Helix kit price waived until December 26 at 2:59am EST

Happy Hanukkah! My main qualm with wishing you a happy holiday is that I’m a thorough assimilator and I don’t want to be disemboweled.

For the context, listen to the Stuff You Missed in History Class episode on the Maccabean Revolt. As a Jewish friend of mine once observed, the Maccabees were kind of the Al-Qaeda of their day (today she would have said ISIS).

With that out of the way, I want to give you a heads up that Helix has a sale going until December 26 at 2:59am EST where the $80 kit cost for purchase of any app is waived if you haven’t purchased at app before. Just enter the promotion code HOLIDAY at checkout.

That means presales of Insitome’s Regional Ancestry is no more than $19.99, while Neanderthal is $29.99 and Metabolism is $39.99 (this applies to all of Helix’s products except embodyDNA by Lose It! and Geno 2.0 by National Geographic).

Why does it matter? Again, Helix banks a high quality exome+ (the + is for non-exonic positions) when you purchase any of their apps. If you want subsequent apps you don’t have to sent another kit in, you just buy the app and get the results. Also, I do have to say that from what I’ve seen and heard Helix’s laboratory facilities are top-notch in terms of getting results turned around rapidly.

Your impatience is in your genes! (well, some of it)


Nature Neuroscience has a short communication which is very intriguging, Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry. How’d they get such a large sample size? Collaborating with our friends at 23andMe.

That being said, the abstract leaves a little to be desired:

Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 × 10−8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight.

First, “Delay discounting (DD)”, is another way to say that you have high time preference. That is, you won’t forgo some gains in the short term for greater gains in the long term. You would really “fail” the marshmallow test.

Though there have been legitimate criticisms of the replicability of the effect size of the marshmallow test, there almost certainly is something to time preference and delayed gratification, and its relationship to the ability of young children to master the marshmallow test. In a macroeconomic sense societies characterized by low time preference can sustain lower interest rates, and lower interest rates have all sorts of stimulative properties on long-term economic growth.

But to be clear, the paper above does not detect a variant SNP, rs6528024, which explains 12% of the variance in DD. Rather, 12% of the variance could be accounted for by SNP-chip variance. That is, one could explain the “missing heritability” using the markers they had. The total heritablity of the trait is quite higher, 46% to 62% proportions are citied in the paper (narrow-sense). This means that of the total variance of the trait about half could be explained by additive genetic variance. Obviously the SNP-chip only captured a small minority of that additive genetic variance.

DD is correlated with a lot of things. There is a positive phenotypic correlation with:

  • Smoking
  • Substance abuse
  • Obesity
  • ADHD

They observed a positive genetic correlation between the variants associated with DD and:

  • Smoking
  • Neuroticism
  • Depression

And a negative genetic correlation with:

  • College completion
  • Years of education
  • Childhood IQ
  • Schizophrenia

In relation to the last, schizophrenia and DD are positively correlated phenotypically. That probably means that the underlying genetic causes of schizophrenia and DD are very different.

The patterns of correlations offer up a lot of avenues to speculate. They do a little of it in the paper, but are appropriately cautious. It seems entirely likely that in the near future we’ll be able to characterize a lot of the heriability genomically. When we figure out time preference and intelligence we’ll have come close to answering many of the questions that explain why different people have different life outcomes.

Note: It is no surprise that there is a negative correlation between DD (high time preference) and conscientiousness. Also, the association they found, GPM6B, has pretty clear biological relevance. It’s almost certainly real.

Endless Tigers Most Beautiful


The Thylacine, or the Tasmanian Tiger, is a tragic story that we all know (or should know!). Too late did humans realize how precious it was, a large(ish) marsupial carnivore endemic to Tasmania. Hunted to extinction, the last one died because it was not properly taken care of.

The Tasmanian Tiger is an example of why science is not just instrumental. That is, science is not simply the handmaid of engineering. Most people with an interest in biology have some instinctive reaction to the Tasmanian Tiger and what happened. There’s a natural pathos in it.

If you read The Monkey’s Voyage you know that the marsupials of South America probably derive from a single dispersal event. Genetics has determined that the South American Monito del monte is the most basal of the superorder Australidelphia, which includes all Australasian marsupials. That means instead of the single South American marsupial of this superorder being due to a migration from Australia, the Australian lineages diversified from a single South American ancestor. The Monito del monte is the last living descendent of this once extensive clade.

This means that all of the vareigated marsupials of Australia probably diversified during the Cenozoic, even though the divergence between marsupials and placental mammals dates deep into the Mesozoic. The Koala, the Kangaro, and the Tasmania Devil, all derive from the same source.

Well, a new paper in Nature: Ecology & Evolution does something quite neat, they sequence the whole genome of a Tasmanian Tiger! Genome of the Tasmanian tiger provides insights into the evolution and demography of an extinct marsupial carnivore:

The Tasmanian tiger or thylacine (Thylacinus cynocephalus) was the largest carnivorous Australian marsupial to survive into the modern era. Despite last sharing a common ancestor with the eutherian canids ~160 million years ago, their phenotypic resemblance is considered the most striking example of convergent evolution in mammals. The last known thylacine died in captivity in 1936 and many aspects of the evolutionary history of this unique marsupial apex predator remain unknown. Here we have sequenced the genome of a preserved thylacine pouch young specimen to clarify the phylogenetic position of the thylacine within the carnivorous marsupials, reconstruct its historical demography and examine the genetic basis of its convergence with canids. Retroposon insertion patterns placed the thylacine as the basal lineage in Dasyuromorphia and suggest incomplete lineage sorting in early dasyuromorphs. Demographic analysis indicated a long-term decline in genetic diversity starting well before the arrival of humans in Australia. In spite of their extraordinary phenotypic convergence, comparative genomic analyses demonstrated that amino acid homoplasies between the thylacine and canids are largely consistent with neutral evolution. Furthermore, the genes and pathways targeted by positive selection differ markedly between these species. Together, these findings support models of adaptive convergence driven primarily by cis-regulatory evolution.

The authors are saying that the clear morphological convergences between Tasmania Tigers and canids, which are obvious to anyone with eyes, aren’t detectable in similar sequence identity in regions of the genome known to be functional relevant to the characteristics of interest. Instead of sequence identity they suggest that rather the morphology is being controlled by evoutionary genetic process of cis-regulatory adaptation.

In the Mike Lynch vs. Sean Carroll debate of about ten years back, they’re saying that Sean Carroll was right (see this Hoekstra & Coyne paper for a different take).

Part of the issue here is probably the sort of traits they’re focused on. There seems to be something about the gross morphological characteristics humans find salient that make them the target of cis-regulatory mediated evolutionary processes.

Finally, they suggest with a PSMC plot that Tasmanian Tiger populations crashed around 70,000 years ago, well before Australian Aboriginals arrived. First, I’m not sure that I trust the 70,000 number to be precise enough that we can say it doesn’t overalp with human arrival. But second, is it me, or does every PSMC look like the pot above? It’s probably some sort of publication bias, as you don’t put in PSMC figures if they don’t show a bottleneck. But I’m kind of getting tired of it.

Open Thread, 12/11/2017

Thinking back to The Turks in World History the author points out that even the most explicit Islamic of the late Turkic empires, that of the Ottomans, persisted with a customary law similar and cognate to the Mongol yasa. Perhaps then the folkway of the nomadic Turk was sublimated and integrated into the Islamic superstructure of the Ottoman ruling ideology?

I went to a work-related Christmas party thrown by my company’s law firm. There were a lot of VC guys there. Two of them confused me for a blockchain entrepreneur (one of them was asking about a conflict with the CFO). I think I better get into blockchain….

So the website Everyday Feminism has an article, 10 Things Every Intersectional Feminist Should Ask On a First Date. I only know about this website because of conservative Twitter. It could be that 90% or more of the hits on this website are through viral “hate-clicks”.

Second, I feel the image that goes along with the article is problematic as fuck. The woman pictured seems to be geared toward appealing to cishet male norms of “attractiveness.” On the other hand, if intersectional feminists typically look something like Josie Maran…well, I won’t go there.

I will observe also that I find out about a lot of far-right movements and individuals through Left and Centrist Twitter (the two groups are interested for different reasons).

As noted in the comments, The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland. At this point, I think I can say this: unless it’s ancient DNA I’m done with the historical genetics of the British Isles. We know enough. Period.

Why the #MeToo Movement Should Be Ready for a Backlash. I don’t care too much about Al Franken, but digging a little deeper I think there might be some dirty tricks going on there…. I was rather dim on the prospects for Republicans in 2018, but at this rate, the Dems might “struggle-session” their way into defeat.

India Warily Eyes AI: Technology outsourcing has been India’s only reliable job creator in the past 30 years. Now artificial intelligence threatens to wipe out those gains. When I believed in the End of History and the Last Man this would matter to me. Now it’s all a big shrug.

The ancestral animal genetic toolkit revealed by diverse choanoflagellate transcriptomes.

Another reason that helper-AIs can’t come to medicine soon enough:

Chronicler of Islamic State ‘killing machine’ goes public.

As home DNA tests become more common, people must grapple with surprises about their parents:

Until recently, Andrea Ramirez, 43, thought she was part Mexican.

But the results from an at-home genetic test from 23andMe revealed that she is a mix of Northern European, North African and a little Native American.

And not at all hispanic.

There can be no genetic test for being Hispanic because that is a socio-cultural identity. There are Korean, Arab, and Nordic Hispanics. Even the most common genetic profile varies, from mostly European Argentines to mostly indigenous Bolivians to Afro-Cubans and Afro-Colombians.

When I read stuff like this I really wonder what they teach journalists (the Census explicitly declaims the the idea that Hispanic is a racial category).

I spent a fair amount of time this weekend cleaning up scripts that can batch process 23andMe, Ancestry and FamilyTree DNA input files and push them down the pipeline toward generating admixture percentages. I have posted the most current results from the South Asian Genotype Project have been posted.

Two things

1) I’m not happy with the clusters that I used. I may change them (in which case I’ll rerun everything).
2) Once I’ve done that I’ll probably send some of my scripts to Zack Ajmal and he can run all the Harappa individuals with this new cluster.

Finally, people from the “Cow Belt” don’t get genotyped. No submissions from UP or Bihar so far. Very frustrating.

The word problematic is problematic in my opinion. I really want to punch people when they use that word. But I’ve lost that battle.

My friend Chad Niederhuth is starting his plant genomics lab at Michigan State. He’s looking for graduate students and postdocs.

My friend Nathan Pearson’s HLA genomics start-up, Root is out of stealth mode.

Looking at my Kindle stack wondering about which of these five books to tackle next:

Why our society might go “splat!” on the windshield sooner than we think

Ray Kurzweil likes to talk about the fact that humans are bad at modeling exponential rates of growth. In this case, he’s talking about the rate of change in information technology. Whatever you think about Ray’s general ideas as outlined in books such as The Singularity Is Near, I think it’s a pretty good insight that needs reiteration.

More generally in social processes, I think humans living at any given time are not very cognizant of nonlinearities, and the sorts of exogenous shocks that might happen in their lifetimes. And why would we be? The evolutionary psychological model for why we’re bad at conceptualizing rapid change is that until recently not much changed for most people at most times.

That is, humans were animals which lived near the Malthusian limit at a stationary state. The rate of change did increase during the Holocene, but even with ancient Egypt consider how different the life of a peasant in the Old Kingdom was versus the New Kingdom. Over 2,000 years not much had changed. Even at the elite levels, not much had changed (in fact, the Egyptian religion maintained cultural continuity from ~3000 BC to ~500 AD, with the shutdown of the temple at Philae). Now consider the 2,000 years between ancient Rome and the modern West. Or, consider the 300 years between the Augustan Age and revival of the Empire under the Tetrarchy, and contrast that to the present year and 1717.

The modern world is strange because great changes in technology and social values can occur over and over across a single lifetime. Someone born in 1896 would mature and develop a world-view conditioned by the “long 19th century,” which lasted until 1914. Then they’d experience the “shock” of the “War to End All Wars.”

Arguably the period between the Congress of Vienna in 1815 and outbreak of World War I in Europe in 1914 was marked by evolution, rather than revolution, in social and political structures. 1848 did not prefigure a tumult equivalent to the French Revolution or the period of the Napoleonic Wars. Italy and Germany were unified ultimately under conservative nationalists. Darwinism, abolitionism, and women’s rights arguably were movements who were seeded during the Enlightenment and exhibited long pregnancies until the point that they erupted to prominence.

Between 1914 and 1920 a whole world fell away. The Empire of the Tsars collapsed, and was replaced by the chiliastic Bolshevik regime. Austria-Hungary and the Ottoman Empire were dismembered and their monarchies were overthrown, while Germany transformed from a conservative monarchy to a liberal republic.

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The Truth is that history is not evolving toward Truth

My friend Walter Olson pointed me to this from John Locke:

To love truth for truth’s sake is the principal part of human perfection in this world, and the seed-plot of all other virtues.

This is great and inspirational quote, but in most interpretive sieves I believe it is wrong. Hume’s assertion that “reason is and ought only to be the slave of the passions” is closer to the truth in terms of describing the typical human in terms of how they think, and what they value.

One of the insights of modern cognitive science is that the “rational” and “reflective” component of our mind tends to promote some delusions about its role in our decision-making process. Rather than being the conductor, it’s more often the rationalizer. That is, we make a decision, and then we concoct rationales after the fact. One can think of conscious rationality as a public relations outfit, as opposed to the client.

None of this is deep wisdom, and the latest research is all outlined in The Enigma of Reason. But, another issue which I think is important to note is that the propaganda over the generations by the very small proportion of the population for whom reason and truth are prioritized as the summum bonum of human existence, as implied by Locke’s assertion, have biased our understanding of history. The reason being that they are the ones disproportionately writing the history! Our species’ collective memory lies to us because cultural organs of memory have their own agendas (albeit, unconsciously!).

In Near Eastern antiquity the scribal caste was very much a group of literate wizards. No doubt some elements of literacy percolated to the general public, as is evident by graffito hieroglyphics by workers in ancient Egypt, but habitual engagement with the written word was the purview of a small group of professionals. These individuals dealt in abstraction in their day to day, and by the middle of the first millennium B.C. out of the culture of scribes developed the group we would term intellectuals. The philosophers, prophets, and sages of antiquity. A period when religion, magic, and science, were all one.

Of course, many of these intellectuals were not from the scribal caste as such. Many were aristocrats and gentry (e.g., Siddhartha and Plato). But by this time literacy had spread out beyond the scribal castes, and a civilian elite culture had emerged which valued intellectual pursuits in some fashion. Elite male leadership training in some societies began to include intellectual arts as part of their education. But we should be cautious about inferring from this that these elite males valued rhetoric and philosophy as ends in and of themselves. Rather, rhetoric and philosophy exhibited some instrumental (in politics for the former) and signaling value (abstruse philosophical abstraction could only be mastered by those with leisure and means, so it suggested one’s class origin and cultivation).

Across the centuries, and even millennia, the minority of intellectuals who notionally chased the truth, Plato, Sima Qian, and Ibn Khaldun, remain in our memories because their ideas were powerful, attractive, and their intellectual coherency and brilliance impressed future generations of thinkers. But we need not infer from this that in their own time they were of such inordinate fame or glory in relation to others of similar note though intellectual mediocrity. To give a concrete example, for a few shining decades phlogiston and Lysenkoism were bright and influential, even though the latter, and possibly the former, were both fraudulent enterprises.

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Visualizing intra-European phylogenetic distances

Neighbor-joining tree of genetic distances between populations

 

In L. L. Cavalli-Sforza’s The History and Geography of Human Genes he used between population group genetic distances, as measured in FST values, to generate a series of visualizations, which then allowed him to infer historical processes. Basically the way it works is that you look at genetic variation, and see how much of it can be allocated to between groups. If none of it can be allocated to between groups, then in a population genetic sense it doesn’t make much sense to speak of distinctive groups, they’re basically one breeding population. The higher the FST statistic is, the more of the variation is partitioned between the groups.

Roughly this is used to correlate with genetic distance as well as evolutionary divergence. The longer two populations have been separated, the more and more genetic differences they’ll accumulate, inflating the FST value. There are a lot of subtleties that I’m eliding here (see Estimating and interpreting FST: the impact of rare variants for a survey of the recent literature on the topic and pathways forward), but for a long time, FST was the go-to statistic for making phylogenetic inferences on a within-species scale.

Today we have other techniques, Structure, Treemix, fineStructure, and various local ancestry packages.

But FST is still useful to give one a Gestalt sense of population genetic differences. Cavalli-Sforza admits in The History and Geography of Human Genes that European populations had very low pairwise FST, but because of the importance of Europe for sociocultural reasons a detailed analysis of the region was still provided in the text. Additionally, they had lots of European samples (non-European Caucasoids were thrown into one category for macro-group comparisons because there wasn’t that many samples).

Using results from the 2015 paper Massive migration from the steppe was a source for Indo-European languages in Europe, I visualized pairwise genetic distances for European populations, ancient and modern (Han Chinese as an outgroup), on a tree. What the results illustrate is that

  1. Ancient populations were very distinct in Europe from modern ones.
  2. Many modern groups are clustered close together.

The bulk of the population genetic structure in modern Europe seems to have been established in the period between 3000 BCE and 2000 BCE. This is not that much time for a lot of distinctiveness to develop, especially on the geographically open North European plain. I suspect with more and more Mesolithic and early to middle Neolithic DNA we’ll see that some of the modern population structure is a ghost of ancient substrate absorption.

Many of the ethno-national categories that are very significant in recent history, and impact the cultural memories of modern people and their genealogies, have very shallow roots. This does not mean they are not “real” (I don’t know what that’s supposed to mean at all), just that many of the identities which seem so salient to us today may be relatively recent in terms of their significance to large groups of humans….

The Saxon Panmixia


One reason I quite like Norman Davies’ book The Isles is that it is a history of Britain and Ireland which explicitly aims to not privilege the story of the English inordinately. As the most powerful and numerous people of the British Isles the English loom large, but in the period between Gildas and Bede things were very different. In the early 600s the Welsh king Cadwallon ap Cadfan conquered and held Northumbria for a period, northern England from the Irish Sea to the North Sea. But this was the last time that a Celtic monarch held land in eastern England, unless you count the Tudors.

In The Isles, written at the turn of the century, Davies promotes the view dominant among historians at that time that the transition from British Celtic to Anglo-Saxon occurred through diffusion of elite culture. He alludes to the fact that in the year 700 the law code of Wessex alludes explicitly to the fact the weregild paid for the death of a Saxon was many-fold greater than that paid for a Briton (of the same class status). This suggests that many Britons were still resident in the Anglo-Saxon kingdoms. The contrasting view, which was dominant in the early 20th century, was that the English replaced the Celts in toto. The Irish, Welsh, and to some extent the Scots, were viewed as racially distinct from the Germanic English.

2015’s The fine scale genetic structure of the British population answered many of these questions. It turns out the maximal positions were incorrect. The authors estimate that 10-40% of the ancestry in eastern and southern England (the red positions on the map) derive from Germanic peoples which we might term Saxon, Angles, and Jutes. Even if the fraction is as low as 10% that is not trivial. If we take a value closer to ~25%, unless there were massive reproductive advantages for elites, it could not have just been diffusion from the elite. Archaeologists also see wholesale changes in agricultural patterns in eastern England, indicative of a transfer of a whole folkway.

All that being said it is likely that the majority of the ancestry of the population of England proper descends from Britons. In fact, once the Anglo-Saxon cultural hegemony was established it seems that some elite Britons may also have changed their identity. It is always a curious fact that the names of the first kings in the genealogy of the House of Wessex are distinctively Celtic. Just as Romano-Gallic aristocrats began aping the styles and mores of the Frankish elite in the 6th century, so perhaps some British warlords became Saxons.

Using similar methods many of the same authors have now put out a preprint on Ireland, Insular Celtic population structure and genomic footprints of migration. Unlike the earlier work on Britain, they’ve acknowledged the ancient DNA results which have reshaped our understanding of population turnover in Ireland. That being said, they are focused on more recent events, as well as spatial structure in the modern era.

Though they don’t have access to as detailed a regional data set as in the earlier work on Britain, in this case, the authors managed to detect a lot of regional population structure within Ireland. Why? Though the Irish are relatively homogeneous, as all Northern Europeans are, looking at long tracts of the genome and the patterns therein can squeeze out more information.

The figure at the top of this post shows how well they can cluster individuals geographically: they’ve basically recapitulated the “map of the British Isles.” There aren’t too many surprises. Western Ireland seems to exhibit greater genetic differences as a function of distance. Probably because it’s less developed, and perhaps because it has been less impacted by outsiders. Ulster and southern Scotland are strongly connected genetically. There are two issues going on here. First, the famous migration of Protestants into this region of Ireland from Scotland and northern England that occurred after the conquest of the 16th century. And second, the earlier migration of Irish to Scotland, which resulted in the creation of the Dal Riata kingdom.

Additionally, the authors detect more admixture in several parts of Ireland from Norse than they had anticipated. The mixing of Scandinavians and Irish created a hybrid culture, the Norse-Gaels, which was highly influential around the Irish Sea. So it would not be exactly surprising if there was a greater Scandinavian contribution to Irish ancestry than had been anticipated.

Of greater interest to me is the impact of social-political institutions on the genetic structure or lack thereof. Both Britain and Ireland have homogenized modal clusters. In Britain, this is associated with the expanding cultural zone of Anglo-Saxon rule, and later became the core of England. In Ireland, it seems to be the Pale, where Anglo-Norman rule was dominant for many centuries. Rapid cultural change seems to induce a state of panmixia. Genetic distinctiveness in the British Isles seems to have persisted in populations which were geographically isolated, or politically insulated, from expansive, assimilative, and integrative cultures. The modal cluster in Ireland is far smaller than in England, which nicely correlates with the much more limited impact of the Anglo-Norman ascendency of the medieval period.

Genomic ancestry tests are not cons, part 2: the problem of ethnicity

The results to the left are from 23andMe for someone whose paternal grandparents were immigrants from southern Germany. Their mother had a father who was of English American background (his father was a Yankee American with an English surname and his mother was an immigrant from England), and grandparents who were German (Rhinelander) and French Canadian respectively on their maternal side.

Looking at the results from 23andMe one has to wonder, why is this individual only a bit under 25% French & German, when genealogical records show places of birth that indicates they should be 75% French & German (more precisely, 62.5% German and 12.5% French). Though their ancestry is 25% English, only 13% of their ancestry is listed as such.

First, notice that nearly half of their ancestry is “Broadly Northwestern European.” Last I  checked  23andMe uses phased haplotypes to detect segments of ancestry. This is a very powerful method and is often quite good at zeroing in on people of European ancestry. But with Americans of predominant, but mixed, Northern European background rather than giving back precise proportions often you obtain results of the form of “Broadly…” because presumably, recombination has generated novel haplotypes in white Americans.

But this isn’t the whole story. Why, for example, are many of the Finnish people I know on 23andMe assigned as >90% Finnish, while a Danish friend is 40% Scandinavian?

The issue here is that to be “Finnish” and “Scandinavian” are not equivalent units in terms of population genetics. Finns are a relatively homogeneous ethnic group who seem to have undergone a recent population bottleneck. In contrast, Scandinavia encompasses several different, albeit related, ethnicities which are geographically widely distributed.

Ethnic identities are socially and historically constructed. Additionally, they are often clear and distinct. This is not always the case for population genetic classifications. On a continental scale, racial classification is trivial, and feasible with only a modest number of genetic markers. Why? Because the demographic and evolutionary history of Melanesians and West Africans, to give two concrete examples, are distinct over tens of thousands of years. Population genetic analyses which attempt to identify or differentiate these groups have a lot of raw material to work with.

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