Category Archives: Genome

BRISBANE, Calif., Feb. 10, 2022 /PRNewswire/ -- Second Genome, a biotechnology company that leverages its proprietary platform to discover and develop precision therapies and biomarkers, today announced that the Company will advance SG-5-00455, which targets plasminogen activator inhibitor (PAI)-1/2, as a development candidate for the treatment of inflammatory bowel disease (IBD). The Company will present new preclinical data on SG-5-00455 at the virtual 17th Congress of European Crohn's and Colitis Organization (ECCO) on February 18, 2022.

"We are excited to be moving SG-5-00455, our development candidate for the treatment of IBD, one step closer to patients. With its PAI-1/2 inhibition mechanism of action, we are targeting a well validated pathway that has been shown to play an important role in the pathophysiology of IBD. We believe that direct modulation of tissue repair pathways has the potential to directly improve mucosal healing and drive superior therapeutic outcomes, including when combined with the current standard of care anti-inflammatory approaches," said Karim Dabbagh, Ph.D., President and Chief Executive Officer of Second Genome. "This is an important milestone for Second Genome's internal pipeline. We look forward to presenting new data at ECCO'22 and hosting our upcoming IBD KOL expert panel, both of which are occurring later this month, as we plan to file an investigational new drug (IND) application for SG-5-00455 in the second half of 2022."

SG-5-00455 could potentially be a first-in-class precision therapeutic that directly targets mucosal healing in IBD patients. The development candidate was generated using a novel, naturally derived protein (SG-2-0776), that was subsequently engineered into an Lactococcus lactis (L. lactis) drug delivery system, SG-5-00455, for direct, non-systemic delivery to the gut. This enables precise targeting of mucosal healing, a key therapeutic goal for IBD and an important U.S. Food and Drug Administration (FDA) metric for clinical trial outcomes.

At ECCO'22, Second Genome's Chief Science Officer, Joseph Dal Porto, Ph.D. will present, "DOP54: Identification and development of a 1st in class naturally-derived protein that drives mucosal healing and is orally delivered by an engineered cellular therapy targeting the gastro-intestinal tract," during the Virtual Plenary Hall session, "DOP Session 6: The Artic: IBD Basic Science," taking place on Friday, February 18, 2022, at 5:25 6:25 EST (17:25 18:25 CEST).

On Wednesday, February 23, 2022, at 12:00 1:00 p.m. EST, Second Genome will host a virtual KOL panel, "SG-5-00455 and the Role of Mucosal Healing and PAI-1/2 in IBD." Additional details about the event will be announced publicly and a link to the event will be available on the Company's website at https://www.secondgenome.com.

About Second Genome

Second Genome is a biotechnology company that leverages its proprietary technology-enabled platform to discover and develop transformational precision therapies based on novel microbial genetic insights. We built a proprietary drug discovery platform with machine-learning analytics, customized protein engineering techniques, phage library screening, mass spec analysis and CRISPR, that we couple with traditional drug development approaches to progress the development of precision therapies for wide-ranging diseases. Second Genome is advancing lead programs in IBD and cancer into IND-enabling studies. We also collaborate with industry, academic and governmental partners to leverage our platform and data science capabilities. We hold a strategic collaboration with Gilead Sciences, Inc., utilizing our proprietary platform and comprehensive data sets to identify novel biomarkers associated with clinical response to Gilead's investigational medicines. We also hold a strategic collaboration with Arena Pharmaceuticals to identify microbiome biomarkers associated with clinical response for their lead program in gastroenterology, etrasimod. For more information, please visit http://www.secondgenome.com.

Investor Contact: Argot Partners212-600-1902[emailprotected]

Media Contact: Argot Partners212-600-1902[emailprotected]

SOURCE Second Genome

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Second Genome Nominates Development Candidate Targeting PAI-1/2 for the Treatment of Inflammatory Bowel Disease (IBD) - PRNewswire

Representational image.

IIT Jodhpur has identified variations in the RNA of the COVID-19 virus using genomic sequencing methods.

The RNA structure of the coronavirus frequently undergoes minor modifications within the host cells (aintra-host variations').

In the study, published in the journal Nucleic Acid Research, the team studied intra-host Single Nucleotide Variations (iSNV) using a sequencing platform called Illumina.

"One of the most critical aspects to managing the COVID-19 pandemic is to unravel the genetic structure of the virus and pick up early warning signatures, said Dr Mitali Mukerji, Professor and Head, Department of Bioscience & Bioengineering, IIT Jodhpur.

"We observed 16,410 iSNV sites spanning the viral genome, and a high density of alterations were present in critical areas that could alter or override the body's ability to trigger an immune response," she added.

During Phase 1 of the project in 2020, the IIT scientists analysed the RNA structure of virus samples collected from China, Germany, Malaysia, the UK, the US, and different subpopulations of India to map the iSNV across the RNA structure of the virus.

The team has observed similar patterns across populations and waves of the pandemic. It also tracked the iSNVs over time to see if the variants produced inside the host cells can persist outside, thereby becoming fixed as SNVs.

They found that by June 30, 2021, about 80 per cent of the iSNV sites they had identified in 2020 became fixed as SNVs. The conversion of iSNVs to SNVs was substantiated in Phase 2 studies that showed iSNVs were found in most of the Delta and Kappa variants before their fixation as SNVs by February 2021.

"The evolution of SNVs from iSNVs can affect vaccine response by altering the antibody generation in infected individuals," said Mukerji.

Tracking and understanding the fate of iSNV can help predict the variants of concern and plan actionable interventions. It also helps to know the differences in individual and population responses to the infection and assists therapeutic design protocols in treating COVID-19 infections.

The identification of iSNVs can also help identify key sites in the viral RNA that are important for its survival and spread, the researchers explained.

**

The above article has been published from a wire source with minimal modifications to the headline and text.

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Researchers from IIT Jodhpur Identify Variations in RNA of Coronavirus Using Genomic Sequencing | The Weather Channel - Articles from The Weather...

The resignation of Eric Lander as President Bidens lead scientific adviser is not just a blow to one presidents plans for advancing research, but a signpost on the death march of a certain way of doing science. Its not quite big science, which isnt going anywhere. Call it big ego.

In science, big ego isnt exactly a new phenomenon. But in recent decades it grew with the emergence of researchers who could both handle the kind of gloves-off debate that can mark academic discourse and marshal vast resources to make certain types of scientific discoveries, like mapping genomes or understanding how molecular changes in a cell lead to cancer.

Accomplishing those tasks once seemed to require an outsize personality, as well as the ability to translate not only the meaning of science but the excitement of doing it to laypeople, to donors, to politicians. It was in this world that Lander excelled. For decades, he was not only one of the worlds most cited scientists, but also an administrator who built a research empire.

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It started with the Human Genome Project, a government effort to sequence the first human genome that originated with Nobel laureate James Watson, who was, by the way, one of sciences biggest and most toxic egos. (E.O. Wilson famously called him the most unpleasant human being I had ever met.) In recent years, Watson was disowned by the scientific establishment for racist and misogynistic remarks. But in the 1990s, as the co-discoverer of the double helix structure of DNA, he was exactly the kind of person one brought before Congress in order to make research dollars flow.

When Lander became involved, he was a mathematician and former business school professor who had started a sequencing center at Massachusetts Institute of Technologys Whitehead Institute. Watson was replaced as the Genome Projects head after three years, and the effort was slowly progressing toward completion. But another giant personality, the scientist Craig Venter, began work with a for-profit company, Celera Genomics, to generate, perhaps patent, and certainly profit from the genome by sequencing it first. The contest was made for the media. Venter was not only a scientific cowboy, he loved fast cars and big boats and adrenaline.

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Lander muscled his way into increasing control of the project, changing the way that it was organized so that the work could be done faster using new technologies made by Celeras parent company, PE Biosystems. The effort was a success: The public effort raced Venter to a draw in 2001.

Lander was left overseeing a large DNA sequencing center at the Whitehead. In a feat of tough bureaucratic brawling, he moved it to a new organization, the Broad Institute of MIT and Harvard an organization, incidentally, named for its wealthy donor. And under Landers leadership, the Broad became perhaps the premier center for genetic research in the world.

Its hard not to see what happened this week as hamartia, the classic Greek tragic flaw. Politico first reported that Lander had issued an apology to staff for speaking in a disrespectful or demeaning way, and then that a White House investigation had found credible evidence that he had bullied his general counsel and had spoken harshly to colleagues in front of others. Perhaps the same behavior that was forgivable when he was fighting for the free availability of genetic information was not permissible in a modern White House. Perhaps his efforts at creating a new Cancer Moonshot and ARPA-H, a new science funding mechanism within the government, led old bad habits to metastasize. Perhaps he could always be a jerk.

When he was sworn in, Biden had promised to fire anyone who was disrespectful on the spot. But neither Lander nor the Biden administration seemed to see the train that was about to hit them. Lander waited to resign until Politico made public its investigation, which dated back to December. There was plenty of kindling for furor. Many scientists still seethe over a 2016 paper Lander wrote about the gene-editing technology CRISPR that seemed to inflate the Broads efforts and minimize the contributions of Jennifer Doudna and Emmanuelle Charpentier, who later won the Nobel for their work.

The consequences of Landers most recent behavior could be severe, with his role as a public intellectual severely reduced. Already, the American Association for the Advancement of Science has disinvited him from its annual meeting, one of the largest gatherings of scientists. But there are questions over where Lander goes next, and whether hed be welcome back at the Broad.

This is a gigantic change from the way things used to be, one that will likely have a positive impact on the way big-name scientists behave. This is not because ego will no longer play a role in science. It is because the consequences of behaving badly at work have become so large; those who would have openly bullied or disparaged co-workers will simply know that they cant do it if they want to accomplish their goals. In the same way Lander and Venter were selected by the era of big science, this next eras stars will be made of stuff that is less rude.

For years, a camera-grabbing persona and big achievements were enough to grant indulgence for just about any sin. It wasnt until 2007 that Watsons star finally faded completely, after he told a British newspaper that Black people were not as intelligent as white people; it was only after he made similar remarks again in 2019 that he was stripped of his final honorary titles.

Lander has never been accused of anything on that scale. But he did find himself apologizing, in 2018, for agreeing to toast Watson at a scientific meeting.

Lander was a force of energy and connection. When he would rise in the audience at scientific meetings, it was as if he stole the spotlight. He taught introductory biology at MIT for years, and turned mathematicians into biologists. He was immensely quotable. I remember one time when I was granted hours with other Broad scientists, and a short amount of time with Lander. He was pithy and clever and his words coursed with argument and excitement.

But being quotable isnt enough. That rare ability seemed so important, perhaps, in an era when sequencing even a single human genome required assembling rooms the size of football fields full of expensive machines. But it wasnt, really. And other big-name scientists are casting public images that reset the armwrestling, argumentative tone of the genome age. Doudna now heads the Innovative Genomics Institute at UC Berkeley and UCSF, and is in many ways the anti-Lander.

Science, in the end, is built on ambition and curiosity. It requires egos. But they neednt be quite so big.

Go here to see the original:
The fall of Eric Lander and the end of science's 'big ego' era - STAT

Researchers studying bumblebee genomes have identified genes thought to be helping bees overcome environmental challenges, such as climate change.

The study, led by researchers from Queen Mary University of London and Imperial College London, looked at genome sequences of buff-tailed bumblebees (Bombus terrestris) one of the most widespread European species - to understand how they have been adapting to the dramatic environmental change they have faced in recent evolutionary time.

The team searched the genomes to find which parts had been replaced by newer versions over recent decades a term researchers call signatures of selection.They found signs of recent changes to the genome in areas known to be linked to the nervous system and wing development.

The researchers suggest that these genetic changes likely improved the bumblebees ability to forage further for food in response to increasing habitat fragmentation and changes in climate.The results are published in the journal Molecular Biology & Evolution.

Bumblebees and other insects are important natural pollinators of crops and of wildflowers. Recent studies have documented international declines of bees and other pollinators, citing habitat loss, disease, pesticides, and climate change as contributing factors. However, some of these pollinators, such as Bombus terrestris have been doing well, despite changing environmental conditions.

Co-author of this study Dr Richard Gill, from the Department of Life Sciences (Silwood Park) at Imperial, said: Advances in genomic techniques are now providing us with unprecedented insight into how previously overlooked species are responding to environmental change.

Understanding responses of insect pollinators like bees was previously reliant on recorded sightings, but these are not always reliable due to sparse historic records and unstandardised methods. The genome, however, provides an effective diary of how populations are responding.

"By studying these genetic changes, we can better understand why some species are doing better than others and which environmental pressures are the primary culprits, which can inform mitigation strategies.

Lead author of the studyDr Yannick Wurm, from Queen Mary University of London and the Alan Turing Institute, said: We found signatures of recent adaption in genes throughout the bumblebee genome, including for genes involved in the nervous system and in wing development.

Simultaneously analysing many genomes of the buff-tailed bumblebee sheds new light on the health of this species. This species is doing well, and we found that most of the genome harbours extensive genetic diversity and the ability to use it. These traits will support this species in continuing to adapt to the challenges it faces.

Interestingly, the researchers also uncovered some unusual features of the bumblebee genome, including a region containing 53 genes that lacked the diversity found in the rest of the genome.

Dr Thomas Colgan, the first author of the study from Queen Mary University of London, said: In contrast to the high genetic diversity in most of the genome, we found a gene-rich region with the opposite pattern: extremely low diversity in bumblebees and in their relatives, the honeybees.

"We dont fully know the evolutionary reasons for the pattern observed in this region of the genome, nor how it may impact the ability of the species to adapt.

The findings provide important insights into the ability of a key pollinator to adapt and highlight the benefit of genomic approaches for understanding the genetic health of wild populations. The researchers suggest that this type of approach could help develop tools for safeguarding beneficial insects important for ecosystem stability, biodiversity maintenance and crop productivity.

Dr Wurm added: The UK hosts more than 1,500 beneficial pollinator species, including many species of bees. Applying the genomic approach developed here to other pollinators can help identify those species most at risk and inform the development of custom-tailored conservation and mitigation strategies.

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Genomic signatures of recent adaptation in a wild bumblebee by Thomas Colgan, Andres Arce, Richard Gill, Ana Ramos Rodrigues, Abdoulie Kanteh, Elizabeth Duncan, Li Li, Lars Chittka, Yannick Wurm is published in Molecular Biology & Evolution.

Originally posted here:
Genes that may be helping bumblebees adapt to environmental change pinpointed - Imperial College London

Following directions from the Centre, Karnataka Government has directed all ICMR-approved COVID-19 testing labs in the State to send 10% of all positive samples, identified from February 2 to February 28, for genome sequencing.

This is as part of a special genome sequencing surveillance drive to enable detection of new variants proactively. Karnataka has been given a target of 10,000 samples in February.

As of now, routine genome sequencing is being undertaken with 15 samples fortnightly from each district. However, the Centre has now instructed the State to conduct a special genome sequencing surveillance of COVID-19 with a larger proportion of positive samples, stated a circular issued in Bengaluru on February 7.

Samples of patients with international travel history (irrespective of CT value); representative samples from clusters / focal outbreaks with severe morbidity and / or mortality; seriously sick, hospitalised patients and prolonged hospital admissions should be prioritised. Besides, samples from cases of re-infection; breakthrough infections (in fully vaccinated individuals) and from COVID-19 death cases should also be sent for sequencing, the circular stated.

Management of patients with mental illness

Following recommendations by the States Technical Advisory Committee (TAC), all District Health and Family Welfare Officers, Mental Health Programme Officers along with District and Taluk Mental Health Program (DMHP) teams have been directed to ensure uninterrupted availability of out-patient mental health services.

Along with in-person out-patient services, hospitals can also practice telephonic consultation, telemedicine services and e-prescription as per the existing telemedicine guidelines.

According to a circular issued in Bengaluru, hospitals have been directed to procure the required psychotropic drugs through District Mental Health Programme funds, National free drugs funds or Arogya Raksha Samithi funds. All government healthcare facilities, including PHCs and sub-centres, should ensure adequate supply and stock of essential psychotropics, and dispense the drugs to needy patients. Persons with mental illness should get their regular medications to prevent relapse.

All persons with mental illness in quarantine/isolation should be contacted on a daily basis. Those with moderate to severe COVID-19 infection and requiring hospitalisation should be admitted in designated COVID-19 hospitals without any prejudice and should be treated equally. Non-pharmacological interventions, such as counseling and psychotherapy, should be provided simultaneously. Considering the unique challenges faced by persons with mental illness during the pandemic, the officials should stretch their resources and accommodate them without undue referral to other health care facilities, the circular states.

In the wake of increased number of patients in home isolation during the third wave, the available helplines NIMHANS helpline (080-46110007), child helpline (1098) and Yuva helpline (155265) should be used to seek psychosocial support and mental health care, the circular states.

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Special genome sequencing surveillance in Karnataka to detect new variants of COVID-19 - The Hindu

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The top Leading Market Players Covered in this Report are :Agilent Technologies Inc., Biomerieux, Becton Dickinson and Company, F. Hoffmann-La Roche Ltd., GE Healthcare, Genomic Health, Inc., GenMark Diagnostics, Inc., Illumina, NanoString Technologies, Inc., PerkinElmer, Inc., Quest Diagnostics, Qiagen, and Thermo Fisher Scientific.

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Global Digital Genome Market Set for Rapid Growth, to reach Value around $29.1 Billion by 2025 | Exclusive Report by Esticast Research The Grundy...

image:Figure 1: The three ancient populations that form the contemporary European gene pool, with the addition of Siberian (peculiar to the Estonian genomes analysed in this study) are represented here along with the inferred contribution (increase, decrease or nothing) they made to a number of body and health traits in present day individuals. For eye and hair colour, symbols point to the shade most likely contributed by a given ancestry. view more

Credit: Davide Marnetto

A study recently published in Current Biology described the impact of ancient migrations on some complex traits (physiology and appearance) of contemporary Europeans. The study was led by Dr. Davide Marnetto from the Institute of Genomics of the University of Tartu, Estonia and University of Turin, Italy and Prof. Luca Pagani from the University of Padova, Italy.

Background

Most of the contemporary European genetic makeup was shaped by movements that occurred in the last 10,000 years when local European Hunter-Gatherers mixed with incoming Anatolian Neolithic farmers and Pontic Steppe pastoralists. These populations were separated for thousands of years and evolved in different directions. Following this encounter, their DNA, or genome, came in contact and genetic variants characterising each of them intermixed.

What is novel

Previous studies, relying on the information contained in ancient genomes, described some biological traits of these source populations, elucidating the origins and the natural selection forces acting on traits like lactase persistence, height, and skin, eye or hair pigmentation. With our study, instead, we asked how the physiology and appearance of contemporary Europeans are influenced by these ancient footprints that are still embedded in their genomes, said Dr. Marnetto, first author of the study.

What has been done

As a case study, we used the Estonian population, which also displays some genetic components frequent in present-day Siberian populations, because of the rich data provided by the Estonian Biobank, where we could find the genome and trait characterization for more than 50,000 samples. We specifically measured whether having a certain feature, e.g. high cholesterol, is coupled with having inherited more variants from a specific ancestry, exactly in those DNA regions influencing cholesterol levels, continues Marnetto.

What the results say

Our results show that the ancient populations that formed contemporary Europeans were differentiated enough to contribute their own signature to the physiology and appearance of contemporary individuals, says Prof. Luca Pagani, senior author of the study. For example, Steppe ancestry seems to have contributed to a strong build, with tall stature and increased hip and waist circumferences, but also to higher blood cholesterol, which on the other hand tends to be lower in individuals carrying Hunter-Gatherer ancestry at specific genes. The latter seems also linked with higher body mass index (BMI), among others. The best connections made for the Anatolian ancestry are instead a reduced (BMI-corrected) waist-hip ratio and lower heart rate.We also find substantial differences in ancestry or evidence for recent natural selection in eye and hair pigmentation, body caffeine intake, age at menarche and sleep patterns.

What the results do not say

Importantly, we drew our conclusions relying on specific parts of the genome, while using the rest of the genome as control, to observe subtle effects by contrast. This means that it is misleading and naive at best to use any given trait to guess the dominant ancestry across ones genome, says Prof. Mait Metspalu, co-author of the study. He follows up by reminding that to give a biological outcome, it does not just matter how much of a certain ancestry one has in their genome, rather where and which genes this ancestry contributed, even for complex traits encoded by many genes. Metspalu also emphasises that for the same reason it is simplistic to interpret trait patterns across Europe only as the abundance of one ancestry or the other without considering environment and other evolutionary forces. Furthermore, it is important to remark that the link we made between a given trait and a given ancestry does not imply that such a trait was predominant in a particular ancient population or absent in all other groups.

The authors conclude by pointing out that their focus on the Estonian and ultimately European population is connected with the sheer amount of data available, in contrast with the dramatic underrepresentation of other ethnicities in genetic studies.There is absolutely no evidence indicating that Europe encompasses higher genetic diversity and more complex heritage than other continents: an increased coverage of samples from across the world is crucial to enhance our understanding on how past human history shaped the trait variability displayed by contemporary individuals said Marnetto.

Experimental study

Not applicable

Ancestral contributions to contemporary European complex traits

8-Feb-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Excerpt from:
Ancient mixing of ancestries shaped present-day European body and health traits - EurekAlert

This article was originally published here

PLoS One. 2022 Feb 7;17(2):e0263606. doi: 10.1371/journal.pone.0263606. eCollection 2022.

ABSTRACT

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with genetics and environmental determinants. Studies focused on the neurogenetics of MS showed that mitochondrial DNA (mtDNA) mutations that can ultimately lead to mitochondrial dysfunction, alter brain energy metabolism and cause neurodegeneration. We analyzed the whole mitochondrial genome using next-generation sequencing (NGS) from 47 Saudi individuals, 23 patients with relapsing-remitting MS and 24 healthy controls to identify mtDNA disease-related mutations/variants. A large number of variants were detected in the D-loop and coding genes of mtDNA. While distinct unique variants were only present in patients or only occur in controls, a number of common variants were shared among the two groups. The prevalence of some common variants differed significantly between patients and controls, thus could be implicated in susceptibility to MS. Of the unique variants only present in the patients, 34 were missense mutations, located in different mtDNA-encoded genes. Seven of these mutations were not previously reported in MS, and predicted to be deleterious with considerable impacts on the functions and structures of encoded-proteins and may play a role in the pathogenesis of MS. These include two heteroplasmic mutations namely 10237T>C in MT-ND3 gene and 15884G>C in MT-CYB gene; and three homoplasmic mutations namely 9288A>G in MT-CO3 gene, 14484T>C in MT-ND6 gene, 15431G>A in MT-CYB gene, 8490T>C in MT-ATP8 gene and 5437C>T in MT-ND2 gene. Notably some patients harboured multiple mutations while other patients carried the same mutations. This study is the first to sequence the entire mitochondrial genome in MS patients in an Arab population. Our results expanded the mutational spectrum of mtDNA variants in MS and highlighted the efficiency of NGS in population-specific mtDNA variant discovery. Further investigations in a larger cohort are warranted to confirm the role of mtDNA MS.

PMID:35130313 | DOI:10.1371/journal.pone.0263606

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Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis -...

Significance

The Orcadian Neolithic has been intensively studied and celebrated as a major center of cultural innovation, whereas the Bronze Age is less well known and often regarded as a time of stagnation and insularity. Here, we analyze ancient genomes from the Orcadian Bronze Age in the context of the variation in Neolithic Orkney and Bronze Age Europe. We find clear evidence for Early Bronze Age immigration into Orkney, but with an extraordinary pattern: continuity from the Neolithic on the male line of descent but immigration from continental Europe on the female side, echoed in the genome-wide picture. This suggests that despite substantial immigration, indigenous male lineages persisted for at least a thousand years after the end of the Neolithic.

Orkney was a major cultural center during the Neolithic, 3800 to 2500 BC. Farming flourished, permanent stone settlements and chambered tombs were constructed, and long-range contacts were sustained. From 3200 BC, the number, density, and extravagance of settlements increased, and new ceremonial monuments and ceramic styles, possibly originating in Orkney, spread across Britain and Ireland. By 2800 BC, this phenomenon was waning, although Neolithic traditions persisted to at least 2500 BC. Unlike elsewhere in Britain, there is little material evidence to suggest a Beaker presence, suggesting that Orkney may have developed along an insular trajectory during the second millennium BC. We tested this by comparing new genomic evidence from 22 Bronze Age and 3 Iron Age burials in northwest Orkney with Neolithic burials from across the archipelago. We identified signals of inward migration on a scale unsuspected from the archaeological record: As elsewhere in Bronze Age Britain, much of the population displayed significant genome-wide ancestry deriving ultimately from the Pontic-Caspian Steppe. However, uniquely in northern and central Europe, most of the male lineages were inherited from the local Neolithic. This suggests that some male descendants of Neolithic Orkney may have remained distinct well into the Bronze Age, although there are signs that this had dwindled by the Iron Age. Furthermore, although the majority of mitochondrial DNA lineages evidently arrived afresh with the Bronze Age, we also find evidence for continuity in the female line of descent from Mesolithic Britain into the Bronze Age and even to the present day.

Benefiting from the tail end of the Holocene climatic optimum, the British Early Neolithic spread rapidly through Britain and Ireland from the south over 300 to 400 y from 4050 BC (13). The settlers brought with them domesticated wheat, barley, sheep, and cattle, as well as knowledge of carinated bowl ceramics and causewayed enclosures (15), pointing to a likely source in northern France or Belgium.

The Orkney Islands, lying to the north of the Scottish mainland, flourished during the Neolithic (3800 to 2500 BC), becoming a major cultural center (69). Underpinned by a successful farming economy and long-range contacts, the earliest permanent settlements were constructed in wood, followed by stone-built dwellings from 3300 cal. (calibrated) BC onward (9, 10). The use of stone appears to have been a conscious design choice (9, 11, 12) and has resulted in an extraordinary level of archaeological preservation.

While recent genome-wide studies (13) have demonstrated the extent and tempo of continental migration into Britain during the Beaker period, after 2500 BC, there has so far been little or no recognition of the archaeological implications of this for Orkney. The paucity of Beakers and associated material culture in the archaeological record has been taken as an indication that the cultural and population shifts occurring elsewhere in Britain at this time had little direct impact in Orkney (8, 1418) and indeed may have been locally resisted (6). As a result, Orkney has been seen to have developed along a largely insular trajectory during the second millennium BC.

Significant changes in funerary practice did begin to emerge at this time, and research has concentrated on funerary remains. Barrow cemeteries, some of the largest in northern Britain, appeared in Orkney around the end of the third millennium BC. These earthen mounds contained multiple burials, added sequentially and most frequently comprising cremated remains in pits or stone-lined cists (18). Flat cist cemeteries were also in use for both inhumation and cremation burials, and often graves contained the remains of several individuals, but grave goods were infrequent.

Until recently, the low visibility of settlement sites had led to the idea that this was a period of environmental and cultural recession (19). The balance has begun to be redressed through focused environmental analyses (20) and reports on settlements such as at Crossiecrown (9) and Tofts Ness (21). Opportunities to correlate settlement and funerary remains are very rare, and few sites extend across the Neolithic and Bronze Age (BA) periods, making it difficult to draw a coherent picture of change over time. In this respect, the ongoing investigations at the Links of Noltland (LoN) are providing valuable new insights.

The LoN is located on Westray, the northwesterly most island of the Orkney archipelago. The exceptional conditions have preserved extensive settlement and cemetery remains dating from at least 3300 cal. BC up to about 500 BC (2225). While no direct overlap has yet been detected between Neolithic and BA phases of settlement, there is no evidence for a major hiatus in occupation. The BA settlement, distinguished on architectural grounds and dating from 2500 to 1200 cal. BC, includes three separate conglomerations of domestic and ancillary buildings, which, like their Neolithic counterparts, were spread across a contemporary farmed landscape. Built from a mix of stone and earthen banks, often arranged in pairs, they were in use until at least 1200 cal. BC. A cemetery located among these settlements, used between at least 2150 BC and 850 BC, comprised >50 burials, including >100 individuals. Both cremation and inhumation were practiced, at times contemporaneously, and multiple burials within a single grave were common. Material evidence of the Beaker complex, seen across mainland Britain, is scant in Orkney; a few sherds from two Beaker vessels were recovered from the wider area (19), dated to 2265 to1975 cal. BC, but no further pottery or recognizable artifacts have been found in association with the cemetery or settlement.

The study of ancient genomes has shown that across much of Europe, including mainland Britain, the arrival of Metal Age culture was accompanied by the introduction of new ancestry from the Pontic-Caspian Steppe and a predominance of Y-chromosomal haplogroup R1b-M269 (13, 2631). We investigated genomic variation in the Orkney archipelago within the context of this framework. Genome-wide SNP (singlenucleotide polymorphism) capture and shotgun data were available from 21 Early Neolithic Orcadians (13, 32), but only one from the BA (13). To investigate BA Orkney, we generated whole-genome shotgun sequence data from 22 samples from the LoN cemetery and analyzed them alongside these published data. We also included new data from three Iron Age (IA) samples from the multiperiod ritual complex and cemetery site of Knowe of Skea (KoS), on the west coast of Westray, and 12 further prehistoric samples from Scotland and northern England.

We present shotgun genome data from 29 samples from prehistoric Scotland and eight from northern England: 22 from the BA LoN in Westray, Orkney, dating to 1400 to 1700 BC (LoN); three from the IA KoS in Westray, Orkney, dating to the first two centuries AD; one from IA Milla Skerra (MS), Unst, Shetland; one from IA High Pasture Cave (HPC), Isle of Skye in the Hebrides (33); one from Neolithic Strath Glebe (SG), also Skye; a Pictish sample from Rosemarkie Cave (RC), Black Isle in northern Scotland, dating to 430 to 630 AD; a Beaker burial sample from Low Hauxley (LH), Northumberland; three BA samples from West Heslerton (WH), North Yorkshire; two IA samples from Knapton Wold (KW), North Yorkshire; and two IA samples from Carsington Pasture Cave (CPC), Derbyshire. Whole-genome coverage varied greatly from 0.0007 to 0.8207. We undertook genome-wide analysis on samples above 0.009, with samples averaging 0.194. All samples passed contamination tests (Table 1, SI Appendix, Table S1, Dataset S1 A and B, and SI Appendix, Fig. S1). We analyzed these in the context of genome data from Early Neolithic Orkney (n = 21) (13, 32) and Neolithic, Chalcolithic (CA), and BA Europe and 1,856 new mitogenomes from modern Orkney (n = 1,356) and Shetland (n = 500) (Datasets S1C and S2).

Summary of ancient samples reported in this study

ADMIXTURE analysis (Fig. 1A) showed that the samples from BA Orkney closely resembled other northern European BA people in their overall genome-wide profiles and were highly distinct from Neolithic Orkney samples, which resembled more our Neolithic sample from Skye and other British and Irish Neolithic samples. Neolithic samples all lacked the CHG (Caucasus hunter-gatherer) component (in blue) that most clearly signals admixture from Pontic-Caspian Steppe pastoralists (34). The CHG fraction in Orkney (both BA and IA) is somewhat higher (40%) than in other Scottish CA and EBA (Early Bronze Age) samples but within the wide range of values for England (Fig. 1A and SI Appendix, Fig. S2A). Modern Orcadians have an even higher fraction of the CHG component, reflecting medieval Norse settlement, estimated from modern genome-wide surveys at 20 to 25% (35) and 25 to 30% of modern Y chromosomes (36, 37). Geographical and chronological trends are portrayed more clearly in the PCA (principal component analysis) (Fig. 1B and SI Appendix, Fig. S3). LoN BA samples broadly clustered with northern and central European Bell Beaker, CA, and BA samples, and KoS IA samples fell within the same broad cluster.

Visualization of Orkney genome-wide data in context. (A) Unsupervised ADMIXTURE plot (K = 7) of European Mesolithic, Neolithic, BA, and IA samples. The red component maximizes in the WHG, green in the ANF, and blue in the CHG; profiles to the right of each label are from the same population. (B) PCA showing first two principal components of European Mesolithic, Neolithic, and BA samples, projected on present-day European variation. The figure shows a zoom-in of the full plot (SI Appendix, Fig. S3), excluding outlier Yamnaya and Mesolithic samples. LBK, Linearbandkeramik.

(C) Map displaying outgroup-f3 statistics for the LoN samples, showing the close relationship with Bell Beaker and BA samples from the British and Irish mainland and northwestern continental Europe.

D-statistics quantify shared genetic drift among genomes and can thus also be used to estimate the degree of similarity among individuals. We calculated symmetry D-statistics by comparing potential outlier samples (as noted in the ADMIXTURE analysis) to the rest of the LoN using the form D(Mbuti, Test; Potential Outlier, LoN). The LoN samples consistently formed a clade, indicating that they were statistically indistinguishable from each other (SI Appendix, Fig. S4A and Dataset S1D). With D-statistics of the form D(Mbuti, LoN; European BA, European BA), after closest matches to the slightly older published Lop Ness BA sample from Sanday, Orkney, the most common significant similarities were with British Bell Beaker complex (BBC) samples, the Scottish BA, and Orkney KoS IA, as well as to a few continental individuals such as French BBC and the Dutch BA (SI Appendix, Fig. S4B and Dataset S1E). Outgroup-f3 statistics showed a similar pattern, with LoN closest to eastern British, Welsh, Irish, and northwest European BBC and BA samples, albeit with overlapping errors across European BBC and BA samples (Fig. 1C and SI Appendix, Fig. S5A). This indicates that the Orkney BA was most likely settled via the British mainland (possibly the eastern side) by people who arrived in Britain during the Beaker period.

Schematic phylochronology of Y-chromosome haplogroup I2a1b-M423. For detailed branching at the tips, see SI Appendix, Fig. S15.

The software qpAdm (38) summarizes f4-statistics (which are similar to D-statistics) in order to estimate the direction and magnitude of gene flow, or admixture, from one population to another. We modeled admixture fractions with qpAdm using the three major components demonstrated by ADMIXTURE; Steppe, Anatolian Neolithic Farmer (ANF), and Western Hunter-Gatherer (WHG) (SI Appendix, Fig. S6 and Dataset S1F). The LoN comprised 55% of their ancestry from the Steppe, 33% from ANF, and 12% from WHG, broadly similar to published BA samples from across Britain (13).

The populations that contributed to the LoN population were likely admixtures of those three components. To identify more proximal sources for the LoN, we modeled various potential Early Neolithic versus Late Neolithic/EBA source populations (Table 2). The Orcadian BA samples could be plausibly modeled as 4 to 7% local Neolithic and 93 to 96% Scottish BBC populations, but also as 1 to 5% local Neolithic and 95 to 99% French BBC populations or 1% local Neolithic and 99% Danish BA populations. Despite the uncertainty indicated by the SEs, these results clearly imply very high levels of replacement of the Neolithic people by people related to continental BBC immigrants by the EBA, with only 5% assimilation at most of the local autosomal gene pool. However, by the time the descendants of the BBC immigrants reached Orkney, they appear to have lost their Beaker cultural affiliation, as reflected in the dearth of Beaker-associated material culture in Orkney (6).

Putative BA and Neolithic ancestry of LoN MBA and Lop Ness EBA (13) samples modeled with qpAdm

Thus, the picture from the genome-wide analyses suggests a substantial replacement of the Orcadian population between the Late Neolithic and the BA, similar to that seen in mainland Britain (13). However, there are striking and unexpected differences between the patterns displayed by the uniparental marker systems, which can illuminate in more detail how this process took place.

Early Neolithic Orkney (n = 21) includes mitochondrial DNAs (mtDNAs) characteristic of the European Neolithic, suggesting predominantly settlement from the western Neolithic but with a minor contribution from the Danubian Neolithic (SI Appendix, Section S5). By contrast, the BA LoN suite of lineages (n = 20) is very different (Datasets S1G and S2). There are a number of minor H lineages, including H39 (four individuals), H58a, H+195, and two individuals with H1n1. There are also two with J1c2a, three with T2a1b1amatching the EBA individual from Lop Ness (the only previously published BA Orkney sample) (13), two with T2b21, two with U5b2a3, one with K1a3a, one with K1a29a, and one with K1c2. Eight of these individuals (three of the H39 individuals, all three T2a1b individuals, one of the two U5b2a3 individuals, and the K1a3a individual) were part of a multiple burial, of which two were related (see below). The males from the multiple burial also all carried Y-chromosome haplogroup I2a1b-M423/I2a1b1-S185.

The age and geographic distribution of the clusters to which most of the BA LoN lineages belonged suggest that most of them were not inherited from the local Neolithic but arrived later. Many are associated in ancient DNA studies with continental Corded Ware Culture, BBC, or BA populations (SI Appendix, Section S5). For example, T2a1b1 is seen in the German Corded Ware, whereas T2b21 matches German and Czech BBC lineages. While H39 and K1c2 lineages have not been seen in published ancient DNA data, the modern lineages are restricted to northern Europe and date to 3000 BC and 2600 BC, respectively, again suggesting a source in the Corded Ware expansion across northern Europe at 2500 to 3000 BC. Several lineages, such as J1c2*, K1a3a, H1n1, H58a, and H+195, are harder to resolve, but their distribution is in each case consistent with a BBC arrival, although we cannot currently conclusively rule out a local Neolithic source. The IA KoS remains (n = 3) include two identical H1b lineages and one U5a1b1a, both of which can be attributed to either the BBC or the Corded Ware on the Continent.

The lineage most likely to date to before the Beaker Age in Orkney, seen in two LoN individuals, is U5b2a3+16319, which we name here U5b2a3b (Dataset S3). U5b2a3 dates to 8500 BC and is seen in Early Neolithic individuals from both Scotland (13) and Wales (39), and so the Orkney individuals represent potential continuity from the British Neolithic into the BA. Intriguingly, U5b2a3b is also seen in one modern individual from the British Isles (40), as well as an individual from Virginia, United States (founded as a British colony), indicating potential continuity through to the present day. Indeed, with U5b2a* found in Neolithic Orkney (32) and Scotland (13) and, notably, Mesolithic Ireland (41) and U5b2a3 itself also seen in Neolithic Ireland (41), along with the presence of U5b2 lineages in modern Orkney and Shetland (Dataset S2), it is possible that some U5b2 lineages, including U5b2a3b, may signal some of the most ancient lineages surviving in present-day Britain and Ireland, potentially even from the local Mesolithic.

There are 16 known Y-chromosome (Y-DNA) haplotypes from Neolithic Orkney, of which 14 appear to be well resolved (13, 32). All 14 belong to haplogroup I2a, of which seven are I2a1b-M423, four are I2a1b1-S185, one is I2a2-S33, one is I2a2a1b-CTS10057, and one is I2a2a1a2-Y3679 (the remaining two are poorly resolved I and I2). In BA LoN, even though the majority of genome-wide and female lineages most likely arrived in Britain and Orkney with the BBC or BA, all but one of the nine Y-DNA lineages belong to haplogroup I2a1b-M423, with just one belonging to R1b-M269 (SI Appendix, Section S6 and Dataset S1H). We found four distinct haplotypes within I2a1b: I2a1b-M423, I2a1b1-S185, and the more derived I2a1b1a1b-A1150 and I2a1b1a1b1-A8742.

This predominance of I2a1b-M423 is surprising because it is completely absent elsewhere in CA/BA Europe, where the Y-DNA landscape is heavily dominated by R1b-M269 (Figs. 24 and SI Appendix, Figs. S13S15). For example, in a dataset of 21 BBC males from Britain, 20 carry the R1b-M269 lineage and only one I2a, which is on the distinct I2a2a-M223 lineage. If we include CA and EBA Britain and Ireland, 41 out of 43 males carried R1b-M269, two I2a2a-M223, and none I2a1b-M423.

Distribution of Mesolithic and Neolithic Y-chromosome lineages, and their Bronze Age descendants. (A) Britain and Ireland with (B) zoom in on Orkney. Colors represent different Y-chromosome lineages, and distinct outlines represent the time period of the sample. Each circle represents one individual, except for Trumpington Meadows, Cambridgeshire (66), where two brothers are represented by a single circle. Maps prepared with GADM tools (https://gadm.org/data.html) (67) using data from SRTM (68).

Distribution of prehistoric I2a1b-M423 Y-chromosome lineages in Europe. Each circle represents one individual carrying I2a1b. Map modified from Mapswire.com (https://mapswire.com/), which is licensed under CC BY 4.0.

Thus, except for the single R1b-M269 lineage, all sampled LoN BA males carried a subset of the Neolithic Y-DNA pool. These are very unlikely to have been brought to Orkney by BBC or BA migrants from further south in Britain. Not only has I2a1b-M423 not been seen in the European BBC or BA, but it was a minority lineage even during the European Neolithic. Among 389 published male genomes from the European Neolithic, only 12% (47 of them) carry I2a1b-M423, of which 40% (19/47) are from Britain or Ireland (42), and most of those in Britain are from Orkney (Figs. 3 and 4). Even in Britain and Ireland, outside of Orkney most Neolithic Y-DNA lineages belong to haplogroup I2a2-S33 or I2a2a-M223 (Fig. 3), although, curiously, our Neolithic individual from Skye belongs to the very rare I2a2b-S154, seen elsewhere only in Middle Neolithic France (43). I2a1b-M423 seems to be largely restricted to western Neolithic Britain and Ireland, where it occurs rarely alongside I2a2a-M223, as well as I2a1a-CTS595 (41), which has not yet been found in Neolithic Britain. This perhaps suggests a relict distribution, shared by Orkney, Ireland, and western and northern Britain.

A consequence is that not only was the assimilation of Neolithic male lineages very rare during the BBC spread in Britain, but assimilation of I2a1b-M423, which formed a small minority of Neolithic British mainland lineages, must have been even rarer, if it ever happened at all. We conclude that the I2a1b-M423 lineages at BA LoN had most likely persisted from the local Orcadian Neolithic and were not contributed to this population by mainland British Neolithic groups. By contrast, the two sampled males at the IA KoS site, also on Westray, belonged to the R1b-M269 lineage.

I2a1b-M423 likely arrived in Orkney with the first farmers. In the Neolithic, I2a1b-M423 was largely distributed in an arc around the Atlantic faade of Europe, from the western Mediterranean to the Baltic. Outside Britain, most I2a1b-M423 lineages are from Middle/Late Neolithic Spain and France, with one from Germany and a small number from Sweden, where, at a megalithic site on Gotland, all four genotyped males belonged to I2a1b-M423 (Fig. 4) (32). It is also present in several hunter-gatherers in northern and central Europe, including Mesolithic Ireland. This distribution, the molecular-clock age of the two major subclades (I2a1b1-S185 and I2a1b2-S392 both date to 7 ka) (YFull YTree version 8.06.01, 27 June 2020; https://www.yfull.com/tree/), and evidence that the ancestral lineage survives today only in Iberia (YFull tree) suggest assimilation from hunter-gatherers during the spread of the Neolithic into southwest Europe, followed by Neolithic dispersal into northwest and northern Europe, although some further assimilation in northern Europe is also possible.

We assessed runs of homozygosity (ROH) using the program hapROH (44). ROH profiles of BA LoN samples indicate a small effective population size but give no evidence for recent consanguinity, up to third cousin unions (SI Appendix, Fig. S7). HapROH estimated the effective population size to be 400. This is a large decrease from Neolithic Orkney and also much lower than elsewhere in Neolithic, BBC, or BA Britain and northwest Europe (SI Appendix, Table S2). These results suggest a small, endogamous population.

We estimated kinship using Relationship Estimation from Ancient DNA (READ) software (45), coupled with uniparental markers and the age-at-death osteoarchaeological profile. The READ analysis identified almost no evidence for close kinship. Even among the seven individuals in the multiple inhumation who passed the criteria for DNA analysis (out of 11), the only first- or second-degree relationship involved two full siblings: a brother and sister, where the former died in adolescence and the latter soon after birth. The siblings shared an identical, rare mtDNA haplotype (within H39), and the male carried the most common Y-DNA haplotype at the cemetery (I2a1b1-S185). An infant from outside of the multiple burial carried a slightly distinct lineage of mtDNA H39, but we could find no evidence of close kinship using READ (SI Appendix, Fig. S8A).

The low Y-DNA diversity and multiple sharing of rare mtDNA haplotypes both suggest a small, close-knit community, notwithstanding the relatively recent arrival (within the previous millennium) of most of the mtDNAs from overseas. However, the most significant signal remains the contrast between the autochthonous male lineages versus higher-diversity nonlocal female lineages, pointing to ongoing patrilocal marriage patterns, not only in the BA but, by inference from the persistence of I2a1b-M423, at the end of the Neolithic too. We note that although the contrast between the largely indigenous Y-DNA and the largely continental mtDNA and autosomal fraction is very striking, a level of 95% continental genome-wide ancestry could be achieved by the marrying out of indigenous men with immigrant women in only five generations, or 100 to 150 y, which the results suggest were followed by isolation and endogamy (SI Appendix, Section S3.10).

We have investigated genomic variation in BA and IA Orkney and compared it with the available evidence for the preceding Orcadian Neolithic, in the context of Mesolithic, Neolithic, BA, and IA variation from across Europe. Both the mtDNA and Y-DNA variation of Neolithic Orkney point to settlement primarily from the Mediterranean/Rhne/Atlantic dispersal route, via the British mainland, in line with genome-wide analyses for Neolithic Britain as a whole (13, 39). Although this process was largely one of colonization, we find some evidence for potential assimilation and survival of indigenous Mesolithic maternal lineages. The presence of an apparently ancient local branch of mtDNA haplogroup U5b complements genome-wide observations of hunter-gatherer assimilation in western Scotland (39) and Ireland (41).

This study confirms that the drastic shift in the British population in the BA, evident in both the genome-wide (13) and mtDNA patterns, also occurred in Orkney. Orkney was largely resettled from the British mainland by people of substantially recent continental ancestry. Although this demographic shift may have taken place over centuries, it was likely sustained relatively unchanged into the IA; although we have analyzed only three IA samples, they all show a similar pattern.

Unexpectedly, despite this wave of immigration, local Neolithic male lineages persisted well into the BA, at least in Westray. While we do see evidence for male newcomers, in the presence of a single R1b-M269 Y-DNA lineage (in an infant burial), the other males all carry the indigenous I2a1b-M423 lineage. This lineage survived in a single fifth or sixth century Pictish sample from Birsay, northwest Mainland (46), but is only seen in a single family (among 407 males tested) in Orkney today.

The I2a1b-M423 lineage almost vanished elsewhere in western Europe after the end of the Neolithic. None are seen in post-Neolithic European archaeological remains. It is seen at only 1% in modern Britain and is almost absent in most of modern western Europe, although one recent subclade of I2a1b2-S392 has undergone dramatic expansion with Slavic populations in the Balkans (Figs. 24 and SI Appendix, Fig. S13) (47).

A possible explanation can be found in the continuity, stability, and self-sufficiency of farming settlements, such as LoN. These successful household groups, while undoubtedly participating in an Orkney-wide Neolithic society, also developed strong local identities, manifested in locally variant art styles, material culture, architecture, and ritual activity. They may, for example, have pursued their own long-range contacts, as suggested, for example, by the importation of aurochs and local tomb art, distinctive within Orkney and most directly comparable with that found at Br na Binne in Ireland, where patrilineal descent has recently also been inferred from genetic data (41). From a position of strength during the Neolithic, such settlements may have been better placed to mediate inward migration and to make specific choices with regards to the management of lineage.

We propose that we may be seeing the surviving remnants of well-established Neolithic household groups in BA Orkney: a number of distinct male lineages that have persisted when almost the whole of the rest of the population (and genome) has been replaced. While the archaeological signs of these groups may not have been especially ostentatious, the persistence of their lineages for at least a thousand years beyond the point when the vast majority of male lineages elsewhere in Britain were replaced by newcomers might imply a more protracted and perhaps more negotiated process of assimilation than elsewhere, as well as pointing to much less insularity than has often been assumed for the Orcadian BA (25).

There are several caveats to this suggestion. Firstly, we are describing the situation in one of the most remote parts of the Orkney archipelago and at a particular moment in time. It is a snapshot and may not be representative of Orkney as a whole. While the single Lop Ness sample (from another island in the archipelago) confirms the overall pattern of continental immigration, the individual is female and therefore provides no information on the male lineage. Further investigations can help to fill out the picture.

Secondly, there are numerous cremation burials at the site for which DNA analysis cannot be carried out. Is it possible that newcomer R1b-M269 males were mostly cremated? This seems unlikely; substantial numbers of BBC and EBA inhumation burials have been analyzed from England and Scotland, and the males carried almost exclusively R1b-M269 Y-DNA lineages. However, even if this were the case, the persistence in inhumations of the I2a1b-M423 lineage, in the face of an almost 95% replacement at the genome-wide (and probably also the mtDNA) level, remains extraordinary.

Within the European context, the Orkney BA stands in stark contrast as a location, at the northwestern extreme of the continent, where the majority of the genome was overwritten between the Late Neolithic and the end of the EBA but the male lineages somehow persisted. Even so, we can understand this phenomenon in terms of the same patrilocal marriage practices that we see throughout west Eurasia. The ancestral distribution in Orkney demonstrates deliberate marriage patterns involving local men and incoming women. This process of preferential assimilation seems likely to have continued for many generations, given the extent of replacement of the remainder of the Orcadian Neolithic genome.

The existence of a powerful and likely strongly hierarchical strand in Neolithic society has been proposed on the basis of the discovery of an incestuous first-degree union at Newgrange in Ireland (41) and was prefigured by earlier analyses of Ireland and other megalithic cultures in both northwest and central Europe (32, 48). Cassidy et al. (41) argue that it encompassed the whole of Ireland, adding that it may have incorporated the similar megalithic communities of Wales and Orkney, most likely originating in Brittany (1, 49). I2a1b-M423 is seen in both Mesolithic and Neolithic Ireland, and the main cluster seen in Late Neolithic Ireland, I2a2a1a1-M284found in the putative elite lineage at Newgrangematches an Orcadian Neolithic lineage from the Isbister Chambered Cairn (Tomb of the Eagles) on South Ronaldsay (Fig. 3 and SI Appendix, Fig. S13) (13). Both our data from BA Orkney and the Neolithic circumcoastal distribution of the Y-chromosome I2a1b-M423 haplogroup lend further support to this suggestion. European Neolithic society, at one extreme (but hardly peripheral) edge of its distribution, may have been patrilineal, patrilocal, and hierarchical long before the arrival of the Beaker complex and (most likely) Indo-European speech (27, 28, 31, 50).

Our data suggest that Neolithic lineages persisted within particular farming households, which, although not obviously elite, appear to have retained control of specific landholdings over many generations. This linkage of lineage with specific place is strongly suggestive of preferential inheritance along the male line. The continuity which this engendered is likely to have contributed significantly to the longevity of settlements between the third and first millennia BC. The indigenous male lineages remained in place while their people, their culture, their language, and even their genomes were transformed to resemble more and more those of the European mainland from which the newcomers had come.

Our findings both demonstrate EBA migration into Orkney and amplify the recognition that the expansion of the Beaker complex cannot be described by a simple one-to-one mapping of an archaeologically defined material culture to a genetically homogenous population (51). They also highlight that population influx may have occurred even where few archaeological traces have been identified. This prompts a critical reassessment of the origins of Orcadian BA practices, which have hitherto been viewed either as insular development, imitative of distant elites, or the result of gradual filtering-in of influences. The circumstances surrounding the emergence of novel monument types such as barrows and burnt mounds, for example, will need to be reconsidered.

If more widely borne out, these findings suggest that BA Orkney is likely to have seen regular and sustained migration, engaged in long-distance exchange networks, and adopted novel practices. The perseverance of Neolithic lineagesand, potentially, identitiesinto this period adds a further layer of cultural complexity, the implications of which remain to be fully explored.

We describe the archaeological samples and materials and methods fully in SI Appendix. Briefly, we extracted DNA from 37 samples using existing protocols (33, 52, 53). We constructed and UDG (uracilDNA glycosylase) treated next-generation sequencing libraries (42, 54, 55), pooled equimolarly, and sequenced all libraries on an Illumina HiSeq4000 (100-bp, paired-end sequencing; Macrogen). We trimmed sequence reads of adapter sequences and merged them using AdapterRemoval (version 2.1.7) (56). We mapped reads to the human reference genome (UCSC [University of California Santa Cruz] hg19) and the human mitochondrial reference genome (the revised Cambridge reference sequence or rCRS, NC_012920.1) (57) using BWA aln (BurrowsWheeler alignment tool) (version 0.7.12-r1039) (58) and filtered for mapping quality (56, 59). We examined molecular damage patterns to establish data authenticity and levels of mtDNA and whole-genome contamination. As expected from UDG-treated samples, observed damage patterns were minor (SI Appendix, Fig. S9). We carried out uniparental marker analysis and molecular sex determination (60) following established methods. We used GATK (version 3.8) to call pseudohaploid genotypes at known SNP positions, which were then merged with the Human Origins dataset (61), the 1000 Genomes Project data, and realigned published ancient samples (SI Appendix). We investigated population relationships between newly reported samples and other ancient and modern individuals using smartPCA and ADMIXTURE (version 1.3) (62), with D and f statistics calculated using ADMIXTOOLS (63) to formally confirm relationships, and quantified admixture using qpAdm (34). A list of published samples we used in analyses is in Dataset S1I. We inferred kinship relationships using READ (45) and assessed ROH and effective population size with hapROH (44). We describe construction of Y-chromosome phylochronology for I2a and R1b-M269 in SI Appendix, Section S6 and Figs. S10S16. We extracted the modern mitogenomes from the whole-genome Orkney Complex Disease Study (ORCADES) for Orkney (64) and the VIKING study for Shetland (65).

Raw sequencing reads of ancient samples produced for this study have been deposited in the European Nucleotide Archive under accession no. PRJEB46830. Modern mitochondrial genomes generated as part of this study have been deposited in GenBank, accession nos. MZ846240 to MZ848095.

We thank Steve Birch, Jenny Murray, and Sue Black for help with samples; Harald Ringbauer for advice on hapROH; and Joyce Richards for comments on an early draft. Excavations at LoN and KoS are directed by H.M. and G.W., EASE (Environment and Archaeology Services), grant funded by Historic Environment Scotland. M. Ni Challanain, M. McCormick, and D. Gooney undertook osteological identifications and sample selection. K.D., M.G.B.F, P.J., M.S., G.O.-G, A.F., and S.R. were supported by a Leverhulme Trust Doctoral Scholarship program awarded to M.B.R. and M.P. DNA sequencing was also supported by the UK Natural Environment Research Council Biomolecular Analysis Facility (NBAF) at the University of Liverpool, under NBAF Pilot Scheme NBAF685, awarded to C.J.E. whilst at the University of Oxford. P.S., M.P., and M.B.R. acknowledge FCT (Fundao para a Cincia e a Tecnologia) support through project PTDC/EPH-ARQ/4164/2014, partially funded by FEDER (Fundo Europeu de Desenvolvimento Regional) funds (COMPETE 2020 project 016899). PS was supported by FCT, European Social Fund, Programa Operacional Potencial Humano, and the FCT Investigator Programme and acknowledges FCT/MEC (Ministrio da Educao e Cincia) for support to CBMA through Portuguese funds (PIDDAC: Programa de Investimentos e Despesas de Desenvolvimento da Administrao Central)PEst-OE/BIA/UI4050/2014. V.M. and D.G.B. acknowledge the Science Foundation Ireland/Health Research Board/Wellcome Trust Biomedical Research Partnership Investigator Award No. 205072 to D.G.B., Ancient Genomics and the Atlantic Burden. The ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society University Research Fellowship to J.F.W., the MRC (Medical Research Council) Human Genetics Unit quinquennial programme QTL in Health and Disease, Arthritis Research UK, and the EU FP6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The Edinburgh Clinical Research Facility, University of Edinburgh, performed DNA extractions and the Sanger Institute performed whole-genome sequencing. The Viking Health StudyShetland (VIKING) was supported by the MRC Human Genetics Unit quinquennial programme grant QTL in Health and Disease. DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. Whole genome sequencing was supported by the Scottish Genomes Partnership award from the Chief Scientist Office of the Scottish Government and the MRC (grant reference SGP/1) and the MRC Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). We acknowledge Wellcome Trust funding (098051) for the ORCADES whole-genome sequencing. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, Quantitative traits in health and disease (U. MC_UU_00007/10). We also acknowledge the invaluable contributions of the research nurses in Orkney and Shetland, the administrative team in Edinburgh, and the people of Orkney and Shetland.

Author contributions:J.F.W., G.W., H.M., M.P., C.J.E., and M.B.R. designed research; K. Dulias, M.G.B.F., P.J., M.S., G.O.-G., A.F., S.R., F.G., A.M., K. Donnelly, T.J.A., T.S.G.P., V.M., P.S., J.F.W., M.P., C.J.E., and M.B.R. performed research; P.J., R.M., and D.G.B. contributed new reagents/analytic tools; A.C., O.L., G.K., D.P., C.W., G.W., and H.M. provided sample materials and information; and K. Dulias, M.G.B.F., P.J., M.S., R.M., J.B., P.S., J.F.W., G.W., H.M., M.P., C.J.E., and M.B.R. wrote the paper.

The authors declare no competing interest.

A complete list of the Scottish Genomes Partnership can be found in the SI Appendix.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2108001119/-/DCSupplemental.

Excerpt from:
Ancient DNA at the edge of the world: Continental immigration and the persistence of Neolithic male lineages in Bronze Age Orkney - pnas.org

Friday, February 4, 2022

Got an impossible polyploid or highly repetitive plant gene, or perhaps an enormous fungal genome or complex microbial community? Have an impossible dream of cracking pandemic, epidemic & endemic biology, or uncovering neurological disorders and rare diseases?

What was once impossible has become possible with HiFi Sequencing, scientists heard at the 2021 PacBio Global Virtual User Meeting.

The event, HiFi Sequencing: Around the World in 24 Hours, featured 32 speakers and 22 panelists from every region of the globe, covering human biomedical research, plant and animal sciences, and microbiology and infectious disease. There were also Ask the Experts sessions and panel discussions about trending topics, such as the COVID-19 pandemic.

If you missed it, it is now available for on-demand viewing, and here are some highlights:

When genomics gets tough, the tough get HiFi: more stories of HiFi enabled scienceKeynote speaker Jeremy Schmutz of HudsonAlpha and the Joint Genome Institute discussed some of the most difficult genomic challenges he and his colleagues face, including the known hard stuff like the FCGR region of the human immune system, an enormous 1.17 Gb zombie fungi, and the gigantic, super complex polyploid 10 Gb, 130 chromosome sugarcane.

Want to know how to get to the ultimate genome? Schmutzs advice: Start with good DNA. Sequence with HiFi. Add Hi-C, assembly curation, and polishing. Use RNA sequencing for annotation.

Unravelling the mysteries of sex determination in reptiles using HiFi sequencingThe bearded dragon lizard, Pogona vitticeps, is an increasingly popular model organism with a unique sex determination, shaped by both genotype and temperature. In his talk, Ira Deveson of the Kinghorn Centre for Clinical Genomics at the Garvan Institute of Medical Research discussed how he used PacBio HiFi sequencing for genome assembly, phasing, and isoform profiling to elucidate the mechanisms of reptile sex determination.

Rapid, accurate surveillance of SARS-CoV-2 variants across the commonwealth of KentuckyAt the University of Louisville Sequencing Technology Center, Melissa Smith (@SmithLab_UofL) was able to create nearly complete genomes for several lineages of SARS-CoV-2 circulating in Kentucky at the end of 2021, including Beta, Gamma, and Delta, using an early access version of the new PacBio HiFiViral Kit. The new HiFiViral kit enables researchers to see a more comprehensive view of viral variation of all types and enables laboratories to identify viral mutations of all kids. Out of 646 samples run with the early access HiFiViral Kit, she saw 80% genome completion; previous methods had yielded complete genomes in only about 50% of cases, she said at the summit. She noted that she appreciated the protocols high multiplexing capacity (384 samples at a time in her lab), reduced hands-on time (by about 80%), and the end-to-end kitted solution, allowing her to avoid having to source reagents from multiple different vendors (especially during the pandemic, when supply chains have at times been unreliable). Melissa now intends to use the HiFiViral Kit to sequence more than 7,000 samples as part of a statewide virus surveillance effort.

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01Bettina Heidecker and Phillip Suwalski of Charit Universittsmedizin Berlin presented their research investigating HLA as a risk factor for COVID-19. Adjusting for other known confounding factors such as age, BMI, and sex, their data suggests that HLA-C* 04:01 increases susceptibility to SARS-CoV-2 and risk for severe course of COVID-19; the results were reproduced in GWAS data of 7,796 cases and 875,694 controls. HLA typing on the Sequel System also helped contribute to an improved understanding of the pathophysiology of COVID-19.

Characterization of HBV integration patterns with HiFi long readsHow does the hepatitis B virus (HBV) induce hepatocellular carcinoma (HCC), the most common type of primary liver cancer? Professor Kai Ye of Xian Jiaotong University explained how he conducted a genome-wide analysis of HBV cell lines and clinical samples and characterized novel recurrent genome rearrangement types associated with HBV integration, finding that different DNA repair mechanisms activated by virus integration were the major cause of virus-specific genome rearrangements.

A new era for marine microbial researchTaylor Priest (@taylorpriest2) of the Max Planck Institute for Marine Microbiology talked about the value of HiFi sequencing in his study on the ecology of microbial communities in arctic marine ecosystems, particularly microbial carbon degradation. One of the most important, but also the most difficult, aspects of elucidating the ecology of microbial populations is accurately linking phylogeny and function, he said. Using HiFi reads and the PacBio ultra-low input library prep protocol, Priest was able to recover a higher quantity and quality of metagenome assembled genomes (MAGs). And with several complete genes obtained per read, genes could be functionally annotated for community-level analysis without any assembly required.

Interested in learning more about PacBio technology? Visit our HiFi sequencing page or Sequel Systems page to learn more.

Read more:
When Genomics Gets Tough, the Tough Get HiFi: Users Share Stories of PacBio Enabled Science at Global Summit - PacBio - Pacific Biosciences