Why have sex?

On the origins of meiosis.

Of the many innovations that occurred during the evolution of eukaryotes, one of the most mysterious and powerful was the development of meiosis and sexual reproduction. A paper from a few years back delved into how this process might first have started, given that it depends on several complex innovations. (And another paper more recently).

But first, why is sex so durable, evolutionarily speaking, resulting in an Earth where all large, complex life forms engage in it? The costs are quite severe, after all: partners must be found, which can be a particular trial for sessile plants, corals, etc.; selection for fitness can be waylaid by mate selection and other sexual games; Parents give up half their genes in creating each child, compared to creating complete copies as they would by traditional, clonal reproduction; likewise a sexual population has to have males, which double the resource needs compared to a clonal population where every member is functionally female.

The answer lies in population genetics. A clonal population, such as most bacteria, can generate mutations and adapt to external conditions. The development of antibiotic resistance is notorious. But evolution is a parallel process, where the whole population is tested, and many variants are more or less successful. Everyone has deleterious mutations mixed in amongst the beneficial ones, especially since they are always more numerous. So in a clonal population, any good mutation that occurs will be trapped in its current genome and have to compete against all the other clones with all their good and bad mutations. Another good mutation will have to fight the same battle, without the chance to team up with the first one, unless the first one has already taken over the population. This way many beneficial mutations are lost, especially those with weak effects, which are the majority, naturally.

Even worse, bad mutations tend to pile up in each clone lineage, since there is no way to get rid of them. Each mother gives the full complement of her mutations, both inherited and those that happened during her life, to her offspring. In humans, we accumulate about 175 mutations per individual before reproduction, of which roughly 1 or 2 are detectably deleterious. While astonishing repair processes have evolved to keep such errors to a minimum, there are always some, and in a clonal lineage, they are always building up, despite the ongoing selection against those which add up to worse than average problems, a process termed "Muller's ratchet".

What happens in a sexual population? Well, it is critical to realize that it does behave much more like a population- an evolutionary village, so to speak- than as competing clonal lineages. Individual alleles are recombined around and mixed up among offspring, so that there is far more diversity within the population, which allows, stochastically, for good mutations/alleles to come together in some offspring, and deleterious mutations/alleles to come together in others. Given selection where the latter die and the former flourish, the system enables far more effective use of the opportunities provided by mutations throughout the population then clonality does.

The autobiography of Julius Erving, "Dr. J", provides a graphic example. He is extraordinarily gifted in all respects, including writing. Yet his brother Marky was sickly and died very young. The difference is tragic on a human level, but routine on a genetic level. Embryos with especially deleterious alleles will frequently die before birth, hiding the true rate of this genetic "sweeping" mechanism.

Sex is so powerful that bacteria have developed several mechanisms for doing it on a small scale, such as extending pili to partners so that they can exchange limited amounts of DNA. This how antibiotic resistance spreads around so quickly, and helps bacteria exchange out some of their accumulated mutations by homologous repair, (which is common among all organisms), though at the cost of bringing in parasitic DNA elements like transposons and viruses. But bacteria have never developed the full monte: fusion of whole genomes with total remixture and sharing out to subsequent progeny, let alone obligatory sex before reproduction. Eukaryotic sex involves the fusion of complete, haploid genomes, which recombine pervasively, both by way of the independent assortment of whole chromosomes and by smaller sub-chromosomal recombintation events, to create unique, new haploid genomes, which are then sent out as new gametes.

Bacteria share small amounts of DNA though conjugation pili.

The rise of this process is a bit hard to understand because there are several complex events needed, none of which make immediate sense by themselves. First is the meiotic division, which uses most of the tools of normal mitotic cell division, plus some more (suppression of sister separation in the first division and then suppression of DNA replication in the second division) to turn a diploid genome into a carefully reduced haploid gamete genome. Second is the part of the process called synapsis where all chromosomes from the two parents align along their full length. Third is the recombination that is obligatory between these homologs in order to keep them attached at initial stages, and to interchange segments of the respective genomes. This is not to mention the fusion of gamete cells and other perphernalia of sex, which are less innovative from a molecular, and probably evolutionary, standpoint.

Basic model of meiosis, in comparison to mitosis.

The proposal made in this paper, by a luminary in the field, after whom the Holliday junction is named, is that synapsis of homologous chromosomes may have been the leading event in the development of meiosis and sex, and is understandable as a solution to a completely different problem. Quite apart from the recombination that happens when bacteria encounter DNA coming in from other cells, homologous recombination also happens after replication and before division to repair damage, of which replication is a frequent cause. But one of the hallmarks of eukaryotes is size- big cells and big genomes- they are the SUVs of cellular biology. As genomes grew, the chances of making an error in this internal recombination, with all the repetitive DNA and duplicated genes lying about, grew rapidly as well, and posed a serious danger of creating new damage. This led to the preferability of setting up a whole-genome alignment process, i.e. true synapsis, and confining it to the inverval between replication and division.

"To sum up, we propose that the selection pressures for homolog synapsis and the origins of meiosis were to improve recombinational accuracy and to restrict it to a safe interval, while retaining its short-term (repair) benefits. A cell lineage that had evolved this capability for diploid cells would be less error-prone in transmitting its genetic material."

In the original setting of haploid, single cells, as the first proto-eukaryotes undoubtedly were, this would have revolutionized post-replication homologous DNA repair, making the process far more systematic and reliable. Indeed, eukaryotes still have their DNA aligned during most of the cell cycle, though not in the elaborate synaptonemal complex now found in the first phase of meiosis. Since these organisms were not dipoid, but habitually haploid, the subsequent division would have already resembled the second division of meiosis, back to the haploid state.

"In principle, the molecular evolution of a new cohesin molecule that specifically promoted homolog pairing might have provided the crucial trigger for meiosis."

The next step to true sexuality by this model were to adopt the practice of mating between separate cells (which could have been related to the partial genetic exchange common among bacteria) to generate a diploid where truly different alleles over entire genomes are combined in one cell. While this could have worked on its own, (and exists today as parasexual cycles in fungi, where reduction back to a haploid set of chromosomes is more or less random), the addition of DNA replication, as well as synapsis and recombination as above, at this step would have necessitated a special variant of mitosis to become the first (reductional) division of meiosis, whereby the replicated homologs from the two parents align in a novel four-chromosome bundle and each segregate precisely in half, though with random polarity, prior to a second division.

"In many unicellular eukaryotes, haploid sex-cell fusion leads promptly to nuclear fusion, which immediately triggers meiosis, thus regenerating the haploid state. In contrast, in more complex, multicel- lular eukaryotes, meiosis is greatly delayed following the initial fusion of sex cells, taking place much later in the life cycle, during gametogenesis."

Subsequently, organisms would adopt the diploid state as the organismal default (not so difficult in microorganisms), which has powerful effects on genetic diversity, since it allows recessive alleles some breathing space to survive and even to fill strategic niches in the population. With the advent of multicellularity, the meiotic divisions could be re-scheduled to now-vestigial haploid cells as part of a special gamete generating process. Clearly there is a lot to chew on with this model, and a need to flesh out and gather evidence to support the many inferred steps. But it is a highly interesting idea for the stepwise development of a process that is now notoriously complex on the molecular as well as all other levels.

A problem, however, is that modern eukaryotic cells, though they use aligned sisters in a highly regulated fashion for post-replication DNA repair, do not use anything like true synapsis. That makes it difficult to suppose that synapsis ever played a role in this process, or that it was the leading element of the other steps of meiosis. One might counter that haploid cell fusion with para-sexual reduction was perhaps the first step in the sequence, (possibly even originating in a predatory setting), after which the development of replication, synapsis, diploidy, and the special homolog-separating division of meiosis I were developed to better clean up the mess. Anyhow, next week, we will delve into another theory about the origins of eukaryotes.

Overall, sex is a machine for speeding up evolution, generating a quantum leap of accessible genetic diversity within a species / population that allows bad genes to be left behind without discarding everything else in those genomes, and good genes to be concentrated in the winners. Do individuals benefit, or their genes, or the species as a whole? There is an element of group selection intrinsic to this rationale for sex, since the benefits accrue down the line to the genes of the species and the species as a whole, not to the individuals involved now, especially not those stuck with the short end of the genetic stick.

• An unusual meiotic short-circuit & genome mixing pathway in yeast cells.
• Women, and women's work, are not highly valued. Another lesson in the social construction of pay decisions.
• Seniors (and the rich) are doing relatively well, at least vs young workers afflicted by a terrible job market. "I suspect that most Fed policymakers receive relatively little input on the economy from people who are younger than 40."
• Does the US have any place for lower class workers?
• Or does it have the education and institutions to take them to a higher class?
• Mainstreaming MMT.
• Repression is hard work, and Trump, a relief.

Keynes Would be Spinning in His Grave

If he could see what is going on in the Euro Zone.

There are deep structural and policy problems in the Euro Zone which have prevented or muted its recovery from the recession. The policy problem, similar to ours, is a lack of stimulus spending to put an end to general deflation and recession. The structural problem is that the individual countries, while sharing the same monetary unit, can not adjust their levels of general economic activity relative to each other, or have independent monetary policy, except through trade. And their trade relationships are hopelessly unequal, with Germany in the lead, and the peripheral countries like Greece and Spain uncompetitive, at least in fixed Euro terms.

While the going was good, Germany was willing to lend the money which flowed in through trade back out to the southern and peripheral countries. But these were only loans, not fiscal transfers as would happen in a  more integrated country/zone. So then we had the drama of creditors asking for the money back, arranging for debt forgiveness, bailouts, etc., all when the debtor countries were on their knees.

In essence, the Euro Zone operates like an old-fashioned gold standard international system. A common unit of exchange and value is kept stable across supposedly independent countries which each have their own policies of trade, employment, corruption, public services, etc. This unit is not really shared out from the central bank on a per-country basis, let alone to correct specific trade imbalances, but generated in response to economic growth in sum across the whole zone, managing issuance and interest rates with the overarching goal of low inflation (since the Germans are running the ECB, more or less). Thus each country needs to accumulate what is to them a fixed unit of exchange through trade, lest they run into chronic debt to the other countries. Each country is moreover on the hook for its various economic disasters like insolvent banks, unemployment, and social unrest.

Here is what Keynes wrote about this kind of system, as opposed to a system of floating exchange between sovereign nations:

"Never in history was there a method devised of such efficiency for setting each country's advantage at variance with its neighbours' as the international gold (or, formerly, silver) standard. For it made domestic prosperity directly dependent on a competitive pursuit of markets and a competitive appetite for the precious metals. When by happy accident the new supplies of gold and silver were comparatively abundant, the struggle might be somewhat abated. But with the growth of wealth and the diminishing marginal propensity to consume, it has tended to become increasingly internecine."

"I have pointed out in the preceeding chapter that, under the system of domestic laissez-faire and an international gold standard such as was orthodox in the latter half of the nineteenth century, there was no means open to a government whereby to mitigate economic distress at home except through the competitive struggle for markets. For all measures helpful to a state of chronic or intermittent under-employment were ruled out, except measures to improve the balance of trade on income account."

".. those statesmen were moved by a common sense and a correct apprehension of the true course of events, who believed that if a rich country were to neglect the struggle for markets its prosperity would droop and fail. But if nations could learn to provide themselves with full employment by their domestic policy (and, we must add, if they can also attain equilibrium in the trend of their population), there need be no important economic forces calculated to set the interest of one country against that of its neighbors. There would still be room for the international division of labor and for international lending in appropriate conditions. But there would no longer be a pressing motive why one country need force its wares on another or repulse the offerings of its neighbor, not because this was necessary to enable it to pay for what it wished to purchase, but with the express object of upsetting the equilibrium of payments so as to develop a balance of trade in its own favor. International trade would cease to be what it is, namely a desperate expedient to maintain employment at home by forcing sales on foreign markets and restricting purchases, which, if successful, will merely shift the problem of unemployment to the neighbor which is worsted in the struggle, but a willing and unimpeded exchange of goods and services in conditions of mutual advantage."

One might add that this need for markets and trade also drove European countries toward colonialism which was so destructive, especially in the latter phases as laggards like Belgium, Italy and Germany got into the game. It is a wonder (of a negative kind) how, eighty years after Keynes's lessons were introduced in response to the Great Depression, and after several postwar decades during which they were put to such prosperous use, we, and especially his own continent, are struggling in the mire of older orthodoxies that he had laid to rest. I was about to note that we can at least be thankful that none of the current leaders advocate a return to an actual gold standard, but that turns out to be incorrect.

• How is the European Union doing generally?
• Trade plus redistribution.
• The Fed: is OK with continued unemployment, cont.
• Have you been left behind?
• Protest and diversity in Saudi Arabia - ends unhappily.
• Regulation remains important, despite corruption.
• Yes, education spending works.
• This occupation must end.
• Meanwhile the occupation of the Senate by retrograde do-nothings must also end.
• What happens when the Donald finds a mic.
• The species of our debt.
• Can we give half of the earth back to nature?
• Economic graph of the week. Not just wages, but benefits as well have dropped for the poor, while each has risen for the rich.

Shark Tank

Laissez-faire is a system of predation.

A few years back, I scanned through the TV listings and saw a show called "Shark Tank". Sounds nice.. one of those discovery channel nature shows, right? No, it turned out to be a celebration of cut-throat business, a reality show where many are called, few are chosen, and the rest are fired. Capitalism is a system of many faces and contradictions, but a central one is that while competition sometimes gives the consumer a better deal, the same competition also generates criminal activity, corruption at business and government levels, inefficiencies, conspiracies against consumers, and other antisocial effects, on the system as well as on individuals.

Take the sub-prime lending fraud that led to the recent recession. Mortgage lenders and brokers showered money on poor and uninformed purchasers who were pleased to find that they could afford far more house than they thought, virtually no questions asked. Who cared if the ultimate rate was a bit high or the balloon payment unimaginable? These mortgages were sold on to other suckers in an unvirtuous circle that sent millions of homeowners into bankruptcy and bondholders into insolvency. At the heart of this process were fraudulent practices that threw legal and underwriting standards to the winds so that the immediate mortgage lenders could make a quick killing, in return for lying to their clients about their ability to fully afford what they were buying, and for lying to their mortgage bundlers and buyers about the quality of their underwriting.

In advertising, fooling the customer is the standard of practice. Health insurance is a constant battle against adverse incentives. Buying a car is notoriously assymetric. Political corruption by companies and the rich buys favored treatment for them and unfavored treatement of the little people. Lying about the risks of smoking, or the reality of climate change ... the list goes on endlessly. The problem is that while the justification for capitalism, private enterprise, and laissez-faire relies on its efficiency and ultimate good services, embedded within that system is quite another system of brutal predation. While wolves would never represent to the moose that they are interested in its welfare and have some really great long-term care insurance to offer, the human economy runs on putative offers of service that all too often turn out to serve the servers much better than the recipients.

That, of course, is why regulation exists; to keep the knowledgeable from taking advantage of the rubes. One can rely that every time a Republican or libertarian bleats about the horrors of government regulation, they are shilling for business practices that belong on the predatory side of the ledger. Milton Friedman and his fellow prophets of laissez-faire were always careful to choose examples of appalling government corruption (communism, most commonly) to set against examples of efficient and competitive private enterprise. But corruption is possible everywhere. The 1% are set upon by private predators of their own, such as Bernie Madoff and the whole financial wealth management industry, more or less. Donald Trump exemplifies the type as well- a salesman suckering a succession of banks and investors into deal after deal, some of which turn out well, but more of which are losers, or even end up in bankruptcy.

On the other end of the spectrum, the destitute and disabled are cast out of this ruthless system entirely, homeless and on the street, forced upon the charity of those with a modicum of compassion, certainly not those at the top of the food chain who are preoccupied with finding their next unwitting meal.

How should we view this system? On the one hand, the "job creators" insist, with the fawning support of their endowed minions in academia, that they are the risk-takers and wealth creators. It is their phenomenal productivity and accumen that deserves the hundreds of times higher pay than other workers. But at the same time, is obvious that high pay, like that in the financial industry, for example, is able to extract for the priviledge of handling our money, involves virtually no societal benefit. The purveyors of 401Ks are right this minute fighting tooth and nail against being held to a fiduciary standard of service, because this would inhibit them (slightly) from stealing as much money from their marks as they have up till now. The financial industry in particular is the exemplar of competition without remorse, soul, or point, its sole justification being that they are the ones who control the sluices of money.

Likewise, CEO pay scale is clearly more related to how compliant the board is than how well the person or company performs. It also relates to the size of a company, which leads to a mania for acquisitions and debt, even if the business gets impaired in the long run. Pay relates to power much more than to productivity. Even the most morally upright get caught in the vortex heading to the lowest denominator, due to Greshams' dynamic, where the race goes to those most willing to bend and break the law (or have it changed by Congress!), forcing everyone else in the business to adopt the same practices or lose out. Regulation is the key bulwark against this dynamic, helping good businesses and good practices prosper.

But the problem of complexity and traps for the unwary exists at all levels and in government as well. The destitute are mired in a swamp of government programs that require offices to be visited, forms to be filled out, and rules to be observed, often far beyond their capability. It takes a PhD to do one's taxes. The expectations placed on regular citizens to nagivate through the mazes of modern society, including those of red tape and of business predation, can be overwhelming. Thus the society becomes, in toto, a competitive and dispiriting rat race where getting some kind of leg up, whether through family money, credentials, native intelligence, ruthlessness, charm, union or other organizational affiliation, or a particularly nefarious business plan, is the name of the game. Granted, the system in the US is far more civil, lawful and regulated that those elsewhere, such as Russia. But it still diverts far too much effort towards unproductive ends, rewarding antisocial behavior directly, and requiring everyone else to be on their guard with constant vigilence.

It can be granted that competition is pervasive in any case- in politics, in personal life, in the market for mates. There is no way to make life into a utopia of free love. The trend of human civilization and political philosophy, however, is one of reducing predation progressively. At first we put up with any kind of despot who could protect us from outside predators- i.e. the other despots. Then we came up with Magna Cartas, laws, justice, as ways to reduce predation inside the society, holding the rulers within some bound of decency. Next came democracy and civil services, which definitively put the reigns of power under popular control rather than the winners of a dynastic or military competition.

These have been great advances in making our societies more just and less subject to the baneful effects of total struggles for power. And these democratic states have over the last couple of centuries also made great strides in limiting & regulating the natural competitive forces pervading the rest of society, especially the private sector, to serve those whom we (collectively) want them to serve, rather than themselves. This project has taken an enormous step backward over the last couple of decades, under the ideology of laissez-faire. Predators were unleashed at all levels, and the result is the astonishing inequality from bottom to top that we see today. And contrary to its proponents, this regression has not served the overall economy or the middle class, which are sputtering and anemic.

Worst of all, this regression has corrupted our democracy itself. Donald Trump is ultimate expression of a system which does not attract its most talented members to political service, and whose elected officials depend utterly on begging the wealthy and corporations for their sustenance. We have seen the B-team in this campaign, and it has not been pretty. The voters seem to agree that the system must be blown up. But how and to what end?

Obviously raising consciousness about the bizarre defenses of the predatory system within the larger system is one place to start, which Bernie Sanders is doing so well. Republicans and Chicago school economists who sing the praises of freedom of organization for the employer and feudalism for the employee are, on the other hand, part of the problem. Then comes stronger regulation on behalf of workers and consumers. But above all, the political system has to be made safe from corruption by private and corporate interests. Right now it is open season. Trump himself crows about how his past political contributions were strictly business, nothing to do with good policy or public interest, but purely about access and corruption. And these kinds of statements have lost their ability to shock.

Many schemes for public funding of the political system have been advanced and work elsewhere. We could set up something like giving each voter a fund of golden credits, say $200, to contribute to any campaign at any level. This would add up to $60 billion, which is just a guess about how much the political system costs, in terms of elections. The credits would only turn into real money when given to a registered political candidate, with the money itself coming from the federal government, as part of the tax system. Secondly, public official contacts with private entities such as unions, corporations, and officers thereof, would all have to be strictly on the public record, such as in open hearings or other meetings, or in written form.

Such steps in our political system would help decouple it from the predatory private sphere as well as raising its level of transparency and fairness. That would in turn enable it to more seriously serve its constituents by progressively regulating to reduce the costly and unjust predatory aspects of the private sphere.

• Cooperation is risky, so making it pay off better through fair social policy fosters more cooperation generally across a society. Encouraging predation and victimization has the reverse effect.
• How it works in Norway.
• Pay and productivity... where is the relation?
• 401Ks are, and were designed to be, a disaster.
• The evolutions of the GOP.
• Does the economy have capacity to grow?
• Then let's do it. " .. the one policy that nearly all economists are confident will always have traction on nominal demand."
• Bill Black on control fraud and intimidation at the federal home loan agencies.
• Corruption just begets more corruption.
• Democrats and Keynes. Where are they?
• Labor mobility... is lower when effective unemployment is high, and wages are not rising.
• Here's someone who probably pays no income taxes: Donald Trump.
• The Afghan government keeps losing.
• IBM is dying.

Diamonds in the Junk: Medically Important Sites in Intergenic Regions

Finding human genomic variants that are relevant to disease, in regulatory regions.

The human genomes remains a complicated place, and to simplify its study, many researchers and medical screeners stay in the shallow end- the coding regions or "exome", which comprises what is transcribed from protein-coding genes. But there is much more in there, from the introns and other critical elements inside and near genes, to regulatory elements spread over millions of basepairs around their target genes, to junk DNA with no function known at all, yet.

A recent paper offered an improved analysis of these large intergenic regions, and claimed to find medically interesting mutations. The issue is that the vast regions surrounding genes are largely what could be called junk DNA, with occasional quite small and variable regulatory sites that are difficult to find. So mutations are frequent, yet most have no effect. Figuring out which might have medical significance is one of those finding-needles-in-haystacks problems. And doing it over a whole genome to an informative level is unprecedented.

Example of a mammalian genomic region (A) featuring 700,000 bases between neighboring genes. The genes are grey: Nom1, Lmbr1, Rnf32, Shh, Rbm33, Cnpy1, and En2. In color are various regulatory sites (enhancers), coded by their location and the region (B) where they activate gene expression of Shh in a mouse embryo. It is noteworthy that Shh is driven by enhancers lying throughout the intergenic region, and even within the Lmbr1 gene, 850 kbp away.

The researchers start with a few genomes from five people who have allowed their data- genomic and medical- to be used in the public domain. The other starting material is knowledge about 657 DNA-binding transcription regulator proteins, which is about half of all the regulators known in humans; especially what kind of DNA sequences they tend to bind to. Then they add in a phylogenetic conservation analysis of 33 other mammals, which allows them to find putative regulatory regions and sites in their human genomes.

The procedure is then to comb each genome, asking which probable sites in the vast non-coding areas differ from the average or reference human genome. And then of those, which sites are conserved with respect to chimpanzee and other species, indicating that the site is significant over evolutionary time, but was mutated in the person whose genome is being studied.

The innovative part of their analysis, aside from the scale being attempted in terms of numbers of sites, merging of evolutionary and regulatory binding pattern methods, and whole genome coverage, is in their statistical treatment. The object at this point was to describe the various mutated sites that were found in terms of possible medical or biological significance. This routinely depends on the annotation of the nearest gene, which would be the regulatory target and confer whatever ultimate function the site has. It has been customary to address only regulatory sites close to genes, since the demarcation from one gene's regulatory region to its neighbor's is not yet easily predictable from the gnome sequence alone.

Parenthetically, one can note that this demarcation is performed by "insulators". These nucleo-skeletal-tethered sites in the intergenic DNA are bound by specific proteins that form boundaries which keep nearby genes regulated independently. They are under study and will be the subject of a future post.

A second problem is that, if one does range widely over the intergenic spaces to look for relevant mutations and biologically significant sites, it can be statistically hazardous to equate the sum of annotations from huge regions (which tend to surround developmentally important genes, for instance) against the necessarily smaller sets that would come from regions where genes happen to be close together. A correction for the size of the sampled area is called for. These researchers have constructed tools that specifically correct for these and other issues, and sample up to two megabases of intergenic DNA. Their rule is that a gene's core region is 5,000 bases upstream and 1,000 bases downstream of the site where its transcription starts, and everything up to a megabase on either side, or to the core region of the next gene, is fair game for finding associated regulatory sites. This is a rather broad zone, but can only be improved once the insulator sites are better defined.

Since the three billion base human genome contains roughly 22,000 genes, there is an average of 136 kilobases per gene. So a two megabase bound per gene, while large and perhaps sometimes not capturing the largest possible extent of a heavily & diversely regulated gene, should easily capture most regulatory regions and cover most of the genome.

Cranking through the whole analysis, they come up with specifically enriched annotations tied to genes whose conserved regulatory regions have suffered detectable mutations, in each of the five people (acronymized as CoBELs). And the question is whether these annotations match the respective medical histories and problems. With only about 5,000 to 6,000 sites found for each person, these researchers are probably only scratching the surface of genomic variation, picking the very easiest fruit off this tree. It is thus is important that their data come up with significant matches, since if this data is not significant, more and deeper data is unlikely to be any better. And this is what they claim to do.

Outline of results from five individuals, correlating regulatory variants from this whole-genome analysis with their medical syndromes.

The total numbers of variant sites that were flagged by this analysis was:

• Stephen Quake: 6,321
• George Church: 5,291
• Misha Angrist: 5,775
• Rosalynn Gill: 5,861
• James Lupski: 6,447

Thus they come up with statements like:

"Prominent in Stephen Quake’s medical records is a family history of arrhythmogenic right ventricular dysplasia/cardiomyopathy, including a possible case of sudden cardiac death. Strikingly, when Quake’s set of CoBELs is analyzed using GREAT, the top phenotype enrichment (using default parameter settings, optimized for inference power in the original GREAT paper) is “abnormal cardiac output” (57 CoBELs, false discovery rate Q = 1.69 x 10−4). This enrichment is suggestive of susceptibility to heart diseases responsible for reduced cardiac output. Meaningful associations between CoBELs and personal medical records are in fact observed for all five genomes" 

"For example, 33 genes in the human genome are annotated for “abnormal cardiac output”. Their GREAT assigned regulatory domains cover 0.45% of the genome. Of the 6,321 Quake CoBELs, 28 (0.45%) are expected in the regulatory domains of these 33 genes by chance, but 57 CoBELs, over twice as many, are in fact observed." 

"The top enrichment for George Church, who suffers from narcolepsy, is “preganglionic parasympathetic nervous system development” (23 CoBELs, Q = 1.18 x 10−4). The autonomic nervous system is strongly suspected to be involved in narcolepsy. Misha Angrist, whose personal reporting indicates possible keratosis pilaris, a follicular condition manifested by the appearance of rough, slightly red, bumps on the skin, has “epithelial cell morphogenesis” as his top biological process enrichment (60 CoBELs, Q = 1.38 x 10−5)."

This analysis provides something that has been a dream up till now- a way to rigorously evaluate whole personal genomes, not just the coding areas, for medically relevant mutations. There is far more to do, since the 657 DNA binding regulators and their sites are far from the only action in town. There are more functions hidden in the intergenic DNA, like epigentic marks and non-gene transcription units. But this is a very promising start that can be scaled up and added to retail-scale analysis of anyone's fully sequenced genome, not only finding syndromes and weaknesses before they appear for individuals, but also helping the medical research enterprise find disease-causing mutations and pathways.

• Butterfly wings evolve by enhancer shuffling / variation.
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• Speaking of insularity, if orthodox economic models are wrong, why keep using them?
• Romers, Keynes, Freidman. And more on Keynes- imbeciles and delirium.
• Piketty on the Eurozone.. it is a mess.
• Example: Finland.
• Globalization, trade, and World War 1.
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• The deeper psychology of Bernie.
• The Russian model for Syria: Chechnya.
• Clinton, State, and the IG.
• Carbon taxes work.