Regulatory changes raise troubling questions for genomic testing:

By 6 October 2014, many laboratories in the United States must begin honoring new individual data access rights created by recent changes to federal privacy and laboratory regulations. These access rights are more expansive than has been widely understood and pose complex challenges for genomic testing laboratories. This article analyzes regulatory texts and guidances to explore which laboratories are affected. It offers the first published analysis of which parts of the vast trove of data generated during next-generation sequencing will be accessible to patients and research subjects. Persons tested at affected laboratories seemingly will have access, upon request, to uninterpreted gene variant information contained in their stored variant call format, binary alignment/map, and FASTQ files. A defect in the regulations will subject some non-CLIA-regulated research laboratories to these new access requirements unless the Department of Health and Human Services takes swift action to avert this apparently unintended consequence. More broadly, all affected laboratories face a long list of daunting operational, business, compliance, and bioethical issues as they adapt to this change and to the Food and Drug Administration’s recently announced plan to publish draft guidance outlining a new oversight framework for lab-developed tests.

Well, I don’t know. Is it a “defect”? Might be pretty convenient.

At least that’s what you’d think in relation to the latest height & genetics paper, Defining the role of common variation in the genomic and biological architecture of adult human height:

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Three things to note. First, Peter M Visscher (control-f in the author list) predicted this result ahead of time (i.e., x number of loci will explain y % of variation). Nice empirical validation of the theory. Second, in 2009 an interesting paper was published which showed that classical methods way outperformed genomics when it came to height prediction. I’m not sure that we’ll say that in 2019 at current rates of accounting for heritability via genomics. A lot of work needs to be done to make these results robust for prediction in most cases. But we might get there. Third, it looks that the largest height loci have about one magnitude larger effect than intelligence. Visscher was on the recent IQ and genomics paper which presented only a few valid SNPs. So that domain is far behind height. In the early 2000s I read Behavioral Genetics in the Postgenomic Era. It looks to me that that book (and James Watson’s introduction) will be seen to be a generation ahead of its times. Though I’d still recommend the book, as there’s a lot of information in there that it would behoove you to know.

It’s not a big secret that I’m a fan of Elon Musk. I’ve never met the man, but I have met people who have met him, and he’s the type of visionary that nerds would march to the gates of hell for. If you want to know what he’s not reputedly like, watch this pitch from the 1990s, Bill Gates, Future Vision: A Microsoft Plus Program from 1994. Gates’ “vision” has made him rich, and has changed the lives of everyone. He’s succeeded. But he doesn’t inspire in the way that Steve Jobs did. Musk differs even from Jobs. Apple makes beautiful and functional products which integrate seamlessly with our lives and improve them. Musk’s aspires to transform civilization. It’s no surprise that he read and endorsed Nick Bostrom’s Superintelligence (His friend Peter Thiel’s interest in these topics is well known). With that sort of fact in mind the recent piece for Aeon Magazine, Exodus: Elon Musk argues that we must put a million people on Mars if we are to ensure that humanity has a future, is not too surprising. Throughout the piece it’s obvious that Musk is haunted by Fermi paradox.

But there is one aspect, in the subhead itself, where I think Musk errs. He states: “Some individuals might be able to endure these conditions for decades, or longer, but Musk told me he would need a million people to form a sustainable, genetically diverse civilisation.” This just strikes me as wrong. My impression is that most people have incorrect intuitions as to the effect of a population bottleneck on genetic diversity. For example, the Black Death in Europe was not a bottleneck, because not enough of the population died off. A die off on the order of 30% is a tragedy, but it isn’t really a population bottleneck. What matters for genetic diversity is who reproduces, and it might not be implausible that in many organisms 30% of individuals within a given generation do not reproduce (this is why effective population which predicts the variation you actually have is always smaller than census population). Second, because mutation would take a long time to build variation back up after it is lost long term effective population is very sensitive to a bottleneck event. This is why despite our census size of 7 billion long term effective population for humans is closer to the range of 1,000 to 10,000. We went through bottlenecks in our relatively recent past.

One way to measure this genetic diversity that is rather straightforward is to look at heterozygosity. Basically it is the proportion of genotypes which are heterozygotes, that is, alleles are of different state at a locus. Heterozygosity is not the only measure of genetic diversity, nor the most informative, but it is a reasonable one to use for this sort of coarse question. At a single locus heterozygosity peaks when you have a random mating population with alleles segregating at comparable frequencies. So you have two alleles at 50% frequency (this for a diallelic SNP, obviously microsatellites are going to be different), and as per Hardy-Weinberg 50% of the genotypes will be heterozygotes. Because random genetic drift tends to shift the allele frequencies from these mid-points, and result in the extinction of particular variants, populations subject to more drift tend to be less heterozygous. And the power of drift is inversely proportional to population size. Small populations are subject to a lot of drift. So they lose heterozygosity.

The equation to the left can formalize this relation in the context of bottlenecks, where N is the population size, and t is the number of generations. The chart at the top illustrates some results plugging in some values. Basically you can see how a population crash of varying magnitudes and lengths impacts reduction in heterozygosity. Not only does the size of the bottleneck matter, but how long it lasts is also something we need to keep in mind. I don’t think a 50 generation bottleneck is realistic, but I wanted to include that to show you the effect. For the purposes of genetic diversity it seems that ~1,000 humans would be more than enough. Note that this assumes a random sampling from the total human population. On the one hand this means they are unlikely to be related. But it also means you wouldn’t “optimize” for genetic diversity. There’s no reason that Musk would need to sample randomly, and it seems unlikely for many reasons that he would.

Now, it could be that Musk is thinking of such huge population sizes because he wants a lot of variation from which one could select personality types that could flourish on Mars. Even then 1 million is definitely overkill. More plausibly you could select particular personality types, combined with the likely self-selection that would occur. Of course diversity does not matter just for genetics, it matters for culture. There are models which suggest that too small a population can result in cultural poverty, as ideas and skills are lost over time. I think the key to this is that the long term population needs to start growing soon so that more than one individual is the repository for a particular skill. Additionally, literacy and record keeping can allow for the preservation of certain types of knowledge. There’s going to be a lot of “trial and error” on Mars if human existence is sustainable, so I suspect organic growth from a small base will be critical. It isn’t as if we don’t have precedents for small founding groups. Apparently the millions of French Canadians in North America descend overwhelmingly from less than 3,000 founders. The founding stock for Mars is likely to be somewhat more diverse that this group to begin with.

Addendum: Also, I have a hard time believing that a Mars colony wouldn’t have super-advanced CRISPR-like technology, as well as extra sperm and eggs from un-sampled populations, if diversity is needed.

Raw results under the fold
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In an earlier post I mentioned that I was excited to get Xunzi: The Complete Text. But I won’t be reading it for a while, as right now I am in the midst of Armand Leroi’s The Lagoon: How Aristotle Invented Science. As might be predicted from Mutants, it’s beautifully written. Armand really has a way with prose, and he picks very engaging subject matters. As a biologist it’s no surprise that I’m a partisan of Aristotle when it comes to the ancients, so the topic is certainly congenial. In any case, I already recommend The Lagoon to any readers who have some time and energy to put into a book. It’ll be worth it at the end, and the writing is such that you’ll enjoy the endeavor.

Second, I want to make a few notes about comments. As most of you know I moderate comments. Many of you I know, and pre-approve, and many of you I do not. Just a few common sense pointers

1) Comments that begin with a gratuitous insult at me will probably not be published and you’ll be banned.

2) Comments which attempt to lecture me on something I already know about will probably not be published. I’ve been blogging for 12 years now and have written a lot of things about a lot of topics. Just because I don’t address something you think you know about in a specific post doesn’t mean I haven’t addressed it in the past. People on the internet think they are very bright, I get that, but you have to prove it here.

3) I’m good at recognizing elliptical comments which are trying to slip in something in a roundabout way. Just be direct, I don’t smile upon that sort of bashfulness.

When I went to New York last month I was very excited to be eating some Korean in mid-town with some friends. It’s probably my favorite cuisine overall at this point in my life, and has been for a few years. Serious Eats has an interesting article up on how it’s become so trendy, How Korean Cuisine Got Huge in America (And Why It Took So Long). One thing I would want to note is that I’ve been told by friends that Korean cuisine does have some serious regional variation. So we should perhaps be a little cautious about bracketing it all into one class. The seafood inflected fare of Busan is different from what you’ll find further north. I suspect my love of Korean cuisine is due to its very strong flavors. As someone who has something of a hot sauce addiction that’s the sort of thing I crave.

In the following post at Patheos the author reflects on the fact that her teenage daughter inherited her genetic condition, a predisposition toward very fragile bones, Can You Regret Having a Child Who Inherits Your Genetic Baggage?:

I want to be perfectly clear, though, about what I don’t mean. I hate those clichés about how we should be grateful for the shitty stuff in our life because it teaches us so much, about how “Everything happens for a reason.” I don’t believe that one bit.

But I’m beginning to understand that Leah’s inheritance from me is not merely a faulty gene and a fragile skeleton, but also the truest kind of compassion—the kind that arises when you know what pain looks like and feels like, and you recognize another’s need, and know just what to do.

Do I regret that Leah inherited my fragile bones? I don’t love it. I even sometimes hate it.

But while I sometimes wish I could have spared her that particular genetic fate, I’m also profoundly grateful that it was not in my power to decide what kind of kid I would get.

Because I never could have predicted, much less devised, the wounded and gracious person my daughter is becoming.

I appreciate that the author disavowed the clichés whereby parents of children with disabilities or illness reflect upon what a learning experience it was or is. But with preimplantation genetic diagnosis The author could indeed have predicted the outcome today, as opposed to 15 years ago. What would her choice be now? I suspect she would choose to implant only those zygotes which lack the mutation (it seems that it is an autosomal dominant). These are discussions we as a society need to have, and my hope is that the two sides avoid clichés and don’t attempt to shout the other side down. I doubt we’ll be doing much PGD for blue eyes or height, but lots of these sorts of congenital illnesses which are due to major deleterious mutations are going to disappear. Switching to normative mode, and the world will be a better place with less suffering

In about 12 hours I will have Xunzi: The Complete Text delivered to my Kindle. I’m very excited, because Xunzi is an individual who I very much admire for his insights, and, whose thought was extremely influential in Chinese history. Yet from just noting that unlike Confucius and Mencius he does not have a Latinized name, you can infer that his status and prominence is not as great as these two figures. One reason given is that his reputation declined in early China because of his influence upon the Legalist school. These were the ideological brains behind the first Chinese truly unitary imperial state, which collapsed due to its insufferable totalitarianism. But the case can be made that Xunzi’s thought lived on in the substance of what became “State Confucianism”, and would echo down to the early 20th century (in fact the modern Chinese Communist party seems to be resurrecting State Confucianism). Therefore, to understand Xunzi is to some extent to understand a system of social-political governance which maintained itself robustly over ~2,000 years. The continuity of the Han dynasty, 2,000 years ago, down to the Qing dynasty (the Manchus), which fell in the early decades of the 20th century, is such that a mandarin of the earlier period could at least comprehend the basic underlying foundations of the state the society in 1900. Imagine transposing a Roman senator to Italy in 1900.

The great antagonists of the early Confucians, and perhaps the polar opposite of Xunzi’s pessimistic and realist world-view, were the Mohists. Because we know of the Mohists mostly through the commentaries and recollections of their Confucian enemies we must be careful about assuming we know in exact details of what they truly espoused, but one of the clear issues where they seemed to differ from Confucians is that they held to a very flat and universal sense of human affection, affinity, and empathy. In contrast, the Confucians acknowledged that by their nature humans exhibited concentric circles of affinity, from the family outward. The details here may vary from society to society, but it strikes me that we must acknowledge that the Confucians were making peace with a fundamental reality of our evolutionary history as social apes whose lives revolved around different degrees of relations. The Mohist ideal of universal love has an abstract simplicity and Utopian attraction, but it can never serve as the basis of a well ordered society, as opposed to the guiding principle of very particular individuals who are distinctive from the rest of society (religions like Christian and Buddhism seem to make a nod to this when they allow for the creation of religious societies who notionally discard ties with their families and natal communities).

At the heart of Mohism was a great impulse. If compassion toward others is good, why not maximize compassion to all human beings? Why not? The abstraction is elegant in its plain and forceful logic. Ethical ratiocination of this sort is at the heart of works such as John Rawls’ A Theory of Justice or Robert Nozick’s Anarchy, State, and Utopia. But just as the simple elegant maxims of ancient Mohism were marginalized by the messier and less coherent, but more pragmatic, teachings of Confucius and his heirs, modern political philosophy tends to intersect only marginally with modern political policy and economy (actually, State Confucianism fused classical Confucianism with the practical statecraft of Legalism, while later Neo-Confucianism added a metaphysical element, stimulated and borrowed from Buddhism). The Utopian radicalism of Mohism though turns out not be an ancient Chinese novelty. Rather, it issues forth repeatedly in the human experience whenever millenarian Utopianism seems the only solution to the tragedies of the age. Christian radicals in 3rd century Anatolia, Protestant separatists, and the Lingayat movement all touched the same human impulse which resulted in the elaboration of Mohism as an answer to the anarchy of the age. And yet all these movements were tamed and made peace with the world as it is, engaging in evolution rather than revolution, incrementalism instead of overturning the order (social and religious movements which don’t make peace with reality are not long for this world).

Why is any of this relevant today? Because today we are arguing about the same things that the ancients did, and that our descendants will (assuming limitations on post-human transformations). It comes to mind when you read op-eds such as Markus Bergström’s in The Washington Post, Losing the birth lottery. Though a relatively mild and pragmatic case for open borders, it ends with this sentence: “While many opportunities in life are unequally distributed, our legal rights must always be universal.” This sort of universalism is deeply appealing to many. It leads to the emergence of trans-national ideologies, from Marxism to anarcho-capitalism in politics, and of course the world religions. These are systems of government and life which are true, and right, in all times and all places. They presume a sort of leveling of human existence, one way of flourishing above all. Though not as nakedly idealistic, the same mentality has been co-opted by the trans-national capitalist elites. The Wall Street Journal has been proposing open borders for decades, and the global elite sees no downsides in free flow of goods, people, and capital, all of which they can leverage and benefit off of. Prosaically these elegant models seem to overlook the reality of organically developed institutions in which markets and societies operate. To give an extreme example, adding 150 million Cantonese Chinese to Japan would change Japan in many ways which would have economic and social consequences. But rather than rehashing the scholarship on the benefits of social cohesion, it is important perhaps to suggest here that this universalist world-view forgets that humans differ, and that one system may not be beneficial in the same way to all.

Bergström’s logic could just as apply to families, as opposed to nations. Some people are born to families, and endowed with genetics, which give them greater opportunities in this world. Attempts to eliminate this problem, such as in Israeli kibbutzim, have failed. The original collectivist ethos of Black Bear Ranch commune in Northern California began to disappear once individuals began having children, and separating from the whole to create their own nuclear families. One of the ironies of scares over “family values” is that in reality you can push human social arrangements only so far before they veer back toward what is comfortable for us. State Confucianism succeeded, and was a robust ideological glue for the Chinese polity for 2,000 years, because it extended and modulated natural human impulses. It did not attempt to recreate humans de novo based on an abstraction. An elegant but thin fragment of ourselves can not stand against the windows of our deep evolutionary past.

But the tendency to push logic to its limits, beyond the normal range of human behavior and sentiment, is not a limited concern. I think it crops up in this Michael Brendan Dougherty piece, The troubling persistence of eugenicist thought in modern America. In The American Conservative Noah Millman responds:

My own view is that eugenic motivations aren’t suspect as such, but perfectly normal. They just need to be tempered with a whole lot of humility, the recognition that the fantasy of total control is and always will be just that—a fantasy—and the consciousness that if we can’t imagine the joy of the inner life of someone different from us (someone with Down Syndrome, someone deaf, someone gay, someone who sucks at tennis), that’s our problem, not an objective sign of their deficiency. And coercion in a matter as intimate as childbearing should have to clear a very high bar for justification—and I can’t imagine eugenic motivations ever legitimately clearing that bar. Bearing all that in mind, I don’t see what’s wrong with wanting to have the healthiest children we can, and doing what we can to get what we want. Including thinking about their genes.

A GATTACA scenario is not only unrealistic, but probably not a world most of us would want to live in. But there’s a long way between here and there. The Golden Mean is not an exotic or amazing principle, but a way to temper our noble idealism, and yet not be reduced to our most self-interested and basest instincts. The fact that the vast majority of parents would prefer that their children not have Down Syndrome does not mean that democratic majorities would today assent to sending Down Syndrome patients to the gas chambers. Slippery slope arguments are often interesting, but usually they are not relevant, because we as human beings tend to be able to quite easily anchor ourselves somewhere along the slope, balancing our intuitions, reason, and background. Speaking of which, Millman asks straightforwardly whether Dougherty issue isn’t with abortion, and that is a policy and ethical debate which is so polarized that it doesn’t reflect the true common sense perspectives of most humans. No matter what they say most pro-life people don’t think a first trimester abortion is equivalent to premeditated homicide of an individual which has been born and has an independent existence. And no matter what the likes of Amanda Marcotte claim, having an abortion is never going to be like going to the dentist to fill a cavity. No matter what some activists might wish for, but abortion will always have some stigma, just as it will likely remain legal (and is becoming legal in more, not fewer, jurisdictions). Developmental biology does not avail us of clean and simple solutions in this area. The fetus means more to us than a developing collection of cells, but it is not a full person in the sense that your neighbor is a full person.

Where this leaves us is that we need to go case by case, accept that there is some validity in meliorism, but also expect limits to Utopianism because of the modal human hardware/software package. Slavery was the norm among post-hunter gatherer societies for most of the past 10,000 years, but has been abolished over the past 100. Previous ethical-religious philosophies often suggested that it was an institution which did not elevate humanity, or allow society to fully flourish, but they understood that it was an unfortunate basic feature of human existence. But that necessary existence was only conditional on particular social-economic systems of production and organization. Once those systems began to loosen, total abolition could emerge as a viable and realistic option.* But more simple and elementary human realities are not so easily abolished or reformed. The family in some way seems to be a structure and unit which is necessary, and can not be eliminated, even if on the margins it can be modified into distinct and diverse forms. Human prejudices and preferences for particular sorts, whether it be the opposite sex (on the whole), or people of similar kind (whether it be racial, religious, ethnic, or class), are likely going to persist in some form because we are a “groupish” species. Not only have we flourished in groups, our cognitive architecture is geared toward multiple levels of sociality and familiarity. We will never flatten the chain of affinities.

Much of this is banal and obvious to most. But nevertheless it needs to be elaborated, because the commanding heights of our culture are assaulted by the propagandists of logic and reason applied in domains where feelings are preeminent. As David Hume asserted, “Reason is, and ought only to be the slave of the passions.”

* Note that some societies, such as Han Imperial China, tended to limit the prevalence of chattel slavery for various reasons, in contrast to others to which they are compared, such as Imperial Rome, where it flourished.

In general I’m not a big fan of shopping, possibly with the exception of books. As a typical American wedded to my smartphone to figure out anything about the world around me one of the things that really, really, frustrates me about supermarkets is that you always to situate yourself and puzzle out where the items you want are. Of course, this is part of the point, as supermarkets are designed to get you to purchase on impulse high margin items which are strategically located. It’s not a coincidence that the deli is usually in front, or that the ends of the aisles prominently display potato chips and other junk food. Of course many people go to the same store over and over, and so you know where to go. But every time you have to make it to a new supermarket the process of avoiding the bright crap pushed into your face starts all over again.

The problem is general to retail. If getting the customer to the items as fast as possible was the ideal then there would always easy to search map terminals. Or, retailers would long ago have agreed on relatively standardized layouts (obviously to some extent there is some homogeneity because of market and structural demands; produce is always at the edge, magazines are at checkout, etc.). To avoid this many of us are using AmazonAmazon or Google Shopping Express. And now this a resurgence of grocery delivery. Of course it isn’t as if online retail isn’t good at upselling things you didn’t intend to buy, but my personal experience is that Amazon often cross-promotes things that I would normally want to buy.

The future should be interesting.

U.N. Report Details ISIS Abuse of Women and Children
:
According to witnesses cited in the report, Islamic State fighters dumped more than 60 Turkmen and Yazidi children in an orphanage in Mosul after they had witnessed the killing of their parents by the fighters. “It appears some of the older children may have been physically and sexually assaulted,” the report notes. “Later, ISIL fighters returned to the orphanage and made the children pose with ISIL flags so they could take photos of them.”

In a barbaric pre-modern age the children would have been killed. So perhaps ISIS is not quite as 7th century as they like to proclaim. But the intersection of modernity, taking the photos, and barbarity on display here reminiscent of Rwanda more than anything else. But this is more worrisome to me:

The report said the Yazidi girl who was abducted by Islamic State fighters when they attacked her village on Aug. 3 was raped several times by different men before she was sold in a market.

“Women and girls are brought with price tags for the buyers to choose and negotiate the sale,” the report said. “The buyers were said to be mostly youth from the local communities. Apparently ISIL was ‘selling’ these Yazidi women to the youth as a means of inducing them to join their ranks.”

Sunni Arabs in Iraq and Syria do have rational self-interested reasons to align with ISIS, at least temporarily. The barbaric behavior meted out to Shia and non-Muslims is generally not something they have to worry about. Though there are impositions on their personal freedom, from the perspective of a Sunni Arab the erstwhile Maliki regime and that of Assad’s may not have been better bets. But not one forces you go to a slave market and buy slaves.

One of the weird things about the anti-vaccination movement in the United States is that though it is often perceived to be liberal, its political orientation is pretty mixed. Chris Mooney put up a long data filled post a few weeks ago detailing this, including citing some of my old posts looking at GSS data. In general what you see is that for many “anti-science” views the biggest correlate is being stupid, not being liberal or conservative. Basically the less intelligent/educated/wealthy are more suspicious of “book learning,” and that includes science.

But the perception that anti-vaccination sentiment is liberal isn’t coming out of thin air. The issue is that a small and motivated culturally prominent social sector on the Left is promoting this viewpoint, out of proportion to its numbers and policy heft. By the latter, I mean that the liberal political establishment arguably has less sympathy with anti-vaccination sentiment than some of the more conspiratorial Tea Party people on the Right (though I guess Robert Kennedy weighs against that point). Less tendentiously, anti-vaccination sentiment is just plain counter-cultural, and has little traction among the political elites. In California anti-vaccination sentiment as reflected in lower rates of inoculation seem correlated with affluent liberal enclaves. But I stumbled on a more shocking illustration. Number of Marin children without vaccinations continues to grow; health officials worried:

And the rate is much higher than that at some Marin schools. At The New Village School in Sausalito, 14 of the 19 students entering kindergarten in 2012-13, 74 percent, exercised the personal belief exemption. That same year at the Greenwood School in Mill Valley, 14 of 21 incoming kindergartners, 67 percent, used the personal belief exemption. And at San Geronimo Valley Elementary in 2012-13, 13 of 29 kindergartners, 45 percent, avoided vaccinations using the personal belief exemption. Officials at the schools declined to comment.

These are very small numbers. The overall rate of lack of vaccination for young people seems be 7 to 8 percent in the county as a whole (not trivial, since that’s the on the edge of what researchers feel is necessary for “herd immunity”). But I was curious about these schools. The Greenwood School has a tuition of $20,000 per year. New Village is $16,000 per year. San Geronimo Elementary seems to be a public school, but it is notable that the Wikipedia entry references the liberalism of the citizenry.

As I noted above if a large enough fraction of the population is vaccinated then that confers herd immunity. Assuming that 93 percent or more of the population is vaccinated is there any material benefit from avoiding vaccination? Obviously there is the issue with discomfort. My children screamed like the dickens when they were first vaccinated. But I do assume that there are rare cases when vaccination actually does cause problems. A friend of mine from when I was younger died of an allergic reaction to the Anthrax vaccine when he was being inducted into the military. Apparently a small number of deaths can be justified by the greater good in this case.