to learn in genetics.<br /><br />Anyway I am grateful for the answers you have provided me.<br /><br />Sincerely<br /><br />PS: My real name is not Hans but Bruno, Ken Weiss also know my last name because as you probably already guess I prefer remain as anonymous as possible on the Internet.Hanshttps://www.blogger.com/profile/14577768541892325988noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-88779075621456263022012-11-30T11:40:27.181-05:002012-11-30T11:40:27.181-05:00P.S. You're a nonscientist, Hans? I'm im...P.S. You're a nonscientist, Hans? I'm impressed with how much effort you're putting into trying to understand this issue. Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-45217228938326987182012-11-30T11:35:26.983-05:002012-11-30T11:35:26.983-05:00No problem. I'll try to clarify at least how ...No problem. I'll try to clarify at least how I see this. Because there's no right answer to the definition of 'rare,' differentiating between SNPs and SNVs based on nucleotide frequency is semantics, not science. And, since African Americans don't represent the entire continent of Africa, it's impossible to know how well or poorly this sample, even as large as it is, represents the frequency of variants, rare or otherwise, in Africa. So, I'd not worry too much about this question, if it were me. <br /><br />We know that variation in Africa is greater than in Europe because of the age of the population. We know that new variants arise in every population all the time, presumably at the same frequency. We know that complex diseases are generally polygenic, and responses to environmental provocation, not due to single genes, or variants, rare or otherwise. I think that, therefore, it's not correct to draw the kinds of conclusions being drawn from these studies about susceptibility to disease, and that's the basic point we were trying to make in this post. Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-80897153433231750132012-11-30T11:19:37.868-05:002012-11-30T11:19:37.868-05:00Thank you again!
About the false equivalence &quo...Thank you again!<br /><br />About the false equivalence "SNV = rare variant" I think I was initially confused <a href="http://www.politigenomics.com/2009/07/snp-vs-snp.html" rel="nofollow">by this page</a>:<br /><br /><i>«A SNV is a private mutation while a SNP is a mutation that is shared amongst a population.»</i><br /><br />But unfortunately it gets worse, because by reading again <a href="http://www.sciencemag.org/content/337/6090/64.full.pdf" rel="nofollow">the Tenessen's study</a>, I realize that this study really states that African-Americans have more rare SNVs than European Americans <a href="http://img4.hostingpics.net/pics/974586SNV.png" rel="nofollow">see this graph</a>.<br /><br />So you really helped me to understand <a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11690.html" rel="nofollow">the present Nature's Study</a> but I still see a real contradiction with <a href="http://www.sciencemag.org/content/337/6090/64.full.pdf" rel="nofollow">the Tenessen's study</a>.<br /><br />So I think there's still an important thing that I don't understand and perhaps can you also explain me what I don't understand here.<br /><br />Naturally I know it's often difficult to explain simply to a non-scientist a complex scientific topic and I don't want to annoy you with my questions (I hope I didn't). So just in case I specify that if you don't have the time to answer me I will not be offended.<br /><br />Best regardsHanshttps://www.blogger.com/profile/14577768541892325988noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-39426437284816972712012-11-30T09:44:31.730-05:002012-11-30T09:44:31.730-05:00Glad if I helped! No, single nucleotide variants ...Glad if I helped! No, single nucleotide variants are simply sites that have been found to vary at any frequency, not only rare variants. <br /><br />The definition of 'rare' is itself variable -- 5, 3, 2 or 1%. And some rare variants are seen once and only once. And, age of the variant is not implied by the term, simply that more than 1 nucleotide has been seen at that site at least once. Age is determined separately.Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-46245418118553976472012-11-30T09:36:23.759-05:002012-11-30T09:36:23.759-05:00Thank you for your response Anne, it really helps ...Thank you for your response Anne, it really helps me!<br /><br />However I have a last question because I thought that SNVs are a kind of rare variants. But apparently they are not exactly the same thing. So as I understand the topic, SNVs are indeed rare but by the term "rare variant" (some) scientists mean "rare and recent" and/or "very rare" (rarer than the average SNV).<br /><br />But parhaps I'm entirely wrong.<br /><br />Anyway thank you againHanshttps://www.blogger.com/profile/14577768541892325988noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-75622434837729457682012-11-30T08:23:00.787-05:002012-11-30T08:23:00.787-05:00Thanks, Hans. I'll try to clarify. As I unde...Thanks, Hans. I'll try to clarify. As I understand it, the number of SNVs is indeed higher in African Americans, and not surprisingly, in both of these studies. In fact, both of these studies are reporting on the same data. But the proportion of rare or singleton variants is higher in European Americans, and the explanation is that this is because of the Out-of-Africa bottleneck. And, the Nature paper suggests, the recency of these variants means that a high-ish (14%) of them are potentially deleterious. That is, a higher proportion of rare SNVs in European Americans may be associated with disease. <br /><br />I hope that helps! And I hope that's right! Anne Buchananhttps://www.blogger.com/profile/09212151396672651221noreply@blogger.comtag:blogger.com,1999:blog-1812431336777691886.post-81122485946203972212012-11-30T06:34:19.042-05:002012-11-30T06:34:19.042-05:00Hello Anne
First sorry for my bad english and for...Hello Anne<br /><br />First sorry for my bad english and for my ignorance, because I'm quite confused here.<br /><br />Why?<br /><br />Because another study <a href="http://www.sciencemag.org/content/337/6090/64.abstract" rel="nofollow">(Tenessen <i>et al</i> 2012)</a> states that African Americans had<br />significantly more SNVs per exome than European Americans.<br /><br />I'm sure there's something I don't understand because of my ignorance. Can you explain the apparent contradiction of the results of these two studies?<br /><br />Thank you in advance!<br /><br />Best regardsHanshttps://www.blogger.com/profile/14577768541892325988noreply@blogger.com