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June 20, 2018

Three drinks for the ages

Filed under: Alcohol,Coffee,Genetics,milk,science — Razib Khan @ 9:33 pm
Irish Coffee

The “Irish coffee” is a a delicious concoction. Coffee, alcohol, and dairy. What more can you ask for? Man does not live on bread and water alone. Cafes and bars are thick on the ground in large cities, but also grace country roads. Coffee and alcohol are congenial to conviviality among settled peoples, while milk is the staff of life for many pastoralists, consumed raw or turned into cheese.


Of the three, coffee is a new on the scene, discovered within the past 1,000 years. The consumption of milk, whether raw or as cheese, goes back to prehistory. But on the geological scale it a recent cultural development. In contrast, the imbibing of alcohol in some form is probably as old as humanity itself, albeit not as a pint in the pub.

Alcohol is produced naturally by the fermentation process, a metabolic pathway which is far more ancient than the oxygen metabolism that has been dominant for the past few billion years. Humans are omnivores, and our ancestors consumed overripe fruit which had fermented to the point of producing alcohol byproduct. Meanwhile, “good bacteria” in our guts also produced alcohol.

This is not a bad thing. Alcohol is nutritious in that it provides calories.

Though in modern societies we “count our calories”, and the richness of a deep and dark beer is not always a selling point, for the vast majority of our species’ history those calories were a feature, not a bug.

Early civilization ran on beer. The Sumerians even had a goddess of beer, Ninkasi. The workers who built the pyramids of Old Kingdom Egypt were given rations of beer. In other words, the wonders of the ancient world were fueled by alcohol!

And this is not just forgotten history. Until very recently much of the world was awash in alcohol, whether it be beer, wine, or various distilled spirits. Public and private drunkenness were one of the major reasons behind the emergence of the American “temperance” movement. Though Prohibition was deemed a failure, American alcohol consumption has never recovered to its earlier highs.

One of the reasons that Americans, and many other peoples, drank so much is that alcoholic beverages is that not only did they provide calories, but they were often more potable than conventional water. Ancient humans in hunter-gatherer bands did not have to contend to cholera, but the first village societies, and those who lived in early modern cities, lacked modern sanitation. Safe drinking water was one of the major achievements of 20th century engineering, and obviated the role that alcohol had traditionally played in quenching the thirst of the common man.

But alcohol is not a matter just of history, biochemistry and engineering. Humans differ in their ability and capacity to metabolize alcohol due to variation on their genes. In particular, ADH and ALDH2. The ADH genes produce enzymes which breakdown alcohol for processing by later biochemical steps, one of which is catalyzed by the product of the ALDH2 gene.

If you’ve ever seen someone with the flushed face characteristic of having had too much to drink, they may have a mutation on ALDH2 which means that they don’t process acetaldehyde very well. As the cells build up acetaldehyde, a host of physiological reactions kick in. Research has shown that those who exhibit these reactions are much less likely to be alcoholic.

In contrast, those with mutations on ADH tend to process alcohol very well indeed. But in the process they produce more acetaldehyde than the body can handle, resulting in physical discomfort. And similarly to the ALDH2 mutation these individuals are less likely to become alcoholic.

Genetic variation in the ability to process alcohol is a consequence of the long history of human omnivory. In contrast, the evolutionary history around our consumption of milk is much more straightforward and strange. For the vast majority of our species’ existence adults have not had the ability to digest milk sugar, lactose. This is a characteristic we share with all other mammals. The adaptive reason for this is likely that it encourages and forces weaning, so that mothers can bear other offspring.

And yet a minority of modern human adults today can digest milk. How? Why? The LCT gene produces an enzyme lactase, and mutations in this gene allow humans in Europe, parts of Southern Asia, East Africa and the Near East to continue to drink milk into adulthood. Over the past 5,000 years unique mutations in Europe and South Asia, in Arabia, and in Africa, have all been strongly selected.

In Denmark the mutant allele is now at frequencies as high as 90%.

Ancient DNA tells us that the ability to digest milk sugar into adulthood did not arise with agriculture and sedentary lifestyles. It is not implausible that Neolithic people who domesticated goats and sheep fermented milk to produce cheeses, where the sugar was broken down to make it more palatable. But the adaptation to a predominantly dairy dependent lifestyle only emerged with full-blown pastoralism, over the past 4,000 years. The earliest pastoralists on the Bronze Age Eurasian steppe carried the lactase persistent genetic variant, but only at low frequencies.

Dairy is an essential part of the modern food pyramid, at least for the USDA. But perhaps it tells us more about our evolutionary present than the evolutionary past. So often we talk about evolution as a dynamic of the deep past. But with lactose tolerance we see evolution as a process which is just initiating.

Finally, there is coffee. Though variation on the CYP1A2, Cytochrome P450, effects how fast caffeine is metabolized, coffee is such a recent cultural invention that it is unlikely that there are any adaptive dynamics related to it on a genetic level. Rather, CYP1A2 is locus which controls processes designed to cope with toxic chemicals by breaking them down. Caffeine in some ways is such a chemical, and those who metabolize it fast need to drink more coffee to feel its effects than those who have more efficient metabolization.

The effect of caffeine on humans is literally inefficiencies of bodily detoxification.

Milk nourishes. Alcohol both nourishes and alters the mental state of those who imbibe it. In contrast, caffeine does not nourish, but stimulates. For the past few million years our species likely never interacted with caffeine, but we were pre-adapted because of our consumption of a wide range of plants which manufacture chemical defenses.

The legend of coffee dates back 1,000 years, when an Ethiopian goatherd saw one of his animals behave strangely after eating a coffee plant. Within the next five hundred years coffee beans were cultivated across the hillocks of the lands around the Red Sea, from Ethiopia to Yemen, and became part and parcel of Islamic culture. To this day the coffeehouse is a major social and cultural nexus in the Middle East, though colonialism has taken it far afield, from Java to Colombia.

By the Renaissance coffee had reached Europe, and the proliferation of coffeehouses, and their stimulative effects, may have triggered the early modern Enlightenment intellectual revolution. While alcohol softens and dims the outlines of world around you, coffee is a stimulant which sharpens our perceptions and accelerates our cognitive pace.

Coffee, alcohol, and milk, are such central aspects modern culture that it is hard to imagine our existence without them. Though there is genetic variation in how we can process them, their relevance to our lives transcends biology, and extends to economics, history, anthropology, and in the case of wine, religion. Though they may not be the ambrosia of the gods, modern civilization arguably stands on the shoulders of these beverages.

Wondering if you are lactose tolerant based on your genetics? Check out Metabolism by Insitome.

Three drinks for the ages was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

June 13, 2018

The days of the All-Fathers

Filed under: Father's Day,Genetics,History — Razib Khan @ 11:12 am
Citation: Zerjal et al.

“A man’s greatest joy is crushing his enemies.”

— Genghis Khan

There are many apocryphal quotes attributed to Genghis Khan. And there’s a reason for that — in a single generation he led an obscure group of Mongolian tribes to conquer most of the known world. His armies, and those of his descendants, ravaged lands as distant as Hungary, Iran and China. After the great wars, though, came great peace — the Pax Mongolica. But the scale of death and destruction were such that in the wake of the Mongol conquests great forests grew back from previously cultivated land, changing the very ecosystem of the planet.

It is no great surprise then that if there were ecological impacts of the Mongol conquest, there were also genetic ones. About ~10% percent of the men who live today within the former territories of the Mongol Empire at the death of Genghis Khan carry a particular Y chromosome lineage. About 15 years ago researchers tried to assess the relationship of these individuals on their Y chromosome, and were confronted by the reality that there wasn’t any neat relationship…the phylogeny was a “star.”

Citation: Zerjal et al.

What this means is that at some point in the past men who carried this Y chromosome underwent a very rapid expansion. So rapid that the genetic tree simply “explodes,” rather than accumulating mutations in a gradual manner which could outline different relationships between parental and offspring Y chromosomes. By looking at the pattern of diversity of the branches of the star lineage scientists concluded that this cluster must have expanded about ~1,000 year ago in the past.

Genghis Khan

What happened about ~1,000 years ago? It is notable that the lineage, the “star haplotype,” is most diverse and frequent in and around Mongolia. The conclusion was unmistakable: this Y-chromosome lineage comes down from the tribe of Genghis Khan, and its explosive growth occurred due to the explosive growth of the Mongol Empire.

Genes reflect history and social norms. The history of the Mongol expansion and the extermination of local elites across vast swathes of Inner Asia has left its legacy in the genomes of modern people, with the signature of explosive growth in the Genghis Khan Y haplotype, which stretches far and wide. The persistence and frequency of this lineage across nearly 1,000 years attests to the social prestige attached to be a direct male scion of Genghis Khan and his descendants.

The cultural importance of descent from Genghis Khan in Inner Asia can not be underestimated. Though he was a pagan through-and-through, among Muslim Turkic peoples descent from him became highly prestigious, and a mark that one was meant to rule.

Citation: Karmin et al.

In the case of the the Genghis Khan Y lineage there is a historical record that explains the cause of the genetic phenomenon. What about other Y-chromosomes?

It turns out that about 4,000 to 5,000 years ago a widespread bottleneck followed by an expansion occurred specifically on the Y chromosome for many lineages, not just one. This is particularly true of Eurasia.

For example, Y haplogroups R1a, R1b and I1 seem to have undergone expansion at this time after a population reduction. R1b is the most common haplogroup in Western Europe. R1a is the most common in Eastern Europe, Central Asia, and much of South Asia. I1 is the dominant haplogroup of Scandinavia. But 5,000 years ago ancient DNA tells us that R1a ad R1b were very rare where today they are common. I1 seems to be a relic of the Pleistocene hunter-gatherers of Europe, but it only began expanding at the same time as R1a and R1b.

Unfortunately 5,000 years ago most of the world was cloaked in prehistory.
Light war chariot

History provides few clues about why a few Y chromosomal lineages came to be so dominant. But we do know that this was around the time when pastoralism and horse-powered warfare, in the form of the light chariot, came into being. New research suggests that only theoretical models that rely on “inter-group competition” can explain the Y-chromosome pattern we see. That is, it can’t be polygyny, where a few men have many wives within the tribe. Rather, it has to be a tribe as conceived of as a patrilineal kinship unit. The victory of one tribe was total loss for the males in another tribe, and each tribe was represented by a particular Y-chromosomal lineage.

Which sounds awfully familiar to the descendants of Genghis Khan…

Interested in learning where your ancestors came from? Check out Regional Ancestry by Insitome to discover various regional migration stories and more!

The days of the All-Fathers was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

June 11, 2018

Genetic variation in South Asia

Filed under: Genetics — Razib Khan @ 1:33 am

I don’t have too much time right now. So a quick data post. The map above shows India’s scale in relation to Europe.

Below is an NJ tree that shows pairwise Fst values (genetic distance):

Please notice the small genetic difference between Britain/Spain/Poland. Compare to Gujrati vs. Sindhi, let alone Gujrati vs. Telegu.

Now, PCA:

Genetically Sindhis occupy a place between South Indians and Iranians. Some Gujaratis are nearly where Sindhis are, but many are far more shifted toward South Indians. The Fst display masks this since it aggregates populations.

Treemix shows the relationships and their scale. South Asians have a lot of drift between them.

Some of you are probably bored by this post and wonder about it’s practical implication. If so, keep on paging down (or up).

June 6, 2018

Genetical observations on caste

Filed under: Caste,Genetics — Razib Khan @ 10:49 pm

One of the more interesting and definite aspects of David Reich’s Who We Are and How We Got Here is on caste. In short, it looks like most Indian jatis have been genetically endogamous for ~2,000 years, and, varna groups exhibit some consistent genetic differences.

This is relevant because it makes the social constructionist view rather untenable. The genetic distinctiveness of jati groups is very hard to deny, it jumps out of the data. The assertions about varna are fuzzier. But, on the whole Brahmins across South Asia have the most ancestry from ancient “steppe” groups, while Dalits across South Asia have the least. Kshatriya is closer to Brahmins. Vaisya has lower fractions of “steppe”. And so on. These varna generalizations aren’t as clear and distinct as jati endogamy. Sudras from Punjab may have as much or more “steppe” than South Indian Brahmins. But the coarse patterns are striking.

As a geneticist, and as an irreligious atheist, a lot of the conversations about “caste” are irrelevant to me. They’re semantical.

You can tell me that true Hinduism doesn’t have caste, that it was “invented” by Westerners. They may not have had caste, but the genetical data is clear that South Asians were endogamous for 2,000 years to an extreme degree. Additionally, the classical caste hierarchy seems to correlate with particular ancestry fractions.

Second, you can say Islam, Sikhism, Jainism, and Buddhism don’t have caste. That they picked it up from Hinduism. Or Indian culture. That’s true. But I think Islam, Sikhism, Jainism, and Buddhism are all made up, just like Hinduism. I don’t care if made up ideologies don’t have caste in their made up religious system. I am curious about the revealed patterns genetically.

I have a pretty big data set of South Asians. Some of them are from the 1000 Genomes. Here is where the 1000 Genomes South Asians were collected:

Gujarati Indians from Houston, Texas
Punjabi from Lahore, Pakistan
Bengali from Dhaka, Bangladesh
Sri Lankan Tamil from the UK
Indian Telugu from the UK

Some of the groups showed a lot of genetic variation, so I split them based on how much “Ancestral North Indian” (ANI) they had. So Gujurati_ANI_1 has more ANI than Gujurati_ANI_2 and so forth.

Here is a tree showing pairwise genetic distances between the groups:

The positioning of some groups near each other is an artifact. Dai from China is an outgroup, as are Iranians and Baloch. So all are pushed near each other.

Treemix with 3 migrations shows similar patterns:

Now let’s do a PCA:

Click the link above and you’ll see Bangladeshis are all shifted toward Dai. The Iranians are at the bottom, but nearest to them are the Baloch. Then the Pathan. Then Punjabi_ANI_1.

Let’s zoom in on the South Asian groups.

Do you notice something about the Bangladeshis? They don’t have much South Asian ancestry variation. Their variation is all due to East Asian ancestry, which seems to have a west to east gradient (I’m way on the right edge, and my family is from the eastern edge of eastern Bengali).

This is not the case for Punjabis.

As you can see, the Punjabis sampled in Lahore range form almost Pathan to almost South Indian. This totally shocked me. This is a huge range of variation.

Compare to Gujus:

I’m pretty sure there are only a few Gujurati_ANI_4 because the sampling occurred in Houston, TX (Indian gov. stingy about genetic testing/sampling, so usually done in Diaspora). Notice that Gujus, mostly Hindu, have the same genetic variation as Punjabis!

Now let’s compare Dalits to Brahmins.

To my surprise, Chamars from UP are quite like South Indian Dalits (there is some “steppe” admixture you can detect in Chamars, so they’re not identical). South Indian Brahmins have some local admixture.

What’s my point here?

In some of the comments, there was talk about how Bengali Muslims have their own form of caste. This seems plausible, though I wouldn’t know personally. I wasn’t raised in Bangladesh. But these data make it clear that there’s almost no caste-like structure in Bangladesh genetically. The variation is almost all due to the mixture with East Asian-like people, and that’s almost certainly due to geography (West Bengalis have this, but to a lesser portion, and people from eastern Bangladesh have more than people from western Bangladesh).

In contrast, when you look at the 1000 Genomes Telugu or Tamil sample structure jumps out. First, there are a small number of Brahmins. But there is also a large group which is clearly scheduled caste. Looking at Gujuratis, they are very diverse. The Patels probably anchor the Sudra/ middle-class component dominant in the region.

Punjab looks like the Indian groups, not Bangladesh. I have no idea about Pakistani caste or class dynamics, but the genetics makes it look like the social structure of Hindus. In contrast, Bangladesh looks like a non-South Asian population, with most of the variation being due to geography and proximity to a very different group (Tibeto-Burmans).

I don’t think Bengalis are more punctilious Muslims than Punjabis. I think the social landscape of Bengal emerged out of a frontier expansion which destablized the default Indian caste structures that undergired most societies. In Pakistan Islamicization didn’t perturb the underlying Indianness of Punjabis.

The fall of Rome and the wandering of peoples

Filed under: Ancient History,Genetics,History,Roman Empire — Razib Khan @ 12:28 pm
The feat of Atilla

“…The people of the Huns, but little known from ancient records, dwelling beyond the Maeotic Sea near the ice-bound ocean, exceed every degree of savagery. Since there the cheeks of the children are deeply furrowed with the steel from their very birth, in order that the growth of hair, when it appears at the proper time, may be checked by the wrinkled scars, they grow old without beards and without any beauty, like eunuchs”. — Ammianus Marcellinus

In the year 400 AD, the city of Rome was inhabited by around 1 million people. Britain was a thoroughly Roman province with public baths and flourishing cities. By the year 600 AD Rome was home to 50,000 humans, and Britain was on its way to becoming England — dominated by pagan German tribes.

How did this happen?

The short answer is that the Roman Empire fell. The longer story — some scholars argue that Rome did not quite fall, rather, it transformed into something different.

Citation: Lead pollution recorded in Greenland ice indicates European emissions tracked plagues, wars, and imperial expansion during antiquity

To some extent, this is a matter of definitions. What we do know (rather definitively) is that the material conditions of the Western Roman Empire changed greatly over the centuries that we define as the decline and fall of the Empire. Recent work using lead pollution as a proxy for economic production overlaps very neatly to periods of decline and collapse… and subsequently recovery.

There is no doubt today that there were major changes in the later centuries of the Roman Empire, and its transition into the post-Roman world of barbarian kings. These changes were material, as the Roman system of economic production and exchange collapsed, and these changes were cultural, as the Christian religion and Latin language disappeared from provinces such as Britain and the interior of the Balkans.

But were the migrations of the barbarians the movement of distinct peoples, bound by kinship? Or, were they migrations of opportunists, who created identities on-the-fly to take advantage of the vacuum of authority in the collapsing Roman landscape?

King Arthur

The case of Britain, and how it became England, is illustrative of the debate. In the late 19th and early 20th centuries, the assumption was the the arrival of the Angles, Saxons and Jutes resulted in a mass slaughter of the native Romano-British. The conflict was remembered in Welsh folk-memory, and eventually transformed into the pseudo-historical legend of Arthur.

Despite King Arthur’s iconic status as the once and future king of the British Isles, it is important to remember that his enemies were the ancestors of the English!

Or were they? As the 20th century proceeded, a school of thought emerged that said that in fact the Anglo-Saxon hordes were a small group of mercenaries. The vast bulk of the ancestors of the English would have been Romano-British people who took up the culture of the new elites.

Citation: The fine scale genetic structure of the British population
This is where genetics comes in.

Over the past 20 years, a scientific project ambitiously titled “The Peopling of the British Isles” has collected data on thousands of individuals whose genealogies are verified to particular locales within the United Kingdom. Comparing the genetic profiles of British individuals, as well as comparing the British with peoples on the European continent, the group arrived at some conclusions which shed light on the “Anglo-Saxon” question.

It turns out that both extreme viewpoints were wrong. The most numerous population cluster in the British Isles, illustrated in red on the figure above, is a mix of both German and native British. The authors state: “We estimate the proportion of Saxon ancestry in C./S England as very likely to be under 50%, and most likely in the range 10%-40%.”

The majority of the ancestry in England does descend from Romano-British people. They were not exterminated, but rather a substantial minority, which varies by location and also descends from German migrants from the continent. This was not a small group of mercenaries which took over a preexistent order, but the migration of a people, who eventually assimilated the British majority into their folkways.

Of course not all cases were so extreme. Anglo-Saxon England in many ways was totally unrecognizable as Roman Britain, so sharp was the cultural rupture. In much of the post-Roman world, the conquest elite was much smaller, and eventually demographically absorbed by the local “Romans” (as they were still known).

Theodelinda, queen of the Lombards

Yet even in these cases, the distinctiveness of the invaders comes across both in the written records, and now, in the genetics. The Lombards were a German people who invaded and conquered much of the Italian peninsula in the second half of the 6th century A.D. Barely Christianized, and unfamiliar with the ways of the Romans, they are described as a very alien and barbaric people by historians of the period. They were often depicted as blonde.

Though eventually absorbed into the post-Roman elite, they gave their name to the northern region of Italy, Lombardy.

New work in ancient DNA clarifies just how distinct and separate the early Lombards were from their Roman subjects. The Lombards migrated to the Italian peninsula via what, today, is Hungary. A group of researchers excavated DNA from Lombard cemeteries in both Hungary and northern Italy, dating to the middle 6th century to the early 8th century respectively.

What they found is that there were two distinct clusters of people in the cemetery. One group, buried with rich grave goods, and some of whom seem to have very high protein diet, were genetically exactly like Northern Europeans. Another group were more like Southern Europeans. The two groups were generally segregated within the cemetery. The men buried with rich grave goods and of Northern European genetic heritage tended to be related along the paternal lineage.

What are the conclusions one can draw from this?

The Lombard migration was clearly a movement of a coherent ethno-religious group. The historical record is clear that these people were very culturally distinctive from the Romans whom they conquered. Additionally, these results indicate that the Lombards were accompanied by a group of lower status individuals (judging by the lack of grave goods and less rich diet) who were more genetically similar to the native peoples of Southern Europe. Finally, the leadership class of the Lombards were a paternal kinship group.

Finally — the Huns — where we started.

To a great extent the Huns are sui generis. Many of the barbarian peoples recorded in the historical records conquered parts of the Roman Empire and settled down. Eventually, they wrote down their own histories, and even put down their language in written form.

Not so for the Huns. They exploded on the scene in the late 4th century, as recorded by Ammianus Marcellinus. The Christians saw in their arrival the harbinger of the End of Days. A purely nomadic people, the Huns were like nothing the Romans had seen before. The arrival of the Huns set in motion the great migrations which coincided with the collapse of the West Roman Empire. But… where did they come from? Who were they?

The bestial manner in which the Huns are described by Classical authors has suggested to some historians that the descriptions were tropes. The power and vitality of the Huns had to be accompanied by descriptions which were as startling and novel. They had to be a force of nature to sweep all the peoples before them as they had.

But the Huns faded as quickly as they arrived. After the defeat of Attila in the middle of the 5th century, they slowly disappear from history. But they persist in archaeology. The Huns seem to have dispersed into the Balkan interior, and slowly become absorbed into the local population. Though they were never a literate people, they did have particular custom of skull deformation which leaves archaeological records. This practice persists in some locales deep into the 6th century.

Citation: Population genomic analysis of elongated skulls reveals extensive female-biased immigration in Early Medieval Bavaria

Recently, a paper was published that revealed a distinctive genetic profile, likely of females of Hunnic background. In Bavaria around 500 A.D. a group of high status males seem to have married women who were migrants from the Balkans, as adduced from isotope analysis. Some of these women exhibited distinctive skull deformations associated with Huns and other Central Asian peoples. One of these women was ~20% East Asian.

One hypothesis has been the Huns descend from a Turkic group present in Mongolia named the Xiongnu. The Huns were the westernmost extension of the Xiongnu horde. These results are the first definitive evidence that the Huns were in fact of East Asian provenance. When Ammianus Marcellinus commented on the beardlessness of the Huns, he may simply have been observing a characteristic more typical of East Asian peoples.

These examples show that the relationship between history, genetics, and archaeology is complex. Until recently the genetic component was not available to us. Now that researchers have access to the genetics of ancient peoples they can confirm or reject the hypothesis that these groups were distinct ethnolinguistic entities. Genetics also allows researchers to explore in depth the diversity and range of migration which characterized the collapsing post-Roman world, transforming vague guesswork into probabilities.

Interested in learning where your ancestors came from? Check out Regional Ancestry by Insitome to discover various regional migration stories and more!

The fall of Rome and the wandering of peoples was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

May 25, 2018

Arise the coalescent!

Filed under: Biology,Evolution,Genetics,science — Razib Khan @ 12:14 pm
Citation: Modeling Human Population Separation History Using Physically Phased Genomes

Evolution is sometimes difficult to comprehend in terms of how it plays out in your mind’s eye. This is different from believing that evolution occurred. Evolutionary ideas were in the air when Charles Darwin and Alfred Russell Wallace both developed a theory of morphological change and speciation driven by adaptation in the middle of the 19th century. Their genius was introducing natural selection as the motive force underlying the change. But both of these thinkers lacked a true mechanism of heredity, so the formal extension of the field was hobbled.

With the emergence of genetics in the years after 1900, evolutionary science developed into a new and powerful form, what we now call the “Neo-Darwinian Synthesis.” This project combined the descriptive richness of natural history, the explanatory power of classical conceptual Darwinism, and the formal precision of population genetics.

The Neo-Darwinian Synthesis rests to a great extent on population genetic models. The most elementary of those models is that of the Hardy-Weinberg Equilibrium (HWE) — a large random mating population not subject to selection or drift. Deviations from the conditions of these models allow us understand the processes that are occurring in specific populations.

In the lab, researchers use matings between organisms such as Drosophila that deviate from the assumptions underneath the models, and see what the outcomes are. Scientists mate together flies with similar or dissimilar traits, violating random mating. They select individuals based on their characteristics, or collapse reproductive pedigrees down to a family lineage to explore inbreeding, introducing selection and random genetic drift.

But laboratory research can be both time intensive and tedious. With the rise of powerful computing tools in the last half of the 20th century scientists realized that they could simulate outcomes of their models. Just like in an experiment, researchers could change the conditions, the parameters, and see the results to the final outcome!

State of the art simulator, 1985

In the beginning, the power of simulations and computing seemed almost magical to researchers. No more time intensive sampling in the field, or expensive construction of laboratory facilities.

But over time, they began to realize that simulations also have their limitations. Computer memory and disk space costs money too, and scientists quickly found that the law of scarcity was not abolished. They couldn’t explore infinite possibilities because infinite took forever, even in a computer.

Imagine that you start with a few hundred individuals and simulate them randomly “mating.” You stipulate that their population grows 2% every generation. After a 100 generations, your population size is 10 times larger. The possible number of “mates” in your program is now 10 times greater, and there are so many more possible interactions. Anyone who has tried to work with large files knows that computing resources are finite, and simulations running forward in time run into the limits of that finitude soon enough.

But what if you moved back in time? Imagine you began with 10,000 individuals, and traced the ancestors of these 10,000 back across the generations. Genealogies can be complicated. But consider a single gene copy in your body, and compare it to another copy in another person. At some point in the distant past, the two copies share a common ancestor — they coalesce.

The coalescent sounds science fictional, but really it’s just a way to work backward from the genetic data you have now, to the past. You can create a tree of relationships back into the distant past, reversing direction with a genetic time machine. And the beauty of the coalescent from the perspective of 2018 is that computationally it is much more feasible to work back in time. With each step, you have fewer and fewer branches in the genealogy to model — back to a single common ancestor.

Instead of being overwhelmed by computational tasks, the coalescent converges upon the elegant simplicity of the last common ancestor, bring together late 20th century mathematics, 21st century computing, and the original conceptual insight of Darwin and Wallace of common descent.

Explore your Regional Ancestry story today.

Arise the coalescent! was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

May 16, 2018

The tribe more diverse than all of Asia!

Filed under: Africa,Genetics,science — Razib Khan @ 1:17 pm

In 2010, a paper, which sequenced the whole genome of Bishop Desmond Tutu, revealed that the San Bushmen of South Africa show more genetic difference between two men from different tribes than the differences between a European and an East Asian. In other words, two San Bushmen men from different populations within South Africa are more genetically distinct than a Chinese person is from a British person.

A follow-up paper from 2014 revealed that over the course of human history, the San Bushmen in fact had the “largest population” of any modern group. This seems surprising and ridiculous. There are over 1 billion Han Chinese, and only 100,000 San Bushmen.

Citation: Khoisan hunter-gatherers have been the largest population throughout most of modern-human demographic history

How can this be?

The first thing to keep in mind is that we’re talking about genetic diversity. When you look at the genome of a San Bushmen individual, it’s a lot more genetically diverse than that of a Han Chinese individual. A typical San Bushmen has more than 4 million genetic variants (SNPs), while a typical Chinese has only over 3 million genetic variants. This difference reflects population history.

One of the major keys to solving this mystery is to remember that the “Out of Africa” migration imposed a bottleneck on all non-African populations. That means that 50 to 100 thousand years ago, a small group of humans were the ancestors of all groups outside of Africa. All non-African populations exist in the shadow of this bottleneck, from the over 1 billion Han Chinese to a few hundred tribesman in the Amazon.

In contrast, the ancestors of Africans did not experience such a bottleneck.

The number of genetic variants that Africans carry did not decrease due to an “Out of Africa” bottleneck, and of all the people of Africa, the San Bushmen seem to have occupied a wide zone of southern Africa in their current state from an immemorial time. This stability has left an imprint on their genome, which is more genetically diverse than any other human group.

If you could use a time machine to count the number of people in the groups of humans which gave rise to the San Bushmen, they would always be larger than the small migration “Out of Africa.” This is why a tribe of San Bushmen have more genetic diversity than billions of Asians!

Interested in learning where your ancestors came from? Check out Regional Ancestry by Insitome to discover various regional migration stories and more!

The tribe more diverse than all of Asia! was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

May 9, 2018

The “X” in the sex chromosome

Filed under: Genetics,Genomics,mothers-day,science — Razib Khan @ 3:48 pm

There are ~3 billion base pairs in the human genome. Of that ~5% are in the X chromosome. The X is fully functional, unlike the famously hamstrung Y. It harbors one of the longest genes in the human genome, DMD, at 2,300,000 base pairs. In contrast, the human Y chromosome only has 72 protein coding genes! (it’s perhaps no surprise that, aside from sex determination, many of these genes are involved in things such as spermatogenesis)

And yet it is the Y chromosome which gets full treatment in popular science books. Like the C student who receives praise for a B-, the Y chromosome is given high marks simply for doing a few things here and there, most especially its role in driving the emergence of biological males. But the reality is that males would not be viable if it wasn’t for the X.

Can you see that it says 74?

Because the Y chromosome is so handicapped, filled with repetitive “junk DNA,” the heavy-lifting is shifted onto the single X that males carry. Though the Y is what makes males male, the X is what keeps males alive.

Anyone familiar with sex-linked characteristics knows this. Red-green color blindness is found 8 percent of human males and 0.6 percent of human females. Many more women are carriers of color blindness than who are color blind themselves.

The genes responsible for detection of some colors are found on the X chromosome, and are subject to high mutation rates. If a female has a broken copy she usually has a fallback in a functional second copy. She’s a carrier. In contrast, because males have only one X chromosome (inherited from their mother), they don’t have a backup. If a color-vision gene on the X chromosome is broken, then they’re out of luck when it comes to perceiving the full vibrancy of the world.

In other words, the male X chromosome does not possess recessive traits. All traits express due to the state of the single copy of the gene determining the trait. Every mutation on the X chromosome can potentially produce a mutant that will be exposed to natural selection.

Neanderthal-modern human hybrid

This results in some interesting evolutionary quirks when it comes to how natural selection shapes the genome and drives adaptation within populations and speciation between them. Crosses between different species can leave hybrids infertile. In mammals this often happens in males because mutations on the X chromosome can interfere with proper reproductive development. Selection against the genes of other species then happens because males can’t produce offspring.

Studies of Neanderthal admixture confirm this — there is far less Neanderthal ancestry on the X chromosome than across the rest of the genome. There is strong selection against Neanderthal variants in males, because these genes work less well with the rest of the modern human genome.

A wife of Genghis Khan

But the X chromosome is not distinctive just in terms of just natural selection. As two out of three X chromosomes in any population are found in females, its genetic history will be biased toward that sex. Differences between the X chromosome and the non-sex genome can tell us differences in the histories of men and women.

For example historically many more of the female ancestors of admixed people of the New World tended to be non-European, whether it was indigenous or African. As such, the genetic profile of the X chromosome in terms of similarity to worldwide variation would be different from the non-sex chromosomes, because those come equally from the father and mother. This is exactly what we see. There is less European ancestry on the X chromosome.

More generally mating systems such as polygyny — men having multiple female partners — result in far fewer males than females who contribute to future generations. Among Mongols during the era of Genghis Khan, a small number of males descended from Genghis and his Mongol horde had children with numerous women. Because X chromosomes tend to found in women, more of whom are reproducing, they will more diverse than non-sex chromosomes (where a few men contribute half the genes), while the Y chromosome will be the least diverse of all (where only a few men contribute genetic variation).

Men have only one X chromosome, but the one they have is genetically essential to them. X chromosomes are not exclusive to women, but for all males they are the singular legacy of their mothers. Because of this bias the X can shed light on the history of the women of our species, while the uniqueness of inheritance the X chromosome may even extend to driving the emergence of our species.

Explore your Neanderthal story today.

The “X” in the sex chromosome was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

May 2, 2018

The genetics of forensic identification

Filed under: criminology,dna-sequencing,Forensics,Genetics — Razib Khan @ 4:03 pm

The arrest of a suspect in the infamous “Golden State Killer” DNA evidence was notable for how he was identified. The media attention the case has garnered means that forensics genetics have come to public attention again in 2018. Not that the public has not been aware of the power of genetics in legal and criminal contexts: The Innocence Project famously leveraged DNA results to show that some individuals had been falsely convicted by eliminating them due to lack of a DNA match from the crime scene.

But the recent illustration of the power of 21st century genomics, with researchers digging through public databases to search for relatives of the potential suspect, was revelatory for much of the world, which had not kept up with the breakneck pace of change in genetics.

The first human genome cost $3,000,000,000 and took more than a decade to complete. Today a good quality human genome sequence can be had for less than $1,000, and generated in around a day in a pinch. The field has been subject to massive changes in the last 10 years, crashing through Moore’s Law and transforming what geneticists are capable of in the present.

The arrest of a suspect in killings that date back four decades has awakened the public to the reality that geneticists have already been living in in the 21st century. It’s like Clark Kent transforming into Superman.

Obviously using genetics to resolve legal disputes is not new at all. Blood group inheritance patterns were understood early in the 20th century, and brought to bear in cases such as paternity disputes. But blood groups are only a small number of traits, with a limited about of variation. In a huge number of cases inheritance patterns wouldn’t resolve anything. If ~25% of the population had blood group A, then finding that wouldn’t allow for narrowing across a broad cross-section of the population even if it would be useful in specific cases.

But even techniques as primitive as blood group inheritance illustrate the power of genetic techniques in the 20th century: they could eliminate a large number of possibilities. ~75% of the population does not have blood group A, so if you are looking at a large number of suspects then removing three out of four possibilities might be worth it.

By the latter decades of the 20th century, forensic genetics took this to the next step. With the molecular revolution in biology, geneticists didn’t have to focus on blood groups — rather, they could look at variation at specific genes that they obtained from various types of biological samples. With the development of new techniques of amplifying DNA from infinitesimally small samples in the 1990s, the amount of genetic material needed declined greatly, making it feasible to revisit cases where DNA analysis was previously deemed impossible.

The combination of molecular biology and genetics in the late 1990s was a
forensic “killer app”, but there was still the problem that geneticists needed to target loci that had enough variation that they could differentiate individuals. If, for example, scientists tackled a genetic position where 99% of the population population has one variant, and 1% the other, in most cases there wouldn’t be much novel information that one could use.

Because forensic labs could only focus on a specific number of genes, they quickly realized that the biggest “bang-for-the-buck” was in highly variable regions. In particular they looked at “short tandem repeats” (STRs). These are regions of the genome subject to expansion or contraction in the number of repeat units during DNA replication, thus generating usable repetitive variation. Where “single nucleotide polymorphisms” (SNPs) are limited to four different bases (A, C, G, and T — and typically only two of the four possible bases), STR loci can differ over many different copy number variants. Because STRs loci are mutate rapidly, they are more polymorphic and vary a great deal even across families.

All this is why they are at the heart of CODIS, Combined DNA Index System, a governmental database used by law enforcement, and centralized at the federal level since 1998. Originally starting with 13 markers, today CODIS uses 20. Because of the high level of variation in these markers, random matches are rare. Though some geneticists dispute the statistics, the FBI estimates that a random CODIS profile should appear about 1 in 10 million cases. That means that there should be more than 30 matches to a profile just based on chance in the United States. Obviously not all of these individuals would be a suspect. All but one would be false positives through DNA testing.

With limited markers, false positives — or more precisely the inability to distinguish between individuals — are always going to be an issue. Just by chance some people will match others within a subset of the genome, even at these highly variable positions. In contrast, the lack of the match eliminates someone from the pool of suspects.

This is why CODIS was useful for exonerating people: if one did not match the DNA sample, one knew that this was not a statistical fluke. A negative match gives a certain conclusion: the individuals are different.* A positive match gives a probability: the individuals are likely the same.

But CODIS is 1990s genetics. The apprehension of the suspect in the rapes and killings from the 1970s and 1980s in California was done with state of the art genetics. While CODIS focuses on 20 markers at most, by 2010 tens of thousands, and today tens of millions, of people were getting large swaths of their genome genotyped, usually at 500,000 to 1,000,000 SNP positions. CODIS relied on STRs because of the expense of genotyping genetic positions in the 1990s.

But today “SNP-chips” cost less than $50 and return nearly a million markers. Data constraints are no longer an issue, and aligning patterns of SNPs across each chromosome allows for highly accurate assessment of relationships between people. Instead of returning the result that two individuals are probably siblings or parent-offspring, one can now conclude that two individuals are siblings, and share 46.5% of their genome in common! (including what segments of each chromosome they share)

With individual DNA data no longer being in short supply, what was needed was a database. CODIS may have about a million profiles, but those are not genotyped on modern DNA technology. Consumer genomics firms such as Ancestry, 23andMe, and Family Tree DNA do have SNP databases of more than a million (Ancestry has more than 10 million), but these are not accessible to law enforcement without a subpoena. However, there are public databases available with SNP genotype profiles. GEDMatch is one of those, with ~1 million entries.

The combination of hundreds of thousands of genetic markers across millions of individuals is powerful. Bringing these together unleashes the ability to look into the pedigrees of thousands of individuals who weren’t tested with just a single sample. There are ~300 million Americans. If GEDMatch has ~1 million samples in its database it is likely that the vast majority of Americans will have matches. Obviously the vast majority of people will not have a perfect match, but because modern methods use hundreds of thousands of variable positions a perfect match is not just a probability anymore, but a surety (barring identical twins there will be only one perfect match in the database per person at most). Matches with 2nd cousins and closer are also ones that can be made with very high confidence. This means people who descend from common great-grandparents — but even without that many people can make matches with people more distantly related; the suspect in the case above shared common great-great-grandparents with people in the GEDMatch database.

Genetic genealogists have become adept at looking at patterns of probabilistic matches that are quite distant, and triangulating them with other pieces of data to establish high confidence genealogical connections. Once those connections are made, obtaining DNA from suspects would yield a result that law enforcement could have near-perfect confidence in.

Law enforcement, the media, and the public are living in the genetic 1990s. The future is actually happening in the present, led by consumer genomics databases and “citizen scientists.” The lesson we can distill from the headlines is that genetic privacy may, in many ways, now be a 20th century novelty in the eyes of the law.

Explore your Regional Ancestry story today.


* There are exceptions to this when it comes to genetic mosaicism.

Regional Ancestry

The genetics of forensic identification was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

April 27, 2018

Closing the genetic chapter

Filed under: Genetics — Razib Khan @ 8:51 am

Indus Valley People Did Not Have Genetic Contribution From The Steppes: Head Of Ancient DNA Lab Testing Rakhigarhi Samples:

In other words, the preprint observes that the migration from the steppes to South Asia was the source of the Indo-European languages in the subcontinent. Commenting on this, Rai said, “any model of migration of Indo-Europeans from South Asia simply cannot fit the data that is now available.”

Some more comments at my other weblog.

At this point, we need to move to other things. I think the broad genetic framework is pretty clear.

1) The Indus Valley Civilization (IVC) people were a mix of eastern West Asian (from modern Iran) people and native South Asian peoples (~80% of South Asian mtDNA are haplogroup M).

2) ~1500 BC a major incursion from the steppe occurred and overlaid upon #1 to various extents as a function of region, language, and caste.

3) ~0 to 500 AD the strong endogamy that characterizes modern South Asians seems to have established itself.

April 25, 2018

DNA, from genetics to genomics

Filed under: DNA,Genetics,Genomics,science — Razib Khan @ 11:59 am

In the early 1950s scientists established that the molecular structure of DNA was a double helix. The had discovered the physical substrate of heredity. With this discovery the field of molecular genetics was born (and eventually a Nobel Prize given!).

And yet we also know that Gregor Mendel discovered the laws of heredity, the “law of segregation” and the “law of independent assortment”, nearly a century before the discovery of DNA.

It was literally the product of a garden.

The mature field of genetics itself developed fifty years before the discovery of the structure of DNA, as a host of scientists stumbled upon Mendelian insights simultaneously. Most were biologists who worked with plants, flies, or even algebra — no need for a powerful microscope or structural models of molecules.

Though DNA has been the key to many of the discoveries of the past fifty years, it is important to remember that the field of genetics is predicated on an abstract understanding of how inheritance works across pedigrees, as opposed to the biophysical basis of that transmission. Before DNA, before chromosomes, what Mendel and his heirs understood is that inheritance occurs through a process where discrete units of heredity, “genes”, are passed down from generation to generation.

These genes usually come in two copies, ‘alleles,’ for many organisms.

Recessive expression patterns of a trait, where parents do not express a characteristic found in their offspring, becomes comprehensible when a Mendelian model is adopted. Prior to this many had an intuitive “blending” understanding of inheritance, where the characteristics of the parents mixed together to produce offspring. The ultimate problem with blending inheritance is that it had difficulty in explaining how variation persisted over time. A problem solved by the Mendelian insight that genetic variation never disappeared…it simply rearranged itself every generation!

Genetics was born on the backs of Drosophila

Between the reemergence of Mendelian thought around 1900 and the discovery of DNA in the 1950s much research occurred in the field of genetics. The Neo-Darwinian Synthesis built upon the mathematical foundations of population genetics, which took the Mendelian framework and formalized and extended them, to create a model of evolutionary biology for the 20th century. Medical geneticists began to understand the patterns of inheritance of rare diseases in humans with the aim of preventing illness. Those researchers working with fruit flies discovered many of the phenomena which define modern genetics, such as recombination. Finally, biochemists established that heredity and nucleic acids were intimately connected.

Just as an understanding of the discrete basis of inheritance in a Mendelian framework opened up the systematic scientific study of heredity, so the understanding of the double helical structure of DNA paved the way for the molecular revolution of the second half of the 20th century, and the genomic revolution of the 21st. An understanding of DNA as the mode of inheritance allowed for the development of techniques that traced transmission of variation at the level of genes themselves, as opposed to expressed traits.

Illumina sequencing machine

And while in the 20th century we spoke of genetics, and specific genes, today we speak of genomes and the whole set of genes organisms possess. That revolution can not be understood without the knowledge of DNA as the mode of inheritance. If classical Mendelian genetics is pattern recognition across pedigrees, 21st century genomics is a synthesis of classical genetics, post-DNA era biophysics, and cutting-edge computing. Genomics is as much engineering as it is science; and “big data” as much as information theory.

The understanding of DNA created the world where genetics transformed itself from an esoteric science of probabilities, to a mass market product of possibilities.

Classical genetics tells you that your relatedness to your brother or sister is expected to be 0.50. Modern genomics might tell you that your relatedness to your brother or sister is shared across 46.24% of your genome. A fuzzy probability becomes a crisp reality. As a science, genetics can be imagined without DNA. It was born and matured decades before we understood the importance of the double helix, but as a part of our lives, one can’t imagine genetics without DNA.

Learn more about where your traits for food tolerance fall on the spectrum and explore your Metabolism story today.

DNA, from genetics to genomics was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

April 23, 2018

The water rises and Canute drowns

Filed under: Genetics — Razib Khan @ 11:49 pm

The Genetic History of Indians: Are We What We Think We Are?. The answer is that people of all races have always been what they always were. What we think about what we were…well, that changes.

“I KNOW PEOPLE won’t be happy to hear this,” geneticist Niraj Rai says over the phone from Lucknow. “But I don’t think we can refute it anymore. A migration into [ancient] India did happen.” As head of the Ancient DNA Lab at Lucknow’s Birbal Sahni Institute of Palaeosciences (BSIP), he earlier worked at the CCMB in Hyderabad and has been part of several studies that employed genetics to examine lineages. “It is clear now more than ever before,” he says, “that people from Central Asia came here and mingled with [local residents]. Most of us, in varying degrees, are all descendants of those people.”

Some researchers, even those associated with the current study like Shinde, aren’t quite convinced that an ancient influx of people into the subcontinent from the northwest has finally been established by the latest findings. Shinde does not like the word ‘migration’. “It is better to say movement,” he says, implying a two-way pattern. “Everyone back then was moving to and fro. Some people were moving here and some were moving out. There was contact, yes. There was trade. But local people were involved in the development of several things. So I am not very sure of the interpretation.”

As Rai points out, the analysis of the DNA sample they will present will be of a period before the Steppe people supposedly arrived in India. If R1a is absent in the Indus Valley sample, it suggests that it was brought into South Asia, perhaps by a proto-Indo- European speaking group, from elsewhere. “How do I say it? See, I am a nationalist,” Rai says over the phone. “People will be upset. But that’s how it is. All the studies are showing that people came here from elsewhere.”

I’ve been hearing from Indian journalists that some of these researchers have only “evolved” over the last few months. First, it’s a credit to them if they changed their views on the new data. If the above is correct they got usable DNA from one Rakhigarhi sample. I predict it will be like “Indus Periphery”, but with more AASI. It seems rather clear they’re going to submit a preprint within a month or so (that’s the plan, but it’s been the plan for a year!), but the results are being written up now.

Meanwhile, the ancient DNA tsunami is going to come in further waves in the near future. Various groups have huge data sets from Central Eurasia that are going to surface. Unfortunately, samples are going to be thin on the ground from India, but we have enough now that in broad sketches most people are now falling in line with what happened demographically from the northwest. The “AASI” ancestry is deeply rooted in South Asia, and it doesn’t look like there’s much of an impact of this outside of the subcontinent aside from nearby regions.

The real action is now in understanding the cultural and archaeological processes involved in the perturbation in the years after 2000 BCE. I’ve talked to a few of the geneticists working in this area over the past month or so, and they agree.

April 18, 2018

The braided estuary of human evolution

Filed under: Genetics,Human Evolution,paleontology,science — Razib Khan @ 2:22 pm

Metaphors matter because they evoke images, and images are often one of the best ways to understand something in a deep fashion. Consider Charles Darwin’s musing:

“It is interesting to contemplate a tangled bank…

He brought something memorable and familiar to make evocative the dynamics at play in his novel theory of evolutionary change through natural selection. The tangled bank has haunted us for over 150 years, though as a friendly apparition to be sure.

Other metaphors are less useful, and even downright destructive. The great chain of being hooks into deep human intuitions about our “special” place in nature and centrality in the universe. “Previously made in the image of our Creator” in the 19th century, science confirmed peoples’ expectations that modern humans are the pinnacle of evolution and the end of a long process of change; from the slouching ape, to the shuffling caveman, and finally, to the upright and thinking man.

The earlier view of Neanderthals was typical and illustrative of where we once were. Originally relegated to a primitive dead-end of our family tree, Neanderthals were depicted as bestial half-men at best. As late as the 2000s many researchers, such as the influential paleoanthropologist Richard Klein, doubted that humans and Neanderthals could produce offspring. There was skepticism from these quarters that Neanderthals could speak, or that they even used fire!

With the confirmation through myriad genetic analyses published from 2010 onward that in fact humans outside of Africa carry 1–2% Neanderthal ancestry, a transformation occurred in our perceptions of our cousins…or rather, our ancestors.

Clearly our understanding of human evolution is conditioned by our cultural preconceptions, our biases. Evolutionary biologists have long warned of the tendency to see in the “tree of life” directionality or purpose, but in the public’s mind the purpose of the universe is manifested in our own lineage. All of the pitfalls that we’ve attempted to avoid when considering evolutionary biology became stark and endemic in the study of humanity.

Unfortunately, paleoanthropology often fed into this narrative because of the paucity of remains.There was very little data, and an empire of theory and supposition cropped up in its place. The prominence of superstar researchers and their associated singular remains, Raymond Dart and the Taung child, Richard Leakey and the Turkana boy, and Donald Johansen and Lucy, highlighted the almost artisanal quality of the field.

As a result of only a few individuals being able to analyze the material evidence for the evolution of our own species, we eventually assembled a relatively neat ascending tree, with a few stray side branches. Like modernist architecture, paleoanthropology constructed a spare and elegant scaffold within which to understand the emergence of what we call humanity. Our story was simple, singular, and implicitly progressive. All paths led to us.

But just as genetics has changed our understanding of the origins of our species, so paleoanthropology itself is undergoing a revolution of sorts because of the veritable flood of data. Remains.

At the end of 2013 I happened to have been present when Lee Berger, a South African paleoanthropologist, presented work that reported on a deep cave where copious remains of a new hominin, Homo naledi, were being assembled and analyzed. Whereas previous researchers often focused on fragments, or the skeleton of a single individual, Berger explain that many remains were to be found in the cave system. This was going to be statistically-sound science, because he had much more than one sample.

To assemble the team that was small and nimble enough to venture into the cave, he reached out to paleoanthropology researchers via social media. And once the data came in, he published it quickly, at the same time releasing the information to other researchers.

The implications for paleoanthropology as it was practiced were revolutionary in and of themselves, but the results were also ground-breaking. H. naledi stood at five feet or shorter. Their cranial capacities were 30% those of modern humans. Meanwhile, their skeletal features were an assemblage of characteristics which seemed both very modern or very ancient. A simple role in a simple story did not present itself.

H. naledi reconstruction

This hominin confounded expectations. If the sample was singular, no doubt there would be skeptics. But Berger had the numbers, so that could not be denied. When the dates came back there was also another shocker: H. naledi flourished a bit over ~200,000 years ago. The reality though is that species invariably are found after and before the datings of particular remains. H. naledi almost certainly occupied the same landscape as early modern humans, who were developing within Africa 200-300 thousand years ago.

Meanwhile, far to east, on the island of Flores, were the Hobbits — H. floresiensis, a diminutive hominin that flourished until modern humans arrived in the region more than 50,000 years ago.

H. floresiensis

The reason that naledi and the Hobbits are important is that they shatter our image of an ascending chain of evolution progressing from lower to higher. The reality that modern human have genes from ancient Eurasian hominins, such as Denisovans and Neanderthals, also refute a simple model whereby humans were born, they came, and they conquered. Humans were both the conquered and conqueror.

Hundreds of thousands of years ago our lineage was highly speciose, with many diverse branches. Modern genetic technology implies that human lineages branch and come back together again and again, like an eternal cycle. The proliferation of ancient remains that are startling in their novelty and shocking in their recency also suggests that the shift in human evolution from slouching, small-brained apes to tall, large-brained apes was not the only way to be human. After all, the largest-brained hominins of all were Neanderthals, who eventually merged back into the much more massive stream of African humans who are our primary forebears.

Maybe you have some Neanderthal or Denisovan in your DNA. Discover your story today with Neanderthal by Insitome.

The braided estuary of human evolution was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

April 11, 2018

The “g” in genes

Filed under: behavioral-science,Genetics,Psychology,science — Razib Khan @ 1:12 pm
What’s next?

Intelligence, or smarts, is once of those words which has many meanings. That’s why we say “street smart” or “book smart.” When psychologists speak of intelligence, however, they are usually referring to something more precise and specific. The image above is a sample of a question from the Raven’s Progressive Matrices test, which is “used in measuring abstract reasoning and regarded as a good non-verbal estimate of fluid intelligence.”

Fluid intelligence “is the capacity to reason and solve novel problems, independent of any knowledge from the past.”

When I was an undergraduate student, my physics professor would often assign problems on the exam which had no explicit corollaries in the problem sets or lecture. During one after-exam review session, one student brought this issue up, and the professor simply offered that given what we learned in the course, we should be able to “derive a method to solve a general class of problem.” I suspect from the distribution of scores that more than half the time a typical student couldn’t derive a method in the allotted period. I know this was often the case with me.

In relation to tests which measure one’s analytic skills or cognitive tasks like memory recall, researchers have found that outcomes are positively correlated. If you do well on one test of this sort, you tend to do well on another such test.

The variable which summarizes these correlations is termed the “general intelligence factor,” often just shortened to g.

When it comes to intelligence, this is what psychologists are really interested in — not the outcome on one specific test. General intelligence is the most distilled and reduced aspect of “book smarts” that psychologists have been able to construct.

So what good is it? More than half of the variation in academic achievement is predicted by variation in g. People in higher status and higher paying jobs tend to have higher general intelligence. And higher g also correlates with a longer lifespan. Because of these correlations it is no surprise that intelligence testing was originally used to identify children who were not performing as well as their peers, and see if they might benefit from special attention.

Not only does general intelligence correlate with many things in one’s life, there is also a correlation between parents and offspring. The most recent work suggests that about 50% of the variation in general intelligence in the population can be accounted for by variation of genes. That is, intelligence is 50% heritable.

Multivariate Gaussian distribution

The implication here is that though parents and children, or siblings, may exhibit a correlation, it is imperfect. The brilliant mathematician Carl Friedrich Gauss came from unexceptional parents, and his numerous descendants are not particularly exceptional. In contrast, the Bernoulli family were a literal mathematical dynasty.

For a complex trait which exhibits a distribution, there are many variables at play, and genes are just one of them. Because so many genes seem to control behavioral and cognitive traits, such as intelligence, until recently, we couldn’t pinpoint any specific region of the genome which impacted variation on these characteristics within the normal range.

With modern genomic methods, which survey variation across the whole genome across huge numbers of people, this is changing. For example, a new paper establishes links to variation in intelligence at over 500 genes! This is still a small number in the grand scheme of things, but whereas five years ago we didn’t know any genes associated with intelligence, today we know hundreds.

A “chip” which asseses thousands of genetic markers

Though indirect methods, such as comparing correlations with and across families, allow us to arrive at a 50% proportion for what is heritable in intelligence, known genomic variation only accounts for a few percent of this heritable component as of this writing. But within the year, it seems likely that the 10% value barrier will be broken, and eventually we may know most of the genetic positions that account for the heritable component of intelligence within human populations.

Then the full story can begin to be told, because once we start to establish the boundaries of the genetic basis of intelligence, we can explore the environmental territory — which accounts for the other 50% our intelligence.

Explore your Regional Ancestry story today.

The “g” in genes was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

April 5, 2018

The Jewish people: genetic unity in diversity

Filed under: Genetics,History,Jews,science — Razib Khan @ 4:17 am
The Western Wall

The religion of the Jews has had a great influence on the history of the world. Both Christianity and and Islam look to the Jewish tradition. Figures such as Moses are iconic in the Abrahamic context as lawgivers, setting a precedent for modern nation-states. The stories of the Bible suffuse Western civilization.

David and Goliath

But the Jews are also a people with their own history. For the past 2,000 years the custom among most Jews has been to determine one’s Jewishness through the maternal line, irrespective of religious practice. And yet as Jews have spread across the world, from Spain to China, they have mixed with local populations. Conversion to Judaism enables one to become a Jew. Like Ruth, becoming a Jew confers membership in the Hebrew tribes.

Jews are identified with a religion and a “tribe”

Today there are brown-skinned South Indian Jews, fair-haired Lithuanian Jews, and olive-skinned Persian Jews. They may all be united by religious custom, but clearly there are differences in heritage.

Though Jews have been part of the landscape of human history for millennia, only within the last 20 years has their genetic ancestry been well studied. This research has highlighted the fact that most Jewish people seem to exhibit both commonalities from shared ancestors and differences shaped by more recent history.

The high priest Aaron

In 1997 researchers noticed a pattern in the Y chromosomes of men who belonged to the Cohen lineage — the priestly caste of Jews descended in a direct male line from the brother of Moses, Aaron. They have a very similar subtype of haplogroup J1. The religious tradition that these men descend from a common male ancestor seems to be true genetically. Using molecular methods the authors eventually estimated that the common ancestor lived about ~3,000 years ago…the time when the Biblical Aaron supposedly lived!

Jewish men with the surname Cohen descend in a direct paternal line from the brother of Moses, Aaron

Since its discovery there has been a great deal of discussion about the “Cohen Modal Haplotype” (CMH) and its origins. Not all Cohens carry the CMH, and not all carriers of CMH are Cohens, or even Jews. The CMH and its brother lineages happen to be common among many peoples in the Middle East, and one of them is frequent in people who claim descent from the Prophet Muhammed!

But what these results showed is that Jews, whether they be German Jews or the Bene Israel of India, share a genetic commonality through the CMH. Jewish men from all over the world, irrespective of region, were very frequently carriers of the CMH. This was the first major clue that Jews are a people in more than ideology, but also as a group with common shared ancestors. And, those common ancestors were rooted in the Middle East, just as the Jewish tradition says.

Most Jews have ancestry from the Middle East

There are also maternal lineages shared in the mtDNA. For the Ashkenazi Jews of Northern Europe it turns out that these lineages are often similar to Europeans, not to Middle Easterners. The plot thickens….did the male and female ancestors of modern Jews differ?

Two papers in 2010 clarified the issue using genome-wide data. That is, hundreds of thousands of markers across the whole genome were analyzed to explore the genealogy of both the maternal and paternal ancestors of hundreds of Jews.

Emmanuelle Chriqui is Sephardic Jewish

The first result was to confirm what Y and mtDNA implied: Jews from varied regions are genetically similar to each other, but they also exhibit differences. The origins of the Jewish people in any given region indicate shared ancestry from a group in the Middle East — the pattern seen in their Y chromosomes. But as Jews spread across Eurasia and North Africa they mixed with local populations, as suggested by the mtDNA.

Jewish communities may have formed through the union of Jewish men with gentile women

European Jews mixed with European peoples, while Jews in North Africa mixed with Berber peoples of that region. Jews in the Near East resemble the peoples who have lived there since time immemorial, while Yemenite Jews resemble the tribes of southern Arabia. Finally, Jews from more exotic locales such as those of India also have mixed with the native groups there, a fact evident in their features and complexion.

Source: The time and place of European admixture in Ashkenazi Jewish history

Today, the most recent work has elucidated the demographic history of Ashkenazi Jews in much greater detail. The Ashkenazim are the the most numerous of the various Jewish cultural groups, and one whose origins are somewhat mysterious. While Ashkenazi Jews have ancestors in the Middle East, but how did they get to distant Russia?

Researchers have known for almost a decade that the Ashkenazi are a mix of Middle Eastern and European. But now they have confirmed rather definitively that their forebears were predominantly a Levantine population, mixed with Southern Europeans such as Italians and Iberians. But the big surprise is that a minority of their ancestry seems to be Northern European, probably Slavic.

Ashkenazi Jews have Levantine, Southern European, and Northern European ancestors
Fred Savage is Ashkenazi Jewish

Genetically Ashkenazi Jews are quite similar to each other, and form a coherent cluster in a way that is less true of Sephardic Jews. This is because the genetic data indicates that the ancestors of these Northern European Jews went through a bottleneck, or reduction in population size, around ~1,000 years ago. The community may have had fewer than 1,000 peoples this point. From this small group — which had migrated from the Mediterranean to western Germany — arose the vast millions who eventually settled in much of Central and Eastern Europe. And it was after the bottleneck as the community was expanding to the east that it likely integrated gentile women from the surrounding Eastern European populations.

Each Jewish community tells similar tales, though that of the Ashkenazi has been explored the furthest genetically. Ancient roots and new syntheses, bound by a shared faith, and bound together by a common genetic lineage.

Explore your Regional Ancestry story today.

The Jewish people: genetic unity in diversity was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

March 31, 2018

South Asian genetics, the penultimate chapter

Filed under: Genetics — Razib Khan @ 10:01 pm

A long post at my other blog, The Maturation Of The South Asian Genetic Landscape, a reflection on the important preprint The Genomic Formation of South and Central Asia. Shorter:

  1. The original inhabitants of the Indian subcontinent who descent from the “out of Africa” migration separated very quickly, ~50,000 years ago, from other eastern populations (East Asians, Andaman Islanders, Papuans, etc.). These are the “Ancient Ancestral South Indians” (AASI).
  2. Agriculturalists from what is today Iran seem to have entered and mixed with the AASI in the Indus Valley earlier than 5,000 years ago, and possibly as early as 9,000 years ago. The only samples they have are from extra-Indian sites, in Central Asia and eastern Iran, as outlier individuals. They call these “Indus_Periphery” (I call then InPe).
  3. The “Ancestral South Indians” (ASI) were created from a mixing of InPe with AASI still extant in much of South Asia ~4,000 years ago.
  4. Between ~4,000 and ~3,200 years ago populations from the steppe arrive, carrying admixture from Iranian farmers, as well as people from the steppe (Andronovo-Sintashta?). They mix with the ASI population, though a few groups, such as the Kalash, mix directly with InPe, and create unmixed “Ancestral North Indian” (ANI).
  5. Subsequent mixing between ASI and ANI populations in various fractions accounts for most of the variation in South Asia.
  6. Some groups are enriched for “steppe” as opposed to the Iranian agriculturalist that first came with InPe. In particular, Brahmins. The hypothesis then is differential ancestry of Indo-Aryan heritage persists to this day.
  7. The Munda of northeast India have a somewhat different origin, mixing Southeast Asian ancestry with ASI and further AASI. The fact that unmixed AASI were present in South Asia indicates that the Munda arrived before the full mixture was complete. Though Austro-Asiatic expansion into northern Vietnam dates to ~4,000 BC, so I think it can’t be that early.

Things I now think are unlikely:

  • Indo-Aryan interpenetration with non-Indo-Aryans in the IVC before 4,000 years ago (I was somewhat agnostic on this). The date for migration now seem very close to the “Classical Model” of arrival around 1500 BC.
  • The AASI is very diverged from the Onge, who form a clade with mainland Southeast Asian Negritos. I now think it is likely that the AASI were primal, and not migrants from Southeast Asia.

It would be nice if the results were published from the Rakhigarhi site, which dates to 4,600 years ago. But it seems less and less necessary. Perhaps at some point we’ll get enough samples from Pakistan to generate a reasonable model….

March 29, 2018

The Indian chapter of Who We Are and How We Got Here

Filed under: Genetics,Indo-Aryans — Razib Khan @ 10:33 pm

Since Who We Are and How We Got Here is out I thought I would spoil the “India chapter” (though you should buy the book!).

– The “Ancestral North Indians” are best modeled as a 50/50 ratio of Yamna-type people from the steppes & “Iranian farmers.” The implication is that the Indo-Aryans mixed with agriculturalists in the BMC on the way into South Asia.

– The “Ancestral South Indians” have about ~25% “Iranian farmer”, along with the indigenous component more like the Andaman Islanders.

Bow before me Dasa!

David Reich clearly believes in a model of the ethnogenesis of South Asian populations detailed in A genetic chronology for the Indian Subcontinent points to heavily sex-biased dispersals. Also, I think I can now say in public when I had lunch with him he indicated that he thinks this is the most likely model. Also, the West Eurasian admixture into South Asian populations is “male-mediated.” R1a1a-z93 for the win!

He also believes there were several admixtures. He notes that his group’s 2013 paper, Genetic Evidence for Recent Population Mixture in India, reported two admixture events in North India, but one in South India. And the North Indian populations had the most recent event. This makes more sense if you consider that much of the admixture probably happened in the Northwest, as a mixed population spread across the subcontinent.

Reich contends that long tracts of ANI ancestry in some North Indians indicate that later people arrived from the first ANI wave. Also, several populations have an atypical Yamna-Iranian ratio in their ANI ancestry, being enriched for Yamna, and not so enriched for Iranian. These are all Brahmin groups.

Finally, he unmasks some of the backstories of difficulties collaborating with researchers in India, who have to be sensitive to cultural and political pressures. 2009’s Reconstructing Indian Population History was hailed in India as refuting the “Aryan invasion theory,” but the evidence was on the contrary, and I said so at the time.

In Who We Are and How We Got Here David Reich makes an explicit analogy between the Indian subcontinent and Europe. Both protrusions from Eurasia are characterized by a synthesis of indigenous hunter-gatherers, intrusive pastoralists from the Eurasian steppe, and migrating West Asian farmers.

March 28, 2018

Complex traits to individual predictions

Filed under: Genetics — Razib Khan @ 12:52 pm

The classical model of genetic inheritance, which dates back to the 19th century, involves discrete traits that are transmitted across generations in easily detectable patterns. These patterns follow what is known as a “Mendelian” model of inheritance: first adopted by the Austrian monk Gregor Mendel, based on his work with pea breeding in the mid-19th century. Largely unrecognized during his lifetime, Mendel’s work was rediscovered in the early 20th century, when biologists adopted it to explain patterns of genetic inheritance. These were the first professional geneticists.

Punnet square for pea pod color

The Mendelian framework is simple. Most complex organisms have two copies of a given gene. These are alleles. The alleles can come in particular varieties. In the example to the left, you see that pea pods come in two colors, and there are two alleles, yellow Y and green y. Because the expression of y is recessive, plants with green pea pods can only produce other plants with green pea pods. In contrast, since Y expresses dominantly, meaning you only need a single copy for the trait to be expressed, two plants with yellow pea pods can potentially give rise to both colors.

This elegant simplicity of Mendelian genetics did two things. First, it replaced the prescientific “blending” model of inheritance, where the physical characteristics of parents “mix” together to produce offspring. For example, they thought cross pollination of a red and a white flower would produce a pink one. This model, which makes intuitive sense, could never explain how populations retained all their variation — as opposed to being blended away. Second, the theoretical basis of modern population and medical genetics derives from Mendelian principles.

Malia, 6'1" (left) is taller than her mother Michelle, 5'11"

Diseases like Cystic Fibrosis and Tay-Sachs express in individuals who carry two copies of the malfunctioning gene. They’re recessive Mendelian diseases, and diseases like these are the basis of much of modern medical genetics.

Not all traits and diseases, however, are like this. Neither height nor risk of developing schizophrenia have a simple inheritance pattern. You probably know tall offspring of short parents, and vice versa. Many people with schizophrenia do not have parents with schizophrenia, and many people who develop schizophrenia don’t have children who later develop it. You can’t just look at a pedigree and figure out simple probabilities, like you can with many simple traits and Mendelian diseases.

We also know that these characteristics are heritable within the population. That is, if you look at the characteristic in parents and offspring, they tend to be positively correlated. It’s not a perfect correlation, but the relationship is strong enough to suggest that there is a genetic disposition within individuals.

The heritability of height and schizophrenia is about 80% or more. That means 80% or more of the variation of the trait in the population is due to variation of genes in the population. This is a statistical inference.

How does this relate to Mendelism?

In the early 20th century, population geneticists realized that if you assume that there are alleles at many different genes, the combined action of those alleles could result in a distribution of outcomes. Instead of two flavors at one gene, there could be different variants across hundreds or thousands of genes. This results in an increase in a wide range of outcomes, as opposed to just two outcomes (as with recessive diseases) — potentially thousands of positions along a spectrum.

There aren’t two categories, tall or short, but a value of how tall you are. It’s a quantitative trait.
Correlation between height prediction and true height

Before modern genomics, which gave us access to the fine-grained variation across the DNA sequence, and computing, which allows for powerful analysis of large quantities of data, we couldn’t relate quantitative traits to individual genes. Luckily, we live in a world where modern genomics and computing do exist. Researchers can look at patterns of variation across the whole genome of many individuals in populations and how that relates to variation in characteristics. A new method can predict 40% of the variation in height simply from the genetic sequence!

Like height, schizophrenia is a highly heritable trait whose variation is controlled by many genes. But unlike height, for schizophrenia we are more interested in the likelihood of developing the disease rather than any quantitative value. Therefore, researchers will construct a “polygenic risk score,” which takes all your “risk” alleles across your genome, and combines them to produce and overall risk against the population norm.

Researchers do this by looking at associations between schizophrenia and particular markers. They assemble a list of markers that are associated with schizophrenia to a level of statistical significance. Then they look at another dataset, and test their markers to see if it predicts the variation of risk within that dataset across individuals. In this way researchers can construct a list of valid markers from the genome and use them to give individually tailored risks.

All of this is state-of-the-art and in its early phase. Most individuals haven’t been genotyped, much less had their genomes sequenced. You can’t construct a risk score on an individual who doesn’t have their genetic data. Additionally, many of these predictions are sensitive to the populations that they were tested in: there is still much medical research that needs to be done in people of non-European origin. Finally, unlike many Mendelian diseases, polygenic risk prediction may not be definitive enough for anyone to act on the results in any concrete manner. If you are told you have a two times greater risk of developing a disease where the average person has a 5% risk, does knowing you are at 10% change your behavior at all?

But knowing who is, and isn’t, as risk within the population is useful for public health and prevention, and probably saves money and lives if you add up all of the individuals. In the end, this is the “big data” direction our society is heading.

Learn more about where your traits for food tolerance fall on the spectrum and explore your Metabolism story today.

Complex traits to individual predictions was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

March 25, 2018

“Because we could”

Filed under: Genetics — Razib Khan @ 9:53 am

March 21, 2018

The Others were people too

Filed under: Genetics,Human Evolution,paleontology,science — Razib Khan @ 12:25 pm
Neanderthals, cousins we knew.

In 2010, our understanding of Neanderthals, our human cousins, changed forever. Before this year, there was a live debate about whether they were human at all, whether they had fully elaborated language, or even culture.

When A Draft Sequence of the Neanderthal Genome was published in Science, we found out that all humans outside of Africa, and some within Africa, had some ancestors who were Neanderthal. In the wake of this finding, a renaissance of Neanderthal humanization occurred. Previously, Neanderthals were just a ‘dead-end’ in our ancestral lineage.

Denisova Cave

In December of the same year, Nature published Genetic history of an archaic hominin group from Denisova Cave in Siberia. While Neanderthals had been part of our cultural landscape for over 150 years, these hominins discovered in Denisova cave were a shot out of the dark. Debates about Neanderthals’ humanity raged for years, and this discovery certainly promoted more.

Called Denisovans, after the Siberian cave they were discovered in, what we know about these mysterious people comes from only a few bones and teeth.

The Denisovans were a total surprise scientifically. The result was not answering any questions because there was no foreknowledge of them. It turned out that about 5 percent of the ancestry of people in places like Papua New Guinea came down from the Denisovans!

Later work, which looked far more closely at mainland populations, showed that there were traces of Denisovan ancestry across the whole of South, Southeast, and East Asia — as well as into the New World. All these populations presumably descend from an African migration which swept east until it reached the Pacific, and then north and south. While Papuans had about 5 percent Denisovan ancestry, these groups had less: 0.1% to 0.5%.

Oddly, the only evidence we have for the Denisovans is in Siberia, but the greatest proportion of their ancestry is found beyond Wallace’s Line, in Oceania. It is very likely then that the Denisovan sequence from Siberia is from a particular population, and this species ranged far and wide across eastern Eurasia — just as Neanderthals did to the west.

A new paper in Cell, Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture, adds a further twist by reporting that there were two interbreeding events with Denisovans. One group of Denisovans contributed to Papuans, Southeast Asians, South Asians, and some of the ancestry of East Asians. It turn out, however, that another group contributed ancestry only to East Asians — up to half the Denisovan ancestry is in Han Chinese.

The way the authors did this is by first compiling a list of sequences, which likely came from Denisovans or Neanderthals. They did this by looking for regions which were anomalously different from modern Africans, who have no Denisovan or Neanderthal ancestry. Once they had this list, they compared them to the genomes of the Neanderthals and Denisovans.

Not surprisingly, Europeans had matches with Neanderthals only. Papuans had more matches with Denisovans than Neanderthals. South, Southeast, and East Asian populations had many more matches with Neanderthals, but a small number with Denisovans.

So far so good.

But the authors noticed that some of the populations had Densiovan matches to the Siberian sequence that were much better than those in other populations. In South and Southeast Asia, and Oceania, there were no high quality matches with the Denisovans. In the Han Chinese, about half the matches were much better with the Siberian Denisovan genome — while half the matches were similar to the ones found in other populations.

This could mean that in Northeast Asian populations, two groups of Denisovans contributed their ancestry, while in southern Asia and Oceania only one did.

These results show us that the human past was complicated even if the early genetic results painted a simple picture. Modern humans in eastern Asia interacted with Denisovans twice. We know from a genome in Europe that there were several admixture events with Neanderthals, but it seems only one persists down to the present — as the first Europeans with additional admixture left no descendants. Perhaps the same is true in Asia, maybe there were more than two admixtures with Denisovans.

The pattern of where Denisovan admixture is found is intriguing. It is found in highest frequency among Han Chinese and somewhat lower in Japanese and the Dai people of South China. It is entirely absent in the Vietnamese. Combined with the fact that Tibetans obtained a high altitude adaptation from Denisovans, this is circumstantial evidence that the admixture occurred in the interior of Eurasia.

Denisovans are a major twist in the understanding of our species, but their widespread distribution, and multiple interactions with modern humans, points to intriguing possibilities. Perhaps the Denisovans persisted down to relatively recent times, and interacted a fair amount with modern humans? We know they interacted enough to mix with us twice. Denisovans complexify our understanding of the past, but they may simplify and illuminate myth!

Maybe you have some Neanderthal or Denisovan in your DNA. Discover your story today with Neanderthal by Insitome.

The Others were people too was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

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