Category Archives: Transhuman News

I am the proud descendant of people who, at least 1,000 years ago, made one of the riskiest decisions in human history: to leave behind their homeland and set sail into the worlds largest ocean. As the first Native Hawaiian to be awarded a Ph.D. in genome sciences, I realized in graduate school that there is another possible line of evidence that can give insights into my ancestors voyaging history: our mookuauhau, our genome. Our ancestors genomes were shaped by evolutionary and cultural factors, including our migration and the ebb and flow of the Pacific Ocean. They were also shaped by the devastating history of colonialism.

Through analyzing genomes from present-day peoples, we can do incredible things like determine the approximate number of waa (voyaging canoes) that arrived when my ancestors landed on Hawaii island, or even reconstruct the genomes of some of the legendary Chiefs and navigators that discovered the islands of the Pacific. And beyond these scientific and historical discoveries, genomics research can also help us understand and rectify the injustices of the past. For instance, genomics might clarify how colonialism affected things like genetic susceptibility to illnessinformation crucial for developing population specific medical interventions. It can also help us reconstruct the history of land use, which might offer new evidence in court cases over disputed territories and land repatriation.

First, lets examine what we already know from oral tradition and experimental archeology about our incredible voyaging history in the Pacific. Using complex observational science and nature as their guide, my ancestors drew on bird migration patterns, wind and weather systems, ocean currents, the turquoise glint on the bottom of a cloud reflecting a lagoon, and a complex understanding of stars, constellations and physics to find the most remote places in the world. These intrepid voyagers were the first people to launch what Kanaka Maoli (Hawaiian) master navigator Nainoa Thompson refers to as the original moonshot.

This unbelievably risky adventure paid off: In less than fifty generations (1,000 years), my ancestors mastered the art of sailing in both hemispheres. Traveling back and forth along an oceanic superhighway the space of Eurasia in double-hulled catamarans filled to the brim with taro, sweet potatoes, pigs and chickens, using the stars at night to navigate and other advanced techniques and technologies, iteratively perfected over time. This would be humankinds most impressive migratory featno other culture in human history has covered so much distance in such a short amount of time.

The history of my voyaging ancestors and their legacy has been passed to us traditionally through our lelo (language), moolelo (oral history) and hula. As a Kanaka Maoli, I have grown up knowing them: of how Maui pulled the Hawaiian Islands from the sea and how Herb Kne, Ben Finney, Tommy Holmes, Mau Piailug and many other members of the Polynesian Voyaging Society enabled the first noninstrumental voyage from Tahiti to Hawaii in over 600 years aboard the waa, Hklea.

Genomes from modern Pacific Islanders have enabled us to reconstruct precise timings, paths, and branching patterns, or bifurcations, of these ancient voyages giving a refined understanding of the order in which many archipelagoes in the Pacific were settled. By working collaboratively with communities, our approach has directly challenged colonial sciences legacy of taking artifacts and genetic materials without consent. Similar tools to the new genomics have no doubt been misused in the past to justify racist and social Darwinist ends. Yet by using genetic data graciously provided by multiple communities across the Pacific, and by allowing them to shape research priorities, my colleagues and I have been able to I ka w mamua, ka w ma hope, or walk backward into the future.

So how can our knowledge of the genomic past allow us to walk toward this better future? Genome sequence data are not just helpful in providing refined historical information, they also help us understand and treat important contemporary matters such as population-specific disease. The time frame of these ancestors arrival in the Pacific, and the order in which the most remote islands in the world were settled, matters for understanding the incidence and severity among Islander populations of many complex diseases today.

Think of our genetic history as a tree, with present-day populations at the tips of branches and older ones closer to the trunk. Moving backward in timeor from the tips to the trunkyou encounter places where two branches, or populations, were descended from the same ancestor. The places where the branches split represent events in settlement histories in which two populations split, often because of a migration to a new place.

These events provide key insights into what geneticists call founder effects and population bottlenecks, which are extremely important for understanding disease susceptibility. For example, if there is a specific condition in a population at the trunk of a branching event, then populations on islands that are settled later will have a higher chance of presenting that same health condition as well. Founder populations have provided key insights into rare population-specific diseases. Some examples include Ashkenazi Jews and susceptibility to Tay-Sachs disease and Mennonite communities and susceptibility to maple syrup urine disease (MSUD).

This research also sheds important light on colonialism. As European settlers arrived in the Pacific in places such as Hawaii, Tahiti, and Aotearoa (New Zealand), they didnt just bring the printing press, the Bible and gunpowder, they brought deadly pathogens. In the case of many Indigenous peoples, historical contact with Europeans resulted in a population collapse (a loss of approximately 80 percent of an Indigenous populations size), mostly as a result of virgin-soil epidemics of diseases such as smallpox. From Hernn Corts to James Cook, these bottlenecks have shaped the contemporary genetics of Indigenous peoples in ways that directly impact our susceptibility to disease.

By integrating digital sequence information (DSI) from both modern and ancient Indigenous genomes in genetic regions such as the human leukocyte antigen (HLA) system, we can observe a reduction in human genetic variation in contemporary populations, as compared with ancient ones. In this way, we can observe empirically how colonialism has shaped the genomes of modern Indigenous populations.

Today fewer than 1 percent of genome-wide association studies, which identify associations between diseases and genetic variants, and less than 5 percent of clinical trials include Indigenous peoples. We have just begun to develop mRNA vaccine-based therapies that have already shown their ability to save the world. Given their success and potential, why not design treatments, such as gene therapies, that are population specific and reflect the local complexity that speaks to Indigenous peoples unique migratory histories and experiences with colonialism?

Finally, genomics also has the potential to impact the politics of Indigenous rights, and specifically how we think about the history of land stewardship and belonging. For instance, emerging genomics evidence can empirically verify who first lived on contested territoriese.g. indigenous groups could prove how many generations they arrived before colonistswhich could be used in a court of law to settle land and resource repatriation claims.

Genetics gives us insights into the impact of both our peoples proud history of migration and the shameful legacy of colonialism. We need to encourage the use of these data to design treatments for the least, the last, the looked over and the left out, and to generate policies and legal decisions that can rectify the history of injustice. In this way, genomics can connect where we come from to where we will go. Once used to make claims about Indigenous peoples inferiority, today the science of the genome can be part of an Indigenous future we can all believe in.

Read more from the original source:
Genomes Show the History and Travels of Indigenous Peoples - Scientific American

Historical and recent mixing of Europeans, Native Americans, Africans, and Asians has resulted in a relatively large number of admixed individuals in the U.S. The amalgamation of DNA segments associated with different races and ethnicities often affects the ability of physicians to accurately use genomic test results to inform precision care.

To help bridge this gap, researchers at the University of California (UC) San Diego School of Medicine have been awarded $11.7 million to launch the Genetic & Social Determinants of Health: Center for Admixture Science and Technology (CAST) to address the issue of admixed individuals whose DNA reflect multiple ancestries. CAST will use the largest genomic datasets of individuals with diverse ancestry, in combination with socioeconomic data, to better predict health and disease in admixed individuals.

CAST is one of the latest additions to the renowned Centers of Excellence in Genomic Science (CEGS) funded by the NIH. Each center focuses on a unique aspect of genomics research with the intention of blazing new trails in our understanding of human biology and disease.

To bring the CEGS program to our campus is a huge honor, and a national recognition of UC San Diego as a major player in genomics, said Lucila Ohno-Machado, MD, PhD, Distinguished Professor of Medicine at UC San Diego School of Medicine, chair of the Department of Biomedical Informatics at UC San Diego Health, and founding faculty of the Halcolu Data Science Institute.

Ohno-Machado will lead the center with Kelly Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine at UC San Diego School of Medicine, and Melissa Gymrek, PhD, assistant professor at UC San Diego School of Medicine and Jacobs School of Engineering.

Researchers need data on many peoples genomes and health outcomes in order to find consistent relationships among them. The health of individuals from different racial and ethnic groups is also affected by social factors, so this information must be included in models of disease. To do all this, CAST will develop computational tools to combine, protect, and analyze data from two national studies:All of UsResearch Program and the Million Veterans Program. These projects aim to recruit one million participants each, equipping CAST with an unprecedentedly large and diverse pool of data.

Their ultimate goal is for anyone to be able to visit their physician, have their genome sequenced, and learn not only if they are at higher risk for any particular disease, but also which prevention and treatment plans are best suited for them.

As it stands, white people will be able to do this, but our existing knowledge may not be useful to most others, said Gymrek. We want to bring the genomic revolution to everyone.

People may not realize that a large number of people living in America are likely admixed, so we would be excluding a large portion of our community if we were not taking these mixed genomes into account, added Ohno-Machado.

CAST will use advanced approaches to study admixed genomes. Their models will consider each individuals unique patchwork of ancestry, rather than grouping individuals into established categories like white or Asian. And while most groups focus on changes in single nucleotide polymorphisms (SNPs), the CAST team will consider a much broader spectrum of genetic variation. This includes investigating tandem repeats and the major histocompatibility complex (MHC), which is one of the most diverse sections of the genome across races, in part because it is related to immune function, which is tailored to each populations local environment.

CAST will also innovate the way large-scale and complex data is processed. The team will develop privacy-preserving algorithms that consult the data in theAll of Usand the Million Veterans enclaves without needing to centralize the data in a single place. They will also use natural language processing to extract information on social determinants of health from patients clinical notes.

These innovations are expected to come from collaborations between informatics researchers at UC San Diego, the Broad Institute, University of Texas Health, Indiana University and the Veterans Administration.

I really think we have the dream team here, said Frazer. Were excited to use our complementary expertise to push the limits of genomic medicine at UC San Diego and beyond.

See the article here:
New UCSD Genome Center Will Address Genetics, Care Disparities of Admixed Populations - Clinical OMICs News

Soumya Kannan is a 2021-22 Yang-Tan Center for Molecular Therapeutics Graduate Student Fellow in the lab of MIT Professor Feng Zhang and co-first author with Han Altae-Tran of a study reporting a new class of programmable DNA modifying systems known as OMEGAs. Credit: Caitlin Cunningham

Researchers find RNA-guided enzymes are more diverse and widespread than previously believed.

Within the last decade, scientists have adapted CRISPR systems from microbes into gene editing technology, a precise and programmable system for modifying DNA. Now, scientists at MITs McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard have discovered a new class of programmable DNA modifying systems called OMEGAs (Obligate Mobile Element Guided Activity), which may naturally be involved in shuffling small bits of DNA throughout bacterial genomes.

These ancient DNA-cutting enzymes are guided to their targets by small pieces of RNA. While they originated in bacteria, they have now been engineered to work in human cells, suggesting they could be useful in the development of gene editing therapies, particularly as they are small (about 30 percent of the size of Cas9), making them easier to deliver to cells than bulkier enzymes. The discovery, reported on September 9, 2021, in the journal Science, provides evidence that natural RNA-guided enzymes are among the most abundant proteins on Earth, pointing toward a vast new area of biology that is poised to drive the next revolution in genome editing technology.

Comparison of (OMEGA) systems with other known RNA-guided systems. In contrast to CRISPR systems, which capture spacer sequences and store them in the locus within the CRISPR array, systems may transpose their loci (or trans-acting loci) into target sequences, converting targets into RNA guides. Credit: Courtesy of the researchers

The research was led by McGovern Investigator Feng Zhang, who is the James and Patricia Poitras Professor of Neuroscience at MIT, a Howard Hughes Medical Institute investigator, and a Core Institute Member of the Broad Institute. Zhangs team has been exploring natural diversity in search of new molecular systems that can be rationally programmed.

We are super excited about the discovery of these widespread programmable enzymes, which have been hiding under our noses all along, says Zhang. These results suggest the tantalizing possibility that there are many more programmable systems that await discovery and development as useful technologies.

Programmable enzymes, particularly those that use an RNA guide, can be rapidly adapted for different uses. For example, CRISPR enzymes naturally use an RNA guide to target viral invaders, but biologists can direct Cas9 to any target by generating their own RNA guide. Its so easy to just change a guide sequence and set a new target, says Soumya Kannan, MIT graduate student in biological engineering and co-first author of the paper. So one of the broad questions that were interested in is trying to see if other natural systems use that same kind of mechanism.

The first hints that OMEGA proteins might be directed by RNA came from the genes for proteins called IscBs. The IscBs are not involved in CRISPR immunity and were not known to associate with RNA, but they looked like small, DNA-cutting enzymes. The team discovered that each IscB had a small RNA encoded nearby and it directed IscB enzymes to cut specific DNA sequences. They named these RNAs RNAs.

The teams experiments showed that two other classes of small proteins known as IsrBs and TnpBs, one of the most abundant genes in bacteria, also use RNAs that act as guides to direct the cleavage of DNA.

Zhang lab graduate student Han Altae-Tran is co-author of a recent Science paper on OMEGAS with Soumya Kannan. Credit: Courtesy of the Zhang lab

IscB, IsrB, and TnpB are found in mobile genetic elements called transposons. Han Altae-Tran, MIT graduate student in biological engineering and co-first author on the paper, explains that each time these transposons move, they create a new guide RNA, allowing the enzyme they encode to cut somewhere else.

Its not clear how bacteria benefit from this genomic shuffling or whether they do at all. Transposons are often thought of as selfish bits of DNA, concerned only with their own mobility and preservation, Kannan says. But if hosts can co-opt these systems and repurpose them, hosts may gain new abilities, as with CRISPR systems that confer adaptive immunity.

IscBs and TnpBs appear to be predecessors of Cas9 and Cas12 CRISPR systems. The team suspects they, along with IsrB, likely gave rise to other RNA-guided enzymes, too and they are eager to find them. They are curious about the range of functions that might be carried out in nature by RNA-guided enzymes, Kannan says, and suspect evolution likely already took advantage of OMEGA enzymes like IscBs and TnpBs to solve problems that biologists are keen to tackle.

A lot of the things that we have been thinking about may already exist naturally in some capacity, says Altae-Tran. Natural versions of these types of systems might be a good starting point to adapt for that particular task.

The team is also interested in tracing the evolution of RNA-guided systems further into the past. Finding all these new systems sheds light on how RNA-guided systems have evolved, but we dont know where RNA-guided activity itself comes from, Altae-Tran says. Understanding those origins, he says, could pave the way to developing even more classes of programmable tools.

Reference: The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases by Han Altae-Tran, Soumya Kannan, F. Esra Demircioglu, Rachel Oshiro, Suchita P. Nety, Luke J. McKay, Mensur Dlaki, William P. Inskeep, Kira S. Makarova, Rhiannon K. Macrae, Eugene V. Koonin and Feng Zhang, 1 October 2021, Science.DOI: 10.1126/science.abj6856

This work was made possible with support from the Simons Center for the Social Brain at MIT, the National Institutes of Health and its Intramural Research Program, Howard Hughes Medical Institute, Open Philanthropy, G. Harold and Leila Y. Mathers Charitable Foundation, Edward Mallinckrodt, Jr. Foundation, Poitras Center for Psychiatric Disorders Research at MIT, Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, Yang-Tan Center for Molecular Therapeutics at MIT, Lisa Yang, Phillips family, R. Metcalfe, and J. and P. Poitras.

See the rest here:
Discovery Points Toward the Next Revolution in Genome Editing Technology - SciTechDaily

Newswise The NIGMS Human Genetic Cell Repository (HGCR) and NHGRI Sample Repository for Human Genetic Research (SRHGR) now offer high molecular weight (HMW) DNA samples isolated from cell lines in the collections. HMW DNA is useful for long-read next-generation sequencing and studies that investigate large-scale genomic variation such as structural variation.

Recent advances in long-read next-generation sequencing technology, including Pacific BiosciencesSingle Molecule, Real-Time (SMRT) sequencingand Oxford Nanopore TechnologiesNanopore sequencing, have made it possible to produce sequence reads of up to 100 kilobases (kb). This has sparked a growing interest from the research community in obtaining high (100-300kb) and ultra-high (>300kb) molecular weight DNA for long-read sequencing.

Long-read sequencing allows researchers to characterize structural variation in regions of the genome that may be more challenging with other approaches, including inversions, translocations, duplications, and other types of repetitive elements. Additionally, longer sequence read lengths improve the accuracy of haplotype phasing and genome assembly. Long-read sequencing was also utilized to generate a complete sequence of a human genome from a hydatidiform mole cell line in arecent 2021 study, and is currently being utilized by theHuman Pangenome Reference Consortiumin their efforts to improve, expand, and diversify the human reference genome.

Coriells Molecular Biology Laboratory usesCirculomics Nanobind technologyfor automated preparation of high and ultrahigh molecular weight DNA (PMID: 27862402). High quality HMW DNA will be available for several reference samples via our catalog, and additional HMW DNA will be available on-demand as a custom service. A complete list of available samples on our catalog can be foundhere. If you are interested in HMW DNA from a cell line that is not currently available, please submit your request as acustom service.

About the Coriell Institute for Medical Research

Founded in 1953, the Coriell Institute for Medical Research is a nonprofit research institute dedicated to improving human health through biomedical research. Coriell scientists lead research in personalized medicine, cancer biology, epigenetics, and the genomics of opioid use disorder. Coriell also hosts one of the world's leading biobankscomprising collections for the National Institutes of Health, disease foundations and private clientsand distributes biological samples and offers research and biobanking services to scientists around the globe. To facilitate drug discovery and disease study, the Institute also develops and distributes collections of induced pluripotent stem cells. For more information, visit Coriell.org.

Excerpt from:
High Molecular Weight DNA Now Available from NIGMS and NHGRI Collections - Newswise

Genetic variation and population substructure in Mexican Indigenous groups is influenced by geography

First, we compared our 716 Mexican Indigenous individuals from 60 ethnic groups (72 communities) with 146 previously published populations worldwide2,8,12, including Mexican Native American populations previously reported by Reich et al.8, Moreno-Estrada et al.2, and Silva-Zolezzi et al.12. The merged data set comprised 3490 individuals from 218 populations and 61,393 autosomal SNVs. Principal component analysis (PCA)13 indicated that Mexican Indigenous populations clustered with other Native American groups from North and South America (Supplementary Fig.1). On the other hand, admixture14 analyses assuming K=4 clusters showed that some Native American individuals are admixed with European and African populations, which is consistent with the history of the Mexican populations. We detected 325 Indigenous samples from the MAIS cohort with at least 0.99 Native American ancestry (Supplementary Fig.2, upper panel).

In order to minimize the effects of recent admixture on our simulations, we performed local ancestry inference using RFMIX15 in each data set, except for Reich et al.8 data set as detailed in the Methods section. Non-Native ancestry tracks were masked in the individuals from Indigenous populations, and the masking accuracy was assessed by running the admixture analyses again assuming K=4 clusters (Supplementary Fig.2, lower panel).

Next, to assess the genetic structure of the Mexican Indigenous populations without the recent European and African ancestry, we combined the masked genomes of the Mexican Indigenous individuals from the MAIS cohort with the data sets from Reich et al.8, Moreno-Estrada et al.2, and Silva-Zolezzi et al.12, yielding a total of 1086 individuals. PCA in the whole Mexican Indigenous masked data set showed that the first axis of variation discriminated the Indigenous Mexican populations from the North, mainly groups from Aridoamerica, from those of Mesoamerica in the Center/South and Southeast (Fig.1b). We also found a correlation between PC1 and the longitude and latitude (Supplementary Fig.3a, b), and a Mantel test showed a significant correlation between genetic and geographical distances (p=0.001, r=0.63, Supplementary Fig.3c). Moreover, PCA of Mesoamerican populations showed that the first two axes of variation separated the populations from the Center/South and Southeast following a geographic pattern (Fig.1c). These results suggest that geographic location influences the genetic structure of these populations.

Furthermore, pairwise-FST comparisons identified the Tarahumara, Pima, Guarijio, and Cucapa in northern Mexico, and previously published populations, such as the Seri (North) and Lacandon (Southeast)2, had the highest levels of genetic differentiation when compared with the other populations based on this statistic (Fig.2a and Supplementary Data1). These observations suggest that these populations have experienced higher degrees of isolation or genetic drift, and possibly various founder effects that amplified this drift.

a Pairwise-FST matrix for all tested populations. Colored bars represent the linguistic family. b FST-based neighbor-joining tree showing the correlation with geographic location independent of linguistic classification (colored names), the numbers above the branches indicate the bootstrap values. Colored vertical lines represent the identified geographic regions: North (blue), Northwest (red), Central-east (orange), South (green), and Southeast (yellow). c Admixture analysis assuming K=9 clusters in Mexican Indigenous populations. Superscript numbers are the corresponding references.

A midpoint rooted neighbor-joining (NJ) tree based on the pairwise-FST population distances showed a correlation between genetic structure and geographic distance, independently of the linguistic classification (Fig.2b). The NJ tree topology revealed five major regions, with high clustering of the ethnic groups according to their geographic location. Furthermore, several ethnic groups from different regions are genetically closer to their geographical neighbors even if they belong to different linguistic families. For example, the Nahuatl from San Luis Potosi (Yuto-nahua), Pames (Oto-mangue), and Huasteco (Mayan) co-inhabiting the Huasteca region fall into the same clade from the NJ tree. Similarly, the Mixe (Mixe-zoque) inhabiting Oaxaca are closer to Oto-mangue linguistic family groups from Oaxaca and the Zoque (Mixe-zoque) from Chiapas are closer to Mayan linguistic family groups (Fig.2a, b).

To better understand the genetic composition of Mexican Indigenous populations, we carried out a genetic clustering analysis with the unsupervised model algorithm ADMIXTURE14 using K=216 clusters (Supplementary Fig.4). The cross-validation procedure showed that, within the Mexican Indigenous populations, the K=9 yields the lowest cross-validation error (Supplementary Fig.5). Based on this K, six of these clusters were mainly observed in a single population (Seri, Tarahumara, Pima, Tepehuano, Huichol, and Lacandon). On the other hand, two of the clusters were mainly observed in several ethnic groups inhabiting the Center and South (here referred to as multi-ethnics), principally in populations from the Oto-mangue linguistic family, and the other cluster in populations from the Southeast that are part of the Mayan linguistic family. We observed that the multi-ethnic and Mayan components had opposite gradients, where the Mayan component was the most prevalent in the Southeast and the multi-ethnic components were more prevalent in the Center and South of Mexico (Fig.2c and Supplementary Fig.6).

To track the demographic histories of Indigenous Mexican populations, we estimated the effective population size (Ne) across time based on two different methods. We included 48 ethnic groups from the masked data set, all of them with sample sizes of at least 10 individuals (Supplementary Table2). Demographic reconstructions based on linkage disequilibrium (LD) analysis16,17 showed little evidence of a fluctuation in Ne before 150 generations ago (Supplementary Fig.7). To evaluate more recent demographic changes, we estimated the Ne based on identity by descent (IBD) tracks implemented in the IBDNe software18,19. We observed a decline in the Ne between 15 and 30 generations ago in all tested populations that overlaps with the beginning of the European colonization of the Americas, followed by an expansion (Fig.3a and Supplementary Fig.8).

a Demographic measure of effective population size across time showing a decline in population sizes in the five main geographic regions identified here: North, Northwest, Center, South and Southeast. b Long-term Ne of all tested populations, shapes represent the long-term Ne and errors bars represent the 95% confidence interval. Colors are according to the legends in Fig.1. Numbers between brackets are the corresponding references. c Divergence time between pairs of populations. d Mean of the observed T between Aridoamerican and Mesoamerican populations expressed in ka.

Next, we estimated the long-term Ne based on LD patterns using Neon Software16,17. The long-term Ne calculated in the whole sample set was 3169 (confidence interval of 29523402), which is similar to previous findings5,20,21. However, here we documented a variation in the long-term Ne between ethnic groups (Fig.3b and Supplementary Table3). The long-term Ne was smaller in highly differentiated populations, such as Seris and Lacandons (984 and 1593, respectively). Other ethnic groups had a long-term Ne between 1825 and 3331 individuals (Supplementary Table3) and are similar to those previously reported in populations such like Tarahumara, Huichol, Triqui, and Maya22. The smaller long-term Ne may have contributed to greater genetic drift and lower genetic diversity in these ethnic groups. To confirm this hypothesis, we inferred autozygosity using runs of homozygosity (ROH). As expected, the Seri and Lacandon groups had the highest proportion of the genome in ROH compared to the other populations tested, suggesting that the high genetic differentiation observed in these populations is due to genetic drift as previously reported2 (Supplementary Fig.9). We did not observe this phenomenon for other divergent populations, such as the Cucapa, Tarahumara, Guarijio, Tepehuano, and Huichol. In addition, the categorization of ROH by size showed that all tested Native American populations have a high proportion of short ROH (12Mb), which is consistent with the fact that these populations have experienced a series of bottlenecks throughout their history23,24. Moreover, with the exception of Yaqui, Mazateco from Oaxaca, Chontal from Oaxaca, and Maya from Yucatan and Quintana Roo, we observed that all tested populations exhibited different proportions of ROH longer than 8Mb (Supplementary Fig.10), which is consistent with the presence of episodes of isolation and/or inbreeding23,24.

Both the long-term Ne and FST between pairs of populations were employed to calculate the divergence time between populations in generations (T) assuming a clean split between them. To scale T in years, we assumed 28 years per generation25. Seri and Lacandon populations have the highest T values compared to other populations (Fig.3c and Supplementary Data2), and the uppermost value of T was observed between Seri and Maya from Quintana Roo (T=11.8 ka ago, Supplementary Data2). Considering the ecogeographic region, we observed a higher T between populations from different regions than those from the same region. Populations from northern Mexico corresponding to Aridoamerica diverged from the populations in the Center/South around 3.969.47 ka ago and from the Southeast populations ~4.84 to 10.15 ka ago (Fig.3c, d and Supplementary Data2).

To better understand the demographic connections among the Mexican indigenous populations, we performed an IBD analysis in 325 individuals from our data set with >99% Native American ancestry using Hap-IBD26 (see Methods section) (Supplementary Table4). We also explored the ethnic group genetic affinities within and between different geographical regions according to those observed in the NJ tree and defined previously by Contreras-Cubas et al.9. In line with that observed with allele frequency-based methods (Supplementary Fig.3), the IBD analysis also showed that the indigenous populations are related to each other following an isolation by distance model, both at the intra and interregional level. Therefore, in most cases, neighboring indigenous populations are more likely to relate to each other than to distant groups (Fig.4 and Supplementary Fig.11). At the intraregional level, this trend is exemplified by Tarahumara and Guarijio from North (Fig.4a) or Chuj and Kanjobal from Southeast (Fig.4e). Additionally, the shared IBD segment analysis revealed gene flow between Indigenous populations from different regions in Mexico. Some examples with shared IBD blocks were observed between Cora from Northwest and Zapoteco from South or Guarijio, Tarahumara and Seri from the North and Mayan groups from the Southeast (Supplementary Data37).

IBD segments analysis performed in Indigenous populations with at least 99% of Native American ancestry inferred from Admixture K=4. Analyses were restricted for segments >7cM. Shared IBD fragments shown proximal and distal connections between populations from the same and different regions. a North IBD segments, b Northeast IBD segments, c Central East IBD segments and d South IBD segments and e Southeast IBD segments. The width of each edge is proportional to the mean IBD length. f Table showing the mean values of IBD sharing within and between regions.

An IBD analysis incorporating all populations per region using both intermediate (510cM) or large (>10cM) shared IBD blocks revealed possible spatiotemporal interaction dynamic patterns among indigenous groups. Intermediate IBD block sizes are suggested to be dated to 5001500 years ago (oldest), while large tracks are thought to be originated 0500 years ago (youngest)27.

Analysis of intermediate block sizes revealed that the Central East, South, and Southeast regions have older connections among them than do the northern regions (Supplementary Fig.11a). Meanwhile, large IBD track analysis suggested that the North region has a more recent gene flow with Northwestern and Central East regions than do South and Southeast regions (Supplementary Fig.11b).

To gain more insight into the early migration patterns, we compared the previously published genomes of the Anzick-128 and Upward Sun River 1 (USR1)29 individuals with our data from the most representative sample of Indigenous peoples in the Mesoamerican and Aridoamerican regions of Mexico to date. First, we compared the ancient genomes with 59 worldwide populations and 325 individuals from our data set with at least 99% Native American ancestry (Supplementary Table4) using an outgroup f3-statistic in the form of f3(Yoruba; Ancient, Modern). This analysis showed a high affinity of both ancient genomes with present-day Mexican Indigenous samples (Supplementary Fig.12 and Supplementary Data8).

We then combined the 325 indigenous samples with seven ancient genomes from American and South American populations3,30 (Supplementary Table5), yielding a total of 111,586 autosomal SNVs. A TreeMix tree on this data set placed the USR1 genome at the basal position of all Native American populations tested, including Anzick-1. Meanwhile, all Aridoamerican populations formed a separate clade from those formed by the Mesoamerican populations and Anzick-1 and the NNA/ANC-B branch. Similarly, a PCA including the ancient samples showed that the Anzick-1 genome is more closely related to Mesoamerican populations than Aridoamerican populations, whereas USR1 is placed as an outlier in the PCA space (Supplementary Fig.13).

The TreeMix tree analysis suggested a deep divergence between populations in Aridoamerica and Mesoamerica (Fig.5a and Supplementary Fig.14) prior to the divergence between Mesoamerica and the Anzick-1 individual. This observation is inconsistent with T<10 ka, as calculated based on FST and long-term Ne (Fig.3c), and the fact that a TreeMix tree allowing 20 migration edges (Supplementary Fig.14) and the IBD networks analyses (Fig.4) exhibited multiple gene flow between Mesoamerican and Aridoamerican populations. To test this, we calculated a D-statistic in the form of D(Yoruba, NNA/ANC-B; AA, MA) using the Ancient Southern Ontario population Canada_Lucier31 and Athabaskan32 ancient genomes as representatives of NNA/ANC-B ancestry. We found these results to be consistent with D ~ 0, suggesting that the NNA/ANC-B populations are an outgroup for those from Aridoamerica and Mesoamerica from Mexico (Supplementary Figs.15 and 16), which is consistent with the TreeMix tree. To test whether Mesoamerican populations form a clade with Anzick-1 to the exclusion of Aridoamerican populations, we estimated a D-statistic in the form of D(Yoruba, AA; Anzick-1, MA). We found that Mesoamerican populations share more alleles with Aridoamerica than Anzick-1 shares with Aridoamerica (Supplementary Fig.17).

a Maximum-likelihood tree inferred from allele frequency, residual plot from the maximum-likelihood tree is shown. b Possible tree topologies resolved by D-statistics. c D-statistic in the form of D(Yoruba, USR1; Mex Nat, Karitiana) shows that all Mexican populations are related to the USR1 genome. d D-statistic in the form of D(Yoruba, Ancient; Mex Nat, Karitiana). Error bars in c, d represent 3 standard errors estimated by a weighted block jackknife. Mex Nat Mexican Native population.

To further explore the relationships between the Indigenous Mexican populations and the ancient samples, we estimated a D-statistic in the form of D(Yoruba, Ancient; Mexican Native population, South American), where the ancient samples were either USR1 or Anzick-1, and the South American samples were either Karitiana or Aymara. We also included the Tzotzil population as an internal control. When USR1 was used to represent the ancient population, we did not observe any significant deviation from zero in any of the tests (Fig.5b and Supplementary Fig.18a, b). However, when Anzick-1 was used in the test, we found that Anzick-1 shares more alleles with the South American population than with some of the Indigenous Mexican populations. This is particularly the case for populations from Aridoamerica, with the exception of Cucapa and Seri, as well as some Mesoamerican populations, such as Totonaco from Veracruz, Nahuatl from Puebla, Otomi from Hidalgo, Mixteco Costa, Chocholteco, Mocho, and as previously observed Mixe. Although we only found significant results (|Z|3.2) when Karitiana and Tzotzil were used in the comparison, we observed a similar trend when Aymara was used in the test (Fig.5c and Supplementary Fig.18c, d). These results suggest that some of the Indigenous populations in our data set carry ancestry from a population that split before the Anzick-1 individual. Previous studies have suggested that the Mixe carry additional ancestry from an unknown population related to the SNA/ANC-A branch that split above the Anzik-1 individual (UPopA)33. Our results are consistent with this observation, suggesting that other populations from Aridoamerica and Mesoamerica may carry this ancestry (Fig.5c and Supplementary Fig.18c, d).

Read the rest here:
The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas - Nature.com

This article was originally published here

Cancer Res. 2021 Oct 12:canres.CAN-21-2056-E.2021. doi: 10.1158/0008-5472.CAN-21-2056. Online ahead of print.

ABSTRACT

Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the non-coding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging non-coding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer.

PMID:34642184 | DOI:10.1158/0008-5472.CAN-21-2056

Visit link:
Reorganization of the 3D genome pinpoints non-coding drivers of primary prostate tumors - DocWire News

Intellia Therapeutics and SparingVision Announce Strategic Collaboration to Develop Novel Ocular Therapies Using CRISPR/Cas9 Technology

Collaboration combines Intellias proprietary genome editing technology platform with SparingVisions significant ophthalmology expertise

Intellia will grant SparingVision exclusive rights to its leading in vivo CRISPR/Cas9 technology for the development of ocular therapies directed to three targets

Intellia will receive an equity stake in SparingVision and will have an option to obtain exclusive US commercialization rights for ocular therapies for two targets

SparingVision to host webcast to discuss the deal at 4pm CEST / 3pm BST / 10am EST

Cambridge, MA, and Paris, France October 13, 2021 Intellia Therapeutics, Inc. (NASDAQ: NTLA), a leading clinical-stage genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, and SparingVision, a genomic medicine company developing vision saving treatments for ocular diseases, today announced a strategic collaboration to develop novel genomic medicines utilizing CRISPR/Cas9 technology for the treatment of ocular diseases.

As part of this collaboration, Intellia will grant SparingVision exclusive rights to Intellias proprietary in vivo CRISPR/Cas9-based genome editing technology for up to three ocular targets addressing diseases with significant unmet medical need. SparingVision will lead and fund the preclinical and clinical development for the genome editing product candidates pursued under the collaboration. In addition, the parties will research and develop novel self-inactivating AAV vectors and LNP-based approaches to address delivery of CRISPR/Cas9 genome editing reagents to the retina.

As part of the licensing agreement, Intellia will receive a 10% equity ownership stake in SparingVision. Intellia will also be eligible to receive certain development and commercial milestone payments (around $200 million per product) as well as royalties on potential future sales of products arising from the collaboration. In addition, Intellia may exercise an option to obtain the US commercialization rights for product candidates arising from two of three collaboration targets. For product candidates Intellia chooses to option, Intellia will pay an opt-in fee, reimburse certain costs, share in 50% of development costs and pay royalties to SparingVision on US sales. Intellia will also maintain the ability to leverage technology advances established under this collaboration for any targets outside the partnership.

Story continues

Stphane Boissel, President and Chief Executive Officer of SparingVision, said: SparingVisions aim has always been to disrupt the ophthalmology field by using cutting-edge technologies to address areas of significant unmet need. This collaboration with Intellia marks a pivotal moment in this mission and is highly complementary to our already mature and growing pipeline of unique mutation-agnostic gene therapies. Intellia is the first company in history to present clinical data supporting precision editing of a disease-causing gene within the body following a single, systemic dose of CRISPR/Cas9 and we are honored to have been selected as a strategic partner. We look forward to working together with the shared goal of radically changing the treatment of blinding ocular diseases.

Intellia has been a pioneer in utilizing CRISPR/Cas9 technology to develop potentially curative treatments for genetic diseases. Todays announcement is another step forward in more fully leveraging the power of our genome editing technology to address diseases inadequately treated with existing medicines, said Intellia President and Chief Executive Officer John Leonard, M.D. We have been thoroughly impressed with the team at SparingVision, particularly regarding their unparalleled understanding of retinal diseases and track-record for developing novel therapies for patients with ocular diseases. We believe SparingVision will be an excellent partner to expand our genome editing capabilities into the field of ophthalmology and we look forward to our new partnership.

The transaction is expected to close in the fourth quarter and is subject to certain closing conditions.

SparingVisions management team will be holding a webcast to discuss the collaboration today (13th October) at 16:00 CEST / 15:00 BST / 10:00 EST, which will include a live Q&A session. Please find a link to join this webcast here: https://us02web.zoom.us/j/83682810928

About Intellia TherapeuticsIntellia Therapeutics, a leading clinical-stage genome editing company, is developing novel, potentially curative therapeutics using CRISPR/Cas9 technology. To fully realize the transformative potential of CRISPR/Cas9, Intellia is pursuing two primary approaches. The companys in vivo programs use intravenously administered CRISPR as the therapy, in which proprietary delivery technology enables highly precise editing of disease-causing genes directly within specific target tissues. Intellias ex vivo programs use CRISPR to create the therapy by using engineered human cells to treat cancer and autoimmune diseases. Intellias deep scientific, technical and clinical development experience, along with its robust intellectual property portfolio, have enabled the company to take a leadership role in harnessing the full potential of CRISPR/Cas9 to create new classes of genetic medicine. Learn more at intelliatx.com. Follow us on Twitter @intelliatweets.

About SparingVision:SparingVision is a genomic medicines company, translating pioneering science into vision-saving treatments. Founded to advance over 20 years of world-leading ophthalmic research from its scientific founders at the Paris Vision Institute, SparingVision is leading a step shift in how ocular diseases are treated, moving beyond single gene correction therapies. At the heart of this is a pipeline of gene independent treatments for rod-cone dystrophies. Lead products, SPVN06 and SPVN20, address mid and late stages of retinitis pigmentosa (RP)respectively. RP is the most common inherited retinal disease affecting two million people worldwide. These novel medicines could form the basis of a suite of new sight-saving treatments with potential applications across many other retinal diseases, regardless of genetic cause.

The Company is supported by a strong, internationally renowned team who aim to harness the potential of genomic medicine to deliver new treatments to all ocular disease patients as quickly as possible. SparingVision has raised 60 million to date and its investors include 4BIO Capital, Advent France Biotechnology, Bpifrance, Foundation Fighting Blindness (US), Fondation Voir & Entendre, UPMC Enterprises, Jeito Capital and Ysios Capital. For more information, please visit http://www.sparingvision.com.

Intellias Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, express or implied statements regarding Intellias beliefs and expectations regarding: its strategy, business plans and focus; its ability to quickly and efficiently realize the scope and potential of its genome-editing technology; its ability to maintain, expand and maximize its intellectual property portfolio and pipeline as well as accelerate clinical validation for its platform; the therapeutic value and development potential of CRISPR/Cas9 gene editing technologies and therapies; its ability to combine its CRISPR genome editing platform with SparingVisions expertise in ocular diseases to create successful therapeutic products; and the expected strategic benefits of any current or future collaborations.

Any forward-looking statements in this press release are based on management's current expectations and beliefs of future events, and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks related to Intellias ability to protect and maintain its intellectual property portfolio; risks related to Intellias relationship with third parties, including its licensors and licensees; risks related to the ability of Intellias licensors to protect and maintain their intellectual property position; uncertainties related to the authorization, initiation and conduct of studies and other development requirements for the new companys product candidates; the risk that any one or more of the collaboration product candidates will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and the risk that Intellias collaboration with SparingVision or its other collaborations will not continue or will not be successful. These and other risks and uncertainties are described in greater detail in the section entitled Risk Factors in Intellias most recent annual report on Form 10-K and quarterly report on Form 10-Q filed with the SEC, as well as discussions of potential risks, uncertainties, and other important factors in Intellias other filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release represent Intellias views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Intellia explicitly disclaims any obligation to update any forward-looking statements, except as required by law.

Contacts:

Intellia Contacts:Investors:

Ian Karp

Senior Vice President, Investor Relations and Corporate Communications

+1-857-449-4175

ian.karp@intelliatx.com

Lina Li

Director, Investor Relations

+1-857-706-1612

lina.li@intelliatx.com

Media:

Lisa Qu

Ten Bridge Communications

+1-678-662-9166

media@intelliatx.com

lqu@tenbridgecommunications.com

SparingVision Contacts:Nathalie Trepo

Director, Investor Relations and Corporate Communications

Nathalie.trepo@sparingvision.com

Consilium Strategic Communications

Amber Fennell, Genevieve Wilson, Priit Piip+44 (0)20 3709 5700sparingvision@consilium-comms.com

**ENDS**

See the original post here:
Intellia Therapeutics and SparingVision Announce Strategic Collaboration to Develop Novel Ocular Therapies Using CRISPR/Cas9 Technology - Yahoo...