Oxford Nanopore finally giving hope to biologist’s dreams

I don’t talk too much about genomic technology because it changes so fast. Being up-to-date on the latest machines and tools often requires regular deep-dives right now, though I believe at some point technological improvements will plateau as the data returned will be cheap and high quality enough that there won’t be much to gain on the margin.

Of course we’ve already come a long way. Fifteen years ago a “whole human genome” cost on the order of billions of dollars. Today a high quality whole human genome will run you on the order of $1,000. This is fundamentally a technology driven change, with big metal machines automatically generating reads and powerful computers to process them. One couldn’t imagine such a scenario 30 years ago because the technology wasn’t there.

I’ve stated before that I don’t think genomics fundamentally alters what we know and understand about evolution. At least so far. But it is a huge change in the domain of medicine. Cleary the human genomicists, especially Francis Collins, overhyped the yield of the technology in relation to healthcare in the 2000s. But with cheap and ubiquitous sequencing we may see the end of Mendelian diseases in our lifetime (through screening and possibly at some point CRISPR therapy).

This has been driven by technological innovation in the private sector around a few firms. The famous chart showing the massive decline in the cost of genomic sequencing over the past 15 years is due in large part to the successes of Illumina. But, Illumina has also had a quasi-monopoly on the field over the past five years (or more), and that shows with the leveling off of the decline in cost. Until the past year….

What gives? Many people believe that Illumina is moving again in part because a genuine challenger is emerging, or at least the flicker of a challenge, in the form of Oxford Nanopore. Oxford Nanopore has been around since 2005, but it really came into the public eye around 2010 or so. But like many tech companies it overpromised in the early years. I remember skeptically listening to a friend in the fall of 2011 talk about how quickly Nanopore was going to change the game…. I didn’t put too much stock into these sorts of presentations to hopeful researchers because I remember Pacific Biosciences making the same sort of pitch to amazed biologists in 2008. Pac Bio is still around, but has turned out to be a bit player, rather than a challenger to Illumina.

But I have to admit that Nanopore has really started to step up its game of late. Probably one of the major things it has accomplished is that it’s made us reimagine what sequencing technology should look like. Rather than refrigerators of various sizes, Oxford Nanopore allows us to imagine sequencing technology which exhibits a form factor more analogous to a USB thumb drive. The first time I saw a Nanopore machine in the flesh I knew intellectually what I was going to see…but because of my deep intuitions I still overlooked the two Nanopore machines laying on the workbench in front of me.

Despite their amazing form factor, these early Nanopore machines had limited application. They didn’t generate much data, and so were utilized by researchers who worked with smaller genomes. Scientists who worked with bacteria seem to have been using them a lot, for example. Additionally the machines were error prone and people were working out their kinks in real time in laboratories (one tech told me early on they were so small that he swore they were affected by ambient vibrations so he found ways to dampen that source of error).

A new preprint suggests we may be turning the corner though, Nanopore sequencing and assembly of a human genome with ultra-long reads:

Nanopore sequencing is a promising technique for genome sequencing due to its portability, ability to sequence long reads from single molecules, and to simultaneously assay DNA methylation. However until recently nanopore sequencing has been mainly applied to small genomes, due to the limited output attainable. We present nanopore sequencing and assembly of the GM12878 Utah/Ceph human reference genome generated using the Oxford Nanopore MinION and R9.4 version chemistry. We generated 91.2 Gb of sequence data (~30x theoretical coverage) from 39 flowcells. De novo assembly yielded a highly complete and contiguous assembly (NG50 ~3Mb). We observed considerable variability in homopolymeric tract resolution between different basecallers. The data permitted sensitive detection of both large structural variants and epigenetic modifications. Further we developed a new approach exploiting the long-read capability of this system and found that adding an additional 5x-coverage of “ultra-long” reads (read N50 of 99.7kb) more than doubled the assembly contiguity. Modelling the repeat structure of the human genome predicts extraordinarily contiguous assemblies may be possible using nanopore reads alone. Portable de novo sequencing of human genomes may be important for rapid point-of-care diagnosis of rare genetic diseases and cancer, and monitoring of cancer progression. The complete dataset including raw signal is available as an Amazon Web Services Open Dataset at: https://github.com/nanopore-wgs-consortium/NA12878.

30x just means that you’re getting bases sampled typically 30 times, so that you have a very accurate and precise read on its state. 30x has become the default standard in medical genomics. If Nanopore can do 30x on human genomes at reasonable cost it won’t be a niche player much longer.

The read length is important because last I checked the human genome still had large holes in it. The typical Illumina machine produces average read lengths in the low hundreds of base pairs. If you have large repetitive regions of the human genome (and you do have these), you’re never going to span them with such short yardsticks. Additionally, these short reads have to be tiled together when you assemble a genome from raw results, and this is a computationally really intensive task. It’s good when you have a reference genome you can align to as a scaffold. But researchers who don’t work on humans or model organisms may not have a good reference genome, or in many cases a reference genome at all.

Pac Bio occupies a space where it provide really long reads for a high price point. Most of the time this isn’t necessary, but imagine you work on a disease which is caused by large repetitive regions. You are likely willing to pay the price that is asked. And because Pac Bio generates very long reads it makes de novo assembly much easier, as your algorithm has to tile together far fewer contiguous sequences, and long sequences are less likely to have lots of repetitive matches in the genome.

But Pac Bio machines are expensive and huge. In the abstract above it alludes to “Portable de novo sequencing of human genomes.” This is a huge deal. The dream, as whispered by some genomicists I have known, is that at a point in the future biologists would carry portable sequencers which would produce very long reads that so that they could de novo assemble sequences on the spot. A concrete example might be a health inspector checking on the sorts of microbes found on the counter of a restaurant, or a field ecologist who might be sample various fungi to discover cryptic species.

Obviously this is still a dream. The preprint above makes it clear that to do what they did required a lot of novel techniques and development of new tools. This isn’t beta technology, it’s early alpha. But because it’s 2017 the outlines of the dream are coming into public view.

Citation: Nanopore sequencing and assembly of a human genome with ultra-long reads
Miten Jain, Sergey Koren, Josh Quick, Arthur C Rand, Thomas A Sasani, John R Tyson, Andrew D Beggs, Alexander T Dilthey, Ian T Fiddes, Sunir Malla, Hannah Marriott, Karen H Miga, Tom Nieto, Justin O’Grady, Hugh E Olsen, Brent S Pedersen, Arang Rhie, Hollian Richardson, Aaron Quinlan, Terrance P Snutch, Louise Tee, Benedict Paten, Adam M. Phillippy, Jared T Simpson, Nicholas James Loman, Matthew Loose
bioRxiv 128835; doi: https://doi.org/10.1101/128835

10 Things About Ancient History You Should Really Know

For this “10 things” I am going to constraint the historical period to the period before 1000 BCE. Basically all that came before Greece and Rome (from a Western perspective).

1) The Bronze Age Near East had its own equivalent of a Westphalian system. See The Brotherhood of Kings.

2) Even in the 3rd Millennium BCE the world was quite international. There are references in Sumerian tablets to expatriate communities of merchants from Meluhha. Meluhha almost certainly referring to what we call the Indus Valley civilization.

3) The relationship between Sumerians and Akkadians prefigures the relationship between the Greeks and Romans. Mesopotamia had long had Semitic speaking groups like Akkadians, as evidenced by their prominence in lists of rulers to an early date, but in the most antique period Sumerians were dominant. Over time though Sumerians disappeared as a distinct ethnicity, and the language was preserved as one of liturgy for thousands of years after their extinction.

4) The longstanding antagonists of Sumer, the nation of Elam in southwest Iran, persisted for 1,500 years after the Sumerians left the scene. They were finally absorbed by the Medes and Persians in the 6th century BCE.

5) Because cuneiform tablets can be baked and preserved our documentary evidence from some earlier periods in Near Eastern history is much better than more epochs, simply due to preservational differences.

6) The Hittite polity, which lasted for nearly 1,000 years as the dominant rival of many other Near Eastern powers, was analogous in some ways to the Hungarian kingdom, with a very distinct ruling class. The Hittites called themselves the Nesa, and ruled over various non-Indo-European popualtions, in particular the Hatti.

7) Sumeria likely had a larger population than the same area after the Mongol sack of Baghdad (there may also be an issue with salinization of lower Mesopotamia over time).

8) The Biblical Philistines may in part have been Bronze Age Greeks (bonus: the political units of Bronze Age Greece may have been larger than during the Classical period because bronze forging requires more mobilization of resources than iron).

9) Pleistocene “megafauna” survived into the Bronze Age.

10) Indo-Europeans of an Indo-Aryan variant called the Mittani were the ruling class in much of the territory ruled by ISIS for the past few years. They even worshipped Indo-Aryan gods.

Addendum: I invite readers to give me better suggestions. I’m not an ancient historian, just an enthusiast!

Mouse fidelity comes down to the genes

While birds tend to be at least nominally monogamous, this is not the case with mammals. This strikes some people as strange because humans seem to be monogamous, at least socially, and often we take ourselves to be typically mammalian. But of course we’re not. Like many primates we’re visual creatures, rather than relying in smell and hearing. Obviously we’re also bipedal, which is not typical for mammals. And, our sociality scales up to massive agglomerations of individuals.

How monogamous we are is up for debate. Desmond Morris, who is well known to many from his roles in television documentaries, has been a major promoter of the idea that humans are monogamous, with a focus on pair-bonds. In contrast, other researchers have highlighted our polygamous tendencies. In The Mating Mind Geoffrey Miller argues for polygamy, and suggests that pair-bonds in a pre-modern environment were often temporary, rather than lifetime (Miller is now writing a book on polyamory).

The fact that in many societies high status males seem to engage in polygamy, despite monogamy being more common, is one phenomenon which confounds attempts to quickly generalize about the disposition of our species. What is preferred may not always be what is practiced, and the external social adherence to norms may be quite violated in private.

Adducing behavior is simpler in many other organisms, because their range of behavior is more delimited. When it comes to studying mating patterns in mammals voles have long been of interest as a model. There are vole species which are monogamous, and others which are not. Comparing the diverged lineages could presumably give insight as to the evolutionary genetic pathways relevant to the differences.

But North American deer mice, Peromyscus, may turn to be an even better bet: there are two lineages which exhibit different mating patterns which are phylogenetically close enough to the point where they can interbreed. That is crucial, because it allows one to generate crosses and see how the characteristics distribute themselves across subsequent generations. Basically, it allows for genetic analysis.

And that’s what a new paper in Nature does, The genetic basis of parental care evolution in monogamous mice. In figure 3 you can see the distribution of behaviors in parental generations, F1 hybrids, and the F2, which is a cross of F1 individuals. The widespread distribution of F2 individuals is likely indicative of a polygenic architecture of the traits. Additionally, they found that some traits are correlated with each other in the F2 generation (probably due to pleiotropy, the same gene having multiple effects), while others were independent.

With the F2 generation they ran a genetic analysis which looked for associations between traits and regions of the genome. They found 12 quantitative trait loci (QTLs), basically zones of the genome associated with variation on one or more of the six traits. From this analysis they immediately realized there was sexual dimorphism in terms of the genetic architecture; the same locus might have a different effect in the opposite sex. This is evolutionarily interesting.

Because the QTLs are rather large in terms of physical genomic units the authors looked to see which were plausible candidates in terms of function. One of their hits was vasopressin, which should be familiar to many from vole work, as well as some human studies. Though the QTL work as well as their pup-switching experiment (which I did not describe) is persuasive, the fact that a gene you’d expect shows up as a candidate really makes it an open and shut case.

The extent of the variation explained by any given QTL seems modest. In the extended figures you can see it’s mostly in the 1 to 5 percent range. In Carl Zimmer’s excellent write up he ends:

But Dr. Bendesky cautioned that the vasopressin gene would probably turn out to be just one of many that influence oldfield mice. Though it is strongly linked to parental behavior, the vasopressin gene accounts for 6.7 percent of the variation in nest building among males, and only 2.9 percent among females.

The genetic landscape of human parenting will turn out to be even more rugged, Dr. Bendesky predicted.

“You cannot do a 23andMe test and find out if your partner is going to be a good father,” he said.

Sort of. The genetic architecture above is polygenic…but not incredibly diffuse. The proportion of variation explained by the largest effect allele is more than for height, and far more than for education. If human research follows up on this, I wouldn’t be surprised if you could develop a polygenic risk score.

But I don’t have a good intuition on how much variation in humans there really is for these sorts of traits that are heritable. I assume some. But I don’t know how much. And how much of the variance in behavior might be explained by human QTLs? Humans don’t lick or build nests, or retrieve pups. Also, as one knows from Genetics and Analysis of Quantitative Traits sexually dimorphic traits take a long time to evolve. These are two deer mice species. Within humans there may not have been enough time for this sort of heritable complexity of behavior to evolve.

There are a lot of philosophical issues here about translating to a human context.

Nevertheless, this research shows that ingenious animal models can powerfully elucidate the biological basis of behavior.

Citation: The genetic basis of parental care evolution in monogamous mice. Nature (2017) doi:10.1038/nature22074

Women hate going to India

For some reason women do not seem to migrate much into South Asia. In the late 2000s I, along with others, noticed a strange discrepancy in the Y and mtDNA lineages which trace one’s direct male and female lines: in South Asia the male lineages were likely to cluster with populations to the north an west, while the females lines did not. South Asia’s females lines in fact had a closer relationship to the mtDNA lineages of Southeast and East Asia, albeit distantly.

One solution which presented itself was to contend there was no paradox at all. That the Y chromosomal lineages found in South Asia were basal to those to the west and north. In particular, there were some papers suggesting that perhaps R1a1a originated in South Asia at the end of the last Pleistocene. Whole genome sequencing of Y chromosomes does not bear this out though. R1a1a went through rapid expansion recently, and ancient DNA has found it in Russia first. But in 2009 David Reich came out with Reconstructing Indian population history, which offered up somewhat of a possible solution.

What Reich and his coworkers found that South Asia seems to be characterized by the mixture of two very different types of populations. One set, ANI (Ancestral North Indian), are basically another western or northwestern Eurasian group. ASI (Ancestral South Indian), are indigenous, and exhibit distant affinities to the Andaman Islanders. The India-specific mtDNA then were from ASI, while the Y chromosomes with affinities to people to the north and west were from ANI. In other words, the ANI mixture into South Asia was probably through a mass migration of males.

But it’s not just Y and mtDNA in this case only. A minority of South Asians speak Austro-Asiatic languages. The most interesting of these populations are the Munda, who tend to occupy uplands in east-central India. Older books on India history often suggest that the Munda are the earliest aboriginals of the subcontinent, but that has to confront the fact that most Austro-Asiatic language are spoken in Southeast Asia. There was no true consensus where they were present first.

Genetics seems to have solved this question. The evidence is building up that Austro-Asiatic languages arrived with rice farmers from Southeast Asia. Though most of the ancestry of the Munda is of ANI-ASI mix, a small fraction is clearly East Asian. And interestingly, though they carry no East Asian mtDNA, they do carry East Asian Y. Again, gene flow mediated by males.

The same is true of India’s Bene Israel Jewish community.

A new preprint on biorxiv confirms that the Parsis are another instance of the same dynamic: The genetic legacy of Zoroastrianism in Iran and India: Insights into population structure, gene flow and selection:

Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present novel genome-wide autosomal, Y-chromosome and mitochondrial data from Iranian and Indian Zoroastrians and neighbouring modern-day Indian and Iranian populations to conduct the first genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we show that Zoroastrians in Iran and India show increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we show that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690-1390 CE and providing strong evidence that the migrating group was largely comprised of Zoroastrian males. By exploiting the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE-746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases amongst these communities.

The paper uses lots of fancy ChromoPainter methodologies which look at the distributions of haplotypes across populations. But some of the primary results are obvious using much simpler methods.

1) About 2/3 of the ancestry of Indian Parsis derives from an Iranian population
2) About 1/3 of the ancestry of Indian Parsis derives from an Indian popuation
3) Almost all the Y chromosomes of Indian Parsis can be accounted for by Iranian ancestry
4) Almost all the mtDNA haplogroups of Indian Parsis can be accounted for by Indian ancestry
5) Iranian Zoroastrians are mostly endogamous
6) Genetic isolation has resulted in drift and selection on Zoroastrians

The fact that the ancestry proportion is clearly more than 50% Iranian for Parsis indicates that there was more than one generation of males who migrated. They did not contribute mtDNA, but they did contribute genome-wide to Iranian ancestry. There are wide intervals on the dating of this admixture event, but they are consonant oral history that was later written down by the Parsis.

So there you have it. Another example of a population formed from admixture because women hate going to India.

Citation: The genetic legacy of Zoroastrianism in Iran and India: Insights into population structure, gene flow and selection.
Saioa Lopez, Mark G Thomas, Lucy van Dorp, Naser Ansari-Pour, Sarah Stewart, Abigail L Jones, Erik Jelinek, Lounes Chikhi, Tudor Parfitt, Neil Bradman, Michael E Weale, Garrett Hellenthal
bioRxiv 128272; doi: https://doi.org/10.1101/128272

Only half of the traffic on this website is from a personal ‘computer’

I spend way too much time semi-competently managing the VPS this site is hosted on. But at least now I can look at Google Analytics. I’ve found some interesting things.

For example, 35% of the traffic on this site comes from phones, and 10% from tablets. That means that conventional computers are only somewhat more than half of the views. Additionally, 50% more of the Facebook shares are via the mobile Facebook app than the normal desktop version (I tend to get the most referrals from Twitter since I have a bigger Twitter following, but at some point I expect Facebook to surpass that as people realize I’m blogging again).

Probably going to make a few changes to make the site more mobile friendly since so many of you tend to read it on that device….

Evolutionary game theory and international relations

The North Korea Paradox: Why There Are No Good Options:

Denny Roy, a political scientist who studies Asian security issues, told me last fall that North Korea “intentionally employs a posture of seemingly hyper-risk acceptance and willingness to go to war as a means of trying to intimidate its adversaries.”

This puts the world in a quandary: How could any outside threat possibly exceed the risk that North Korea already takes on itself? How could any concession remove the North Korean weakness that drives its behavior?

Basically North Korea is a weak state. Its only leverage is to hold the world hostage and act crazy. Unfortunate, but true.

But this piece reminded me a lot of stuff that John Maynard Smith described in Animal Signals. Sometimes it is the weaker and more vulnerable animals which have to engage in high risk agonistic competition, so that they can show more fit individuals that there is going to be a significant cost in initiating hostilities.

It also reminds me of high school. If you are smaller than average, it is best to make it clear to larger bullies that you won’t be passive. You may lose the fight, but by escalating rapidly you can dissuade a bully from targeting you, as opposed to someone who is more likely to be an easier victim.

Of course, bullies need to be “rational” actors here….

In a hopeless world hope is better than resignation

There’s really nothing one can say anymore about what Hugo Chavez did to his country, No Food, No Medicine, No Respite: A Starving Boy’s Death in Venezuela. But now in France a left-wing politician is on the rise who praises Chavez, Left-Wing Politician Shakes Up France’s Presidential Race:

That man is Jean-Luc Mélenchon, admirer of Fidel Castro and Hugo Chávez, sworn enemy of NATO and high finance, and candidate of his own “France Unsubjugated” movement, who has been drawing tens of thousands to his rallies, especially the young, as he did here Sunday at Toulouse on the banks of the Garonne River. They came to hear a veteran French politician give them a dousing of old-fashioned Robin Hood-revolutionary rhetoric, with promises to tax the rich hard, give to the poor and start a “citizen revolution.”

There is a serious chance that this will be the next president of the French republic. This man, who has no problems being called a Communist. If there is one political system where the experiment has been done, it is command economy socialism. There may be cases of market failure where the state needs to intervene, but by and large an economy dominated by the state has not done good for the common man.

And yet the reality is what alternatives are the people being given? They are looking Left and looking Right, because they want hope that the future will have some of the promise that the past had. Sober realistic centrists with broadly liberal views only offer them only hard truths.

Truths such as this: Evidence That Robots Are Winning the Race for American Jobs. The far Left anti-capitalist program in economics really doesn’t offer a long run path to prosperity. But capitalism itself only leads to individual and broad-based prosperity as a side effect of market logic. If returns to capital could accrue without labor inputs, then that would be even “better.”

The Warlord Chronicles

The Winter is Coming website has a post up, What books should you read as you wait for The Winds of Winter? (The Winds of Winter is the next Song of Ice and Fire book).

I don’t have much time for fiction at this point, but the first entry that they suggested was Bernard Cornwell’s Warlord Chronicles. This is a very dark, gritty, and realistic, retelling of the Arthurian legend, written in a fashion more reminiscent of historical fiction than fantasy. I read this series perhaps a year after first reading Game of Thrones, and was struck by similarities of tone.

As it happened this was before George R. R. Martin was quite as famous, and I emailed him at some point in 2000 about various issues relating to his works and inspirations, and asked him about Cornwell’s series. Martin admitted that he was a huge fan, and appreciated that there were similarities of style and tone.

In any case, I second this recommendation. Warlord Chronicles is not the most easy read…but worth it.

Open Thread, 4/16/2017

Happy Easter. Spend most of the day figuring out how to restart Varnish. I don’t really know why there are so many database connection problems and caching…but I inherited the VPS. Might have to bone up on being a sysadmin more. Do any readers know if Varnish is really worth a modest site like mine?

Erdogan Claims Vast New Powers After Narrow Victory in Turkish Referendum. First, I have to say that The Future of Freedom: Illiberal Democracy at Home and Abroad is pretty relevant today. Second, Erdogan has shown many faces to the world over the past 15 years. I remember for example him telling people in post-Arab Spring Tunisia that in a free society atheism is a real option (to some criticism).

Are 90% of academic papers really never cited? Reviewing the literature on academic citations. It’s really a problem in the humanities:

Many academic articles are never cited, although I could not find any study with a result as high as 90%. Non-citation rates vary enormously by field. “Only” 12% of medicine articles are not cited, compared to about 82% (!) for the humanities. It’s 27% for natural sciences and 32% for social sciences (cite). For everything except humanities, those numbers are far from 90% but they are still high: One third of social science articles go uncited! Ten points for academia’s critics. Before we slash humanities departments, though, remember that much of their most prestigious research is published in books. On the other hand, at least in literature, many books are rarely cited too.

White supremacist who created stir at Stanislaus State seen punching woman at Berkeley protest. First, please note that this woman went to the protest to get “Nazi scalps” according to her social media. Second, the image of a white supremacist punching an anti-fascist woman is exactly what Sarah Haider told me was going to be a problem with contemporary Leftist valorization of violence: Left-wing organizations have proportionally many more women than right-wing militant organizations, which isn’t an asset in pitched physical combat.

Theresa May’s Conservatives are 21 points ahead of Labour in new poll. I think Scotland will leave the United Kingdom in the next 5 years.

Suzan Mazur interviews Richard Lewontin. I used to think Mazur was exceptional, and she still is, but only in her artlessness in pushing her agenda.

Treasure your exceptions, progress is real but not universal

The beginning of How the Scots Invented the Modern World describes the execution of a man for the crime of atheism around 1700 in Scotland. More precisely, this individual was rather loud about their heresy, and that is always the problem. Silent dissent is usually tolerated. This is the last time someone was executed for this particular crime in the British Isles.

In the United Kingdom the book was more accurately titled The Scottish Enlightenment. A relatively moderate and low fuss affair, the Scottish Enlightenment gave us Adam Smith and David Hume, to name two. The point of the book is that in it one can see many of the seeds of the liberal Enlightenment in Scotland, which at the beginning of the 18th century was arguably more backward and medieval than its southern neighbor.

But the “modern world” means many different things. Mobile phone technology is ubiquitous, to the point that even the poor in developing nations have it. But a broader consumer affluence is out of reach for many. And the rights and liberties of a liberal democratic order are more an ideal than concrete existence for much of the world’s population (and you have cases such as Saudi Arabia where illiberal norms and politics merge with consumer affluence).

As you may know a young man was killed by his fellow students in Pakistan for the crime of blasphemy a few days ago. Whether he was an atheist or a free thinker, or a skeptic more generally, can be hard to ascertain. But the critical aspect is that he was killed in broad daylight by a mob. He was lynched. This being 2017, you can watch a video of the killing, and hear his screams as he is murdered in front of a crowd.

One aspect people have been noticing is that this was a killing enabled by majority and consensus opinion. Abdul Wali Khan University Mardan is a public university, not a cloistered madrassa or a branch of the Red Mosque network. You can’t blame ISIS or some crazy jihadi network. These were university students.

Pakistan has a population of 182 million. The United States around 300 million. I understand that Americans believe we are the future. That the rest of the world is the exception. But how long will that be? Perhaps the arrow of history is more a circle?