Tag: Genetics

Should we Invest in Curing Rare Diseases or Making Them Rarer?

Posted on by Razib Khan

An guest-post from Noor Siddiqui and Nikki Teran of Orchid

Rare diseases cost Americans around 8 trillion dollars a year. About half of that is direct medical costs. If families are lucky, they may go bankrupt paying for treatment of often questionable effectiveness. The unlucky families may go bankrupt just trying to find a cure; unfortunately less relevant as only about 5% of rare diseases have treatments. 

What can we do to reduce this burden? 

Two options are: 

  1. Incentivize the development of more treatments

or

  1. Reduce the incidence in future generations by screening as early as possible

Towards option one, the FDA created a “golden ticket” to encourage the development of treatments for rare diseases. Their transferable golden ticket (technically a “priority review voucher”) allows its owner to shave four months off the FDA’s review process. Previous vouchers have sold for as high as $350 million. But the program is set to sunset this fall, raising the question of whether the problem of rare diseases will be dealt with at the federal level.

Towards option two, preimplantation genetic testing may provide its own “golden ticket” for preventing rare diseases. Preimplantation genetic testing in concert with in vitro fertilization has already been shown to be cost effective for inherited rare diseases like sickle cell and Huntington’s disease, with cost savings in the millions per individual (not to mention the priceless improvement in quality of life). Advances in whole genome sequencing open up this technology to potentially prevent all rare genetic diseases.

Rare Diseases Aren’t Actually Rare – 10% of Americans are affected 

In the United States, a rare disease is defined as one that affects fewer than 200,000 Americans. Despite each disease affecting no more than .06% of the population, there are about 7,000 different rare diseases, meaning roughly 10% of the U.S. population has a rare disease. 

These numbers may seem large, but it makes sense if you consider the complexity of human genetics and development. Humans have around 20,000 genes. Mutations in some genes are lethal. Mutations in some genes lead to normal human variation; you may not even know the person has a mutation. And mutations in others lead to rare diseases; not lethal at or before birth, but often quite deleterious. Around 80% of rare diseases are genetic and many of these diseases are discovered in children – the mutations are severe enough to be noticed early.

30% of children with rare diseases do not live past the age of 10 

The devastation of rare diseases stems from their chronic, progressive nature and the fact that many involve multi-organ system failure or neurological impairments. For families, this can be unimaginably cruel. Children may be robbed of normal development or, even more brutally for families, regression. In Sanfillipo syndrome, children may develop normally until age four before showing any behavioral changes. They then progressively develop dementia and lose motor function. Most do not make it to adulthood.

The emotional toll is compounded by a profound sense of isolation as healthcare providers often lack expertise with the particular rare condition. Making matters worse, the few treatments that do exist frequently carry price tags in the millions, straining families to the breaking point financially as well as emotionally and physically through caretaking demands.

Just last December a gene therapy treatment was approved for sickle cell disease, which affects around 100,000 Americans and as many as one in every 365 African-Americans. Unfortunately, gene therapy is not a perfect cure. For sickle cell disease, the chemotherapy administered as part of the treatment leads to infertility.

But many rare diseases are too complex for over-the-counter solutions and affect too few people a year to interest drug companies. The market just isn’t there.

The FDA Priority Review Voucher Program Incentivises Orphan Drug Development

The priority review voucher program turns the inefficiencies in the FDA’s approvals process from a bug into a feature. The government created the priority review voucher program to incentivize the development of treatments of certain tropical diseases, rare pediatric diseases, and medical countermeasures against biological, chemical, radiological, or nuclear threats. These are known as “orphan” indications as they otherwise lack the financial incentive needed for a pharmaceutical company to invest in research.

The voucher allows for fast-tracked new drug application approval. Time is money for pharmaceutical companies. Being able to jump the approval line and get a drug approved in six months instead of ten can be huge for pharma company’s bottom lines.

The first priority review voucher sale was used by Regerneron Pharmaceuticals to get their PCSK9 inhibitor to market a month ahead of Amgen’s cholesterol lowering drug targeting the same pathway. 

Pharmaceutical patents last 20 years, but that clock starts when the patent is filed, not when the drug is approved. Patents are typically filed during preclinical trials, which can take upwards of two to five years. These are followed by clinical trials (when the drug is actually tested in people). Clinical trials can take upwards of three to ten years. By the time a drug is ready for FDA evaluation, there may only be a handful of years left on the patent.

Some drugs can make billions of dollars per year, meaning it may make financial sense to spend hundreds of millions of dollars on an extra four months of sales.

https://www.gao.gov/assets/gao-20-251.pdf

Vouchers are sold in more ways than one. Some larger pharma companies will acquire smaller biotechs, or their assets, when the smaller company is going after “voucherable” targets. These acquisitions can help bring to market drugs for orphaned diseases that may not otherwise have had the resources from venture capital to survive.

A friend of mine worked for small drug companies that were pursuing treatments for Ebola primarily because of the priority review voucher program. They weren’t targeting the financial incentive of the antiviral’s sale; they were targeting the voucher itself. 

Unfortunately, the priority review voucher program for neglected tropical diseases has already sunset. Despite (or more realistically due to) the recent pandemic, Congress was unable to reauthorize the Pandemic and All Hazards Preparedness Act this past fall. The neglected tropical disease and medical countermeasure priority review programs are casualties of congressional dysfunction. Without the financial incentives created by this program, many of these drug pipelines will dry up.

The pediatric rare disease program has a little more time — it’s set to sunset this fall — and its fate will likely be the same. Although the program has successfully contributed to 19 new treatments for rare pediatric diseases, even its continuation wouldn’t be enough. What about the other 6,981 rare diseases? For genetic disorders, prevention may be worth five thousand pounds of cure.

https://www.gao.gov/assets/gao-20-251.pdf

Preimplantation Genetic Testing (PGT) Can Prevent Many Rare Diseases

During typical in vitro fertilization (IVF), multiple embryos are created and the “highest quality” embryo is implanted. Historically, the “highest quality” embryo was determined subjectively based on appearance (“morphology”). This appearance often correlated with genetic issues and, inversely, later pregnancy success. Today, success can be increased by looking for the genetic issues directly: preimplantation genetic testing (PGT) has been shown to reduce the miscarriage rate from 9.1% to 2.6%. As genetic issues are more common with age, this particularly increases success in older mothers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8984775/figure/jld220010f2/

Cutting-edge preimplantation genetic testing can read 99.6% of an embryo’s genome, allowing for the identification of mutations that can cause rare diseases. This process works both for mutations that parents may pass on to their children (inherited mutations) and formutations that spontaneously occur (de novo mutations). Orchid performs this cutting-edge version of preimplantation genetic testing. The whole-genome sequencing has provided parents with information on these rare diseases, enabling improved decisions on which embryo to implant. 

Doctors already recommend screening procedures that are similarly priced and arguably less impactful. The chances of a 35 year-old woman having a child with Down syndrome is just under 0.3%. The life expectancy of someone with Down syndrome is 60 years and they generally report living happy, fulfilling lives. In contrast, the combined prevalence of the monogenic disorders Orchid screens for is 3-4%, more than 10 times as likely, and many are fatal at birth. Whole genome screening is able to detect these mutations whether they are inherited from the parents or de novo mutations that are unique to the embryo. Additionally, preimplantation genetic screening also provides information on chromosomal abnormalities like Down syndrome or others that are incompatible with life. Amniocentesis typically costs $4,100 per fetus while Orchid’s whole-genome testing is $2,500 per embryo.

Many of the disorders detectable by whole-genome preimplantation genetic testing carry additional cost beyond just reduced lifespan. 40% of infants in the NICU have a detectable single-gene mutation, meaning many of these babies require intensive care due to their detectable genetic disease. A single day in the NICU costs upwards of $3,500.

Even just alternative forms of diagnosis are comparable to whole-genome preimplantation genetic testing. A 2014 study that looked at neurodevelopmental disorders, which affect more than 3% of children, found the average family spent $19,100 on inconclusive diagnostics alone. That means the families spent nearly $20,000 each on diagnostics, not treatments or other care, before the cost of the test that ultimately provided a diagnosis.

Parents and Patients Should Have As Many Options as Possible

Ideally, biotech companies would have access to priority review vouchers and parents would have access to whole-genome preimplantation genetic testing. The federal government should create policies to maximize the public welfare. The priority review voucher program has encouraged the development of treatments that will change millions of lives. Systematic incentives like the voucher program can only be executed by this sort of top-down approach.

Practically, parents want to provide the best lives possible for their children. Preimplantation genetic testing can prevent monogenic genetic diseases and mitigate risk for chronic diseases like schizophrenia, bipolar disorder, and diabetes. However, the cost of IVF is an impediment to universal access, as the US does not have as extensive coverage as other countries. The federal government could require insurance to cover both IVF and genetic screening of embryos created through IVF. Parents would then have the necessary information to make their own choices about their children.

The voucher program will not be able to create treatments for all rare diseases and genetic tests may never be able to prevent all rare diseases. But the voucher program may be able to make many conditions minor inconveniences and genetic testing may provide families the opportunity to make informed decisions, making both social and financial sense. 

Authors 

Dr. Nikki Teran has worked in biotech at Pfizer, AncestryDNA, and startups. She earned her bachelor’s degree in Molecular Biophysics and Biochemistry from Yale, and her PhD in Genetics from Stanford, focusing on rare disease diagnostics. 

Noor Siddiqui is the CEO of Orchid, a reproductive technology company that built the world’s first whole genome embryo reports. She taught Frontiers in Reproductive Technology at Stanford, where she was an AI and genomics researcher and earned her Master’s and Bachelor’s degrees in Computer Science. 

People in Brazil are quite “mixed-race”

Posted on by Razib Khan

Probably the most famous Brazil American is Gisele Bündchen, erstwhile supermodel and ex-wife of Tom Brady. Bündchen is a German Brazilian, and all the media I see say she is purely German. She grew up in a predominantly German town in the southern state of Rio Grande do Sul, which is often contrasted with the black-dominated areas of northeastern Brazil. About 80% of people in Rio Grande do Sul identify as white, about 10% mixed-race, 5% black and the remaining 5% indigenous, Asian, etc.

These sorts of facts are often used to recapitulate American racial dynamics in Brazil, except here you have a black majority and a white minority, though the latter are still socially, culturally and economically dominant. This is in contrast to the model that Brazilians themselves promoted in the 20th century of being a multiracial and mixed-race society, albeit defined by a fair amount of naked anti-black bias.

The main problem with the first narrative is it is just a plain fact that most Brazilians are mixed-race in the American context. Bündchen is the exception, not the rule. This has been hard to ascertain because of the lack of high density SNP array surveys in the early years of this blog, but I decided to go back and check now that these chips are very cheap, and a paper with 6,500 Brazilians typed on 370,000 SNPs exists to illustrate the ancestry distributions within: A minimum set of ancestry informative markers for determining admixture proportions in a mixed American population: the Brazilian set.

The admixture plot shows that under “11,” sampled in the far southern Brazilian city of Pelotas, only a few individuals on the right portion of the distribution show trace amounts of non-European ancestry. The prevalence of low but widespread Amerindian ancestry is not surprising in Brazil, where the early European settlers seem to have absorbed the natives. Second, under “12” you see samples from the city of Salvador, where 80% of people identify as mixed-race or black. Here you see lots of African ancestry, but only the individuals at the far left of the distribution are as African as the average African American (the rightmost panel is from a central Brazilian city).

This pattern is even more clear on PCA:

What’s the takeway? By American standards most Brazilians are black, because they have African ancestry. This includes a majority of self-identified “white” Brazilians.

The Hui Muslims, two pulses of “western” ancestry 1,000 and 500 years ago, mostly male mediated

Posted on by Razib Khan

There are 20 million Hui people in China. These are traditionally Chinese-speaking Muslims. Though they are found in every region of China (and in the Chinese Diaspora), they are concentrated in the northwest, in Gansu and Ningxia in particular. Their origins have always been curious. They speak the local Chinese dialect, and look mostly Chinese, but they are traditional Muslims. Are they purely the descendants of local converts?  The Hui do not believe so, and some of them physically do look more West Eurasian.

Thanks to genetics we know the answer,  Genetic Origins and Sex-Biased Admixture of the Huis:

To investigate whether there was a sex-biased admixture in the history of NXH, we compared the admixture results obtained from autosomes, X chromosome, mtDNA, and Y chromosome. We estimated the admixture proportion assuming two major ancestral components, that is, western and eastern (fig. 3 and supplementary tables S2 and S3, Supplementary Material online). The estimated genetic contribution of the western ancestry into NXH was 8.6% for autosomes, 5.9% for X chromosome, 3.6% for mtDNA, and 39.3% for Y chromosome, respectively. The results of Y chromosome and mtDNA were consistent with the previous studies (Yao et al. 2004; Wang et al. 2019; Xie et al. 2019). Additionally, though the difference in genetic contribution was small, there was a significant difference in admixture proportions between autosomes and X chromosome (Student’s t-test, P < 107−10−7⁠). This pattern was consistent across different regions in Ningxia (fig. 3C). These results indicated that the admixture of NXH was sex biased to the combination of Eastern females and Western males.

The 39% western Y chromosomes is key. This is probably a floor for the fraction of originally Muslim lineages. The Hui likely had Iranian and Turkic precursors, and the latter would have had eastern Y chromosomes. But the point is that cultural continuity was maintained in paternal lineage systems, and over the generations intermarriage with local Han women resulted in 90% of the genome being replaced over time.

This is a common pattern in large parts of the world. Paternal cultural transmission is a thing.

The Anglo-Saxonization of England happened through a mass migration

Posted on by Razib Khan

The Anglo-Saxon migration and the formation of the early English gene pool:

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture…The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate…Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France

1) More migration than earlier papers. Looks like increasing ancient DNA coverage helped
2) 75% Y chromosomal turnover in eastern England
3) A third component, detected in the PoBI paper, is confirmed, and seems related to continuous later gene flow from northern France. This is ubiquitous across England, and I do wonder now what the Norman Conquest and the unification of large regions of northern France with England did in the early medieval period

The southern arc papers

Posted on by Razib Khan

Since David has not posted, here they are…

The genetic history of the Southern Arc: A bridge between West Asia and Europe:

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe.

A genetic probe into the ancient and medieval history of Southern Europe and West Asia:

Literary and archaeological sources have preserved a rich history of Southern Europe and West Asia since the Bronze Age that can be complemented by genetics. Mycenaean period elites in Greece did not differ from the general population and included both people with some steppe ancestry and others, like the Griffin Warrior, without it. Similarly, people in the central area of the Urartian Kingdom around Lake Van lacked the steppe ancestry characteristic of the kingdom’s northern provinces. Anatolia exhibited extraordinary continuity down to the Roman and Byzantine periods, with its people serving as the demographic core of much of the Roman Empire, including the city of Rome itself. During medieval times, migrations associated with Slavic and Turkic speakers profoundly affected the region.

And, Ancient DNA from Mesopotamia suggests distinct Pre-Pottery and Pottery Neolithic migrations into Anatolia:

We present the first ancient DNA data from the Pre-Pottery Neolithic of Mesopotamia (Southeastern Turkey and Northern Iraq), Cyprus, and the Northwestern Zagros, along with the first data from Neolithic Armenia. We show that these and neighboring populations were formed through admixture of pre-Neolithic sources related to Anatolian, Caucasus, and Levantine hunter-gatherers, forming a Neolithic continuum of ancestry mirroring the geography of West Asia. By analyzing Pre-Pottery and Pottery Neolithic populations of Anatolia, we show that the former were derived from admixture between Mesopotamian-related and local Epipaleolithic-related sources, but the latter experienced additional Levantine-related gene flow, thus documenting at least two pulses of migration from the Fertile Crescent heartland to the early farmers of Anatolia.

I haven’t read the supplements, so no major comment from me, except for one: the Greece-focused paper confirms using phenotypic prediction that West Eurasians have been getting lighter-complected since the late Neolithic/Bronze Age. I have no idea why, but some Nazis are offended by this reality and cherry-pick data, but trust me, I open up all the supplements to look at the HIRIS-plex predictions.

Is ancient DNA a biased view?

Posted on by Razib Khan

Over at my Substack Iberia: Ancient Europe’s Edge of the Earth (part 1) – Unpacking prehistoric Spanish and Portuguese genetics elicited a comment from Walter Bodmer questioning the representative of ancient burials (i.e., were they just elites?).

My response:

– I bet forager societies were in HWE. That is, there’s no major stratification due to class since class differences are minimal/attenuated.

– A single genome has been pretty predictive of future and past diversity for a given population (e.g., WHG).

– There are populations, like India’s, that are highly stratified by class for many centuries (thousands of years?). But this is the exception, not the rule.

Nick Patterson responds to Feldman and Riskin’s NYRB piece

Posted on by Razib Khan

Nick Patterson has responded on his Substack to the NYRB piece Why Biology is not Destiny, which itself is an attack on Kathryn Paige Harden’s book The Genetic Lottery. Patterson does not say anything you can’t find in Stuart Ritchie’s defense, but he is at this stage in his career a very eminent scholar operating from a perch in one of the world’s most prominent population genetics laboratories. So him speaking publically is worthwhile in my opinion, since a lot of this is going to shake out in credential thumping and status signaling (Marcus Feldman in particular is a massive deal in population genetics so it needs to be responded to those in senior positions)…

When Surya left Olga of the Birch Forest

Posted on by Razib Khan


In the recent film The Northman the protagonist, Amleth, has a romantic relationship with a woman, “Olga of the Birch Forest.” Amleth was a Viking who raided Kievan Rus, and Olga was a Slavic woman who was captured in a raid.

Birch trees flourish across the temperate zone, but they’re particularly dominant in the north, due to being hardier. When I wrote about Finnish genetics, history and culture last year I stumbled upon the fact that early Finns who arrived in America (usually they were identified as “Swedes” because they were ruled by the Swedish Crown) often found an immediate affinity with northern Native American tribes. One explanation is that Finns and northern Native Americans are both “birch forest people.” Many aspects of their culture were similar, down to their moccasins.

As it happens, a long long time ago, and far far away, my forefathers were also birch forest people. Long before Olga’s kith and kin occupied the birch forests of northwestern Russia, they were occupied by the Fantyanovo-Balanovo culture. Until recently this cattle-raising society on the northern edge of the Indo-European world was assumed to perhaps be Baltic-speaking due to local hydronyms, but ancient DNA retrieved from Fatyanovo-Balanovo suggests a different answer. The vast majority of the men in their burial grounds carry Y chromosomal haplogroup R1a-Z93. This lineage is now found overwhelmingly in Indo-Iranian people, as well as in the Altai region.

The ancient DNA transect and succession is clear
– Fatnyanovo-Balanovo expanded eastward
– Turned into the Abashevo copper miners west of the Urals
– Gave rise to the Sintashta on the southern slope of the Urals into northwest Kazakhstan

At this point the Sintashta around 2000 BC exploded and turned into the Andronovo Horizon that covered much of Central Eurasia between 2000 and 1500 BC:

At some point Olga of the Birch Forest was left behind. A recent paper estimates that about 8% of the mtDNA lineages among populations like the Kalash and Pashtun in northern Pakistan is of steppe provenance. This is in contrast to about 2% to the south and east in “mainland” South Asia. This is contrast to the frequency of R1a in this region of Pakistan, about 50%, and 25% in mainland South Asia. In terms of total genome ancestry, about 25-30% of the ancestry in northern Pakistan among these groups is steppe, with an average across the subcontinent a bit below 15% (I did a weighted calculation a while ago).

What you see here is a massive drop off in maternal lineages of steppe Indo-Iranians, and a strong persistence of Y chromosomes, with total genome content being about in the middle. Figure 4c of Narasimhan et al. shows the same thing, with R1a fractions way higher than total genome content of steppe heritage.

This sex-specific admixture is not limited to South Asia. It can be found in the European context as well, though rarely as extreme.

So what’s going on here? One thing to note about Indo-European people is that on the whole they are patrilineal and patrilocal and exogamous. That is, one’s identity was determined by one’s father. Women moved into the household’s of their husband, and tended to be unrelated to them. This seems to be a perfect recipe for the assimilation of women into a society. But that’s not the reason all of these culturally and genetically different women are being brought into Indo-European societies. It is because the men are moving, and migrating very long distances.

In a podcast last year with myself and Patrick Wyman David Anthony claimed that they have detected Yamnaya individuals buried in western Mongolia and in Europe who are clearly related to each other. This means that Yamnaya cultural and social networks spanned Eurasia due to their mobility. In The Northman Olga was shipped from Russia all the way to Iceland. But this was the exception, not the rule. As Indo-European men expanded out of the core Eurasia zone, they moved as bachelor groups, and assimilated local women.

And not just Indo-Europeans. Among Uralic people, as well as some Siberians, a particular Y chromosome is very dominant from the Baltic all the way to eastern Siberia.

It’s a branch of N, and it is clearly East Asian in origin. It seems to have shown up in the Baltic region about 2,500 years ago, and it’s now the dominant haplogroup in Finland, and the Baltic countries. And yet the total genome content of modern day Finns that is East Asian is about 5% or so, even if N3a (TAT-C) is about 70%. There are almost no Siberian mtDNA lineages among Finns (OK ~1%). Among the Saami, about 25% of the genome is Siberian, but less than 10% of the mtDNA. Just like the Indo-Europeans, there seems to have been a male-mediated migration west. Why didn’t they bring women?

Can you imagine women and children moving fast across the zone of Eurasia north of the birch forest???

I think the common thing that connects the Indo-European groups here and the Uralic people is that there was a period when they were highly mobile over very long distances. This does not mean that women and children could never be involved. Some women were moving with their men judging by the mtDNA here and there. But, on the whole these were strongly male biased migrations. These were young and robust groups of men with few ties that moved rapidly across territory. There wasn’t time or inclination to have a baggage train.

Another way to look at it is from the gene’s-eye first view. Let’s look for explosive punctuated clusters within haplogroups.

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Happy DNA Day (and whole genome sequencing yourself)

Posted on by Razib Khan

Today is “DNA Day,” I checked Nebula Genomics website to see if there was a deal. So I got the 30x whole genome sequencing for $199+$24.99/month subscription. The deal is you have to get the subscription, but you can cancel at any time. What I plan to do is just download my data when the results come back and the subscription starts ticking, and cancel after that. The other options are more expensive. But, they won’t let you add more than 1 item unless you get the most expensive upfront deal, so what I did was just started separate carts and sent the order to separate email addresses.

And yes, I have my own DNA sequenced. This is for friends and family.

If you want to download my whole genome sequence, from raw reads to bam files to vcf’s, go here.

Update: It was pointed out to me that quarterly would charge $75 as it will be $25 per month quarterly (3 months).

Avars were Rourans

Posted on by Razib Khan

genomes reveal origin and rapid trans-Eurasian migration of 7th century Avar elites:

The Avars settled the Carpathian Basin in 567/68 CE, establishing an empire lasting over 200 years. Who they were and where they came from is highly debated. Contemporaries have disagreed about whether they were, as they claimed, the direct successors of the Mongolian Steppe Rouran empire that was destroyed by the Turks in ∼550 CE. Here, we analyze new genome-wide data from 66 pre-Avar and Avar-period Carpathian Basin individuals, including the 8 richest Avar-period burials and further elite sites from Avar’s empire core region. Our results provide support for a rapid long-distance trans-Eurasian migration of Avar-period elites. These individuals carried Northeast Asian ancestry matching the profile of preceding Mongolian Steppe populations, particularly a genome available from the Rouran period. Some of the later elite individuals carried an additional non-local ancestry component broadly matching the steppe, which could point to a later migration or reflect greater genetic diversity within the initial migrant population.

No big surprises, but I think it is important to note that it looks like the East Eurasian Avar elites brought a lot of Iranian-steppe people as cadet elites. So a lot of the elite non-East Eurasian ancestry turns out to be non-European, and more Central Eurasian (probably Alanic and the like).