Daily Archives: February 3, 2022

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Buxus and Tetracentron genomes help resolve eudicot genome history - Nature.com

Sarah Slavoffs work studying the dark matter of the human genome could lead to the development of more effective treatments for melanoma.

Elizabeth Watson 12:32 am, Feb 03, 2022

Staff Reporter

Courtesy of Elizabeth Watson

Sarah Slavoff, an associate professor of chemistry and of molecular biophysics and biochemistry, won the 2022 Emerging Leader Award from the Mark Foundation for Cancer Research for her work studying the dark matter of the human genome.

Slavoff, who was also recognized for the potential implications of her research in the fight against melanoma, will receive an annual grant of $250,000 for three years. The award will fund her project to investigate proteins that have not yet been identified and their links to melanoma, a type of severe skin cancer.

The work for the Mark Foundation is going to allow us to really deeply identify these genes that are associated with melanoma treatment resistance, or novel unannotated genes, to fully demonstrate their mechanisms of action so that we can understand what theyre doing and how thats affecting the tumor cells, Slavoff said.

Slavoff first became involved in this branch of research during her time as an NIH Ruth L. Kirschstein Postdoctoral Fellow at Harvard University. Although the Human Genome Project was officially completed in 2003, scientists suspected that there were parts of the genome that remained unknown. Alan Saghatelian, Slavoffs mentor at Harvard and the Dr. Frederik Paulsen Chair at the Salk Institute for Biological Studies, used mass spectrometry proteomics to study the proteins present in a given biological sample.

They discovered that, of the thousands of spectra that could be collected in a single experiment, there were some that could not be identified. While at Harvard, Slavoff played an important role in developing the first technologies to begin this identification process.

She [Slavoff] published several papers as a postdoc but the most notable was work describing the discovery of nearly 100 previously unknown microproteins, Saghatelian said. Her work showed a large class of unannotated microproteins that exist stably within cells, suggesting that microproteins should be able to function similarly to longer proteins and lay the foundation for functional studies to characterize these genes. Furthermore, the field has identified thousands of microproteins encoding genes in various genomes, and Dr. Slavoffs work was one of the critical findings that drove this field forward.

Slavoff continued researching this area in her own lab at the Yale Institute of Biomolecular Design and Discovery. Her work focuses on developing not only new methods to detect the unknown microproteins of the human genome, but also ways to understand its function.

The concept behind the term dark matter is that there are genes within the human genome, sometimes referred to as ghost proteins, that have always existed and been expressed but remained undetected because they were smaller than the cutoff size that is used to analyze the genome: 100 amino acid units.

Our hypothesis is that some of these novel genes in this dark matter of the proteome might be associated with the mechanisms by which melanoma escapes from current treatments, Slavoff said. If we can identify that, then we can learn something about those mechanisms, and even more importantly, hopefully an aspirational goal for the future is that they could inform new therapies.

A particular area of interest for Slavoff is the potential connection between dark matter and human diseases.

She has worked in conjunction with Ruth Halaban, a senior research scientist in dermatology at the Yale Cancer Center, to study its relationship in particular with metastatic melanoma.

Now were moving toward asking if this dark matter is linked to disease, and theres lots of preliminary evidence from other groups around the world that it is, Slavoff said. Were asking this specific question with the Mark Foundation about, really a pernicious problem, which are cancers that are drug-resistant or cant be treated.

There are two primary methods that are used to treat patients suffering from melanoma. Patients can either take drugs that can combat the driving enzymes within a tumor or undergo the process of immunotherapy to mobilize the immune system against the tumor. These methods, although capable of shrinking tumors, are not always effective. Roughly half of melanoma patients cannot be treated, according to Slavoff. By focusing upon this dark matter as opposed to the genes traditionally targeted by current treatments, Slavoff hopes to find a way to formulate more effective treatments for melanoma patients.

Jason Crawford, director of the Yale Institute for Biomolecular Design and Discovery, acknowledged the potential ramifications of the research being conducted by Slavoffs lab. He further noted the strong sense of teamwork that Slavoff fosters in her lab.

She is very caring for her students and is a strong mentor and tries to establish a sense of teamwork and team goals, Crawford said. Shes a leader in the area of microproteins, so she and her lab are really pushing the envelope in this new area, a largely understudied area.

Slavoff came to Yale in 2014.

Elizabeth Watson covers breakthrough research for SciTech and illustrates for various sections. She is a first year in Pauli Murray College and is planning to major in STEM and the humanities.

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Yale researcher receives award to investigate dark matter of the human genome - Yale Daily News

Isolation of E. cuniculi ribosomes

To improve our understanding of the evolution of proteins and nucleic acids in intracellular organisms, we set out to isolate E. cuniculi spores from infected mammalian cell cultures to purify their ribosomes and determine the structure of these ribosomes. Large quantities of microsporidian parasites are challenging to produce because microsporidians cannot be cultured in a growth medium. Instead, they grow and reproduce only inside their host cells. Therefore, to produce E. cuniculi biomass for the ribosome purification, we infected mammalian kidney cell line RK13 with E. cuniculi spores and cultivated these infected cells for several weeks to allow for E. cuniculi to grow and reproduce. Using approximately half a square meter of the infected cells monolayer, we could purify about 300mg of microsporidian spores and use them for ribosome isolation. We then broke the purified spores with glass beads and isolated crude ribosomes using a stepwise fractionation of lysates with polyethylene glycol. This allowed us to obtain approximately 300g of crude E. cuniculi ribosomes for structural analyses.

We then used the obtained ribosome sample to collect cryo-EM images and process these images with masks corresponding to the large ribosomal subunit, the head of the small subunit, and the body of the small subunit. In doing so, we collected snapshots of ~108,000 ribosomal particles and calculated cryo-EM maps at 2.7 resolution (Supplementary Figs.13). We then used the cryo-EM maps to build the model of rRNA, ribosomal proteins and the hibernation factor Mdf1 bound to E. cuniculi ribosomes (Fig.1a, b).

a The structure of E. cuniculi ribosomes in complex with the hibernation factor Mdf1 (pdb id 7QEP). b The map of the hibernation factor Mdf1 bound to E. cuniculi ribosomes. c Secondary structure diagrams compare rRNA reduction in microsporidian species with known ribosome structures. The panels indicate the location of rRNA expansion segments (ES) and ribosomal active centers, including the decoding site (DC), the sarcin-ricin loop (SRL), and the peptidyl-transferase center (PTC). d The electron density corresponding to the peptidyl-transferase center of E. cuniculi ribosomes shows that this catalytic site has the same structure in the parasite E. cuniculi and its hosts, including H. sapiens. e, f The electron density corresponding to the decoding center (e) and schematic structures of the decoding center (f) illustrate that E. cuniculi have U1491 residue instead of A1491 (E. coli numbering) in many other eukaryotes. This variation suggests that E. cuniculi may have sensitivity to the antibiotics targeting this active site.

Compared to the previously determined structures of V. necatrix and P. locustae ribosomes (both structures represent the same family of Nosematidae microsporidians and are very similar to each other)31,32, E. cuniculi ribosomes underwent further degeneration of numerous rRNA and proteins segments (Supplementary Figs.46). In rRNA, the most prominent changes include the complete loss of the 25S rRNA expansion segment ES12L and partial degeneration of helices h39, h41, and H18 (Fig.1c, Supplementary Fig.4). In ribosomal proteins, the most prominent changes include the complete loss of protein eS30 and truncations in proteins eL8, eL13, eL18, eL22, eL29, eL40, uS3, uS9, uS14, uS17, and eS7 (Supplementary Figs.4, 5).

Thus, the extreme genome reduction in Encephalotozoon/Ordospora species is reflected in the structure of their ribosomes: E. cuniculi ribosomes have experienced the most drastic loss of protein content among eukaryotic cytoplasmic ribosomes to be structurally characterized, and they are devoid of even those rRNA and protein segments that are widely conserved not only in eukaryotes but across the three domains of life. The structure of E. cuniculi ribosomes provided the first molecular model of these changes and revealed evolutionary events that were overlooked by both comparative genomics and structural studies of molecules from intracellular organisms (Supplementary Fig.7). Below, we describe each of these events, along with their possible evolutionary origin and their potential impact on ribosome function.

We next observed that, aside from large rRNA truncations, E. cuniculi ribosomes possess rRNA variations in one of their active sites. While the peptidyl-transferase center of E. cuniculi ribosomes has the same structure as in other eukaryotic ribosomes (Fig.1d), the decoding center differs due to the sequence variation in the nucleotide 1491 (E. coli numbering, Fig.1e, f). This observation is important because the decoding site of eukaryotic ribosomes typically contains residues G1408 and A1491, compared to bacteria-type residues A1408 and G1491. And this variation underlies different sensitivity of bacterial and eukaryotic ribosomes to the aminoglycoside family of ribosome-targeting antibiotics and other small molecules targeting the decoding site33,34,35. In the decoding site of E. cuniculi ribosomes, the A1491 residue is replaced with U1491, potentially creating a unique binding interface for small molecules targeting this active center. The same A14901 variation is present in other microsporidians, such as P. locustae and V. necatrix, suggesting its wide occurrence in microsporidian species (Fig.1f).

Because our samples of E. cuniculi ribosomes were isolated from metabolically inactive spores, we tested the cryo-EM maps of E. cuniculi for the presence of previously described hibernation factors that bind ribosomes under stress or starvation conditions31,32,36,37,38. We docked previously determined structures of hibernating ribosomes in the cryo-EM maps of E. cuniculi ribosomes. For this docking, we used Saccharomyces cerevisiae ribosomes in complex with the hibernation factor Stm138, P. locustae ribosomes in complex with the factor Lso232, and V. necatrix ribosomes in complex with factors Mdf1 and Mdf231. In so doing, we found the cryo-EM density corresponding to the hibernation factor Mdf1. Similar to Mdf1 binding to V. necatrix ribosomes, Mdf1 also binds E. cuniculi ribosomes, where it blocks the ribosomal E site, possibly helping inactivate ribosomes when parasites sporulate and become metabolically inactive (Fig.2).

Mdf1 blocks the ribosomal E site, which appears to help inactivate ribosomes when parasites sporulate and become metabolically inactive. In the structure of E. cuniculi ribosomes, we found that Mdf1 forms a previously unknown contact with the ribosomal L1-stalk (the part of the ribosome that helps release deacylated tRNAs from the ribosome during protein synthesis). These contacts suggest that Mdf1 dissociates from the ribosome using the same mechanism as deacetylated tRNAs, providing a possible explanation of how ribosomes can remove Mdf1 to reactivate protein synthesis.

Our structure, however, revealed a previously unknown contact between Mdf1 and the ribosomal L1-stalk (the part of the ribosome that helps release deacylated tRNAs from the ribosome during protein synthesis). Specifically, Mdf1 exploits the same contacts as the elbow-segment of deacylated tRNA molecules (Fig.2). This previously unknown molecular mimicry suggests that Mdf1 dissociates from the ribosome using the same mechanism as deacetylated tRNAs, explaining how ribosomes can remove this hibernation factor to reactivate protein synthesis.

While building the rRNA model, we found that E. cuniculi ribosomes possess anomalously folded rRNA segments, which we termed molten rRNA (Fig.3). In ribosomes across the three domains of life, rRNA folds into structures in which most rRNA bases are either base-paired and stacked with each other or interact with ribosomal proteins38,39,40. However, in E. cuniculi ribosomes, the rRNA appears to defy this folding principle by transforming some of their helices into unfolded rRNA stretches.

Structure of the helix H18 of the 25S rRNA in S. cerevisiae, V. necatrix, and E. cuniculi. Typically, in ribosomes across the three domains of life, this linker is folded into an RNA helix, which comprises between 24 and 34 residues. By contrast, in microsporidia this rRNA linker is being progressively reduced to two, single-stranded uridine-rich linkers that comprise just 12 residues. Most of these residues are exposed to the solvent. This figure illustrates that microsporidian parasites appear to defy a common principle of rRNA folding, in which rRNA bases are typically paired with other bases or involved in rRNAprotein interactions. In microsporidia, some rRNA segments adopt unfavorable folding, in which former rRNA helices are turned into single-stranded segments that are stretched out almost into a straight line. Having these unusual stretches allows microsporidian rRNA to connect distant segments of rRNA using the minimal number of RNA bases.

The most striking example of this evolutionary transformation can be observed in the helix H18 of the 25S rRNA (Fig.3). In species ranging from E. coli to humans, the base of this rRNA helix contains 24-32 nucleotides that form a slightly irregular helical structure. In the previously determined structures of ribosomes from V. necatrix and P. locustae31,32 the base of helix H18 is partially unwound yet the base-pairing of nucleotides is preserved. In E. cuniculi, however, this rRNA segment is turned into the minimal-length linkers 228UUUGU232 and 301UUUUUUU307. Unlike typical rRNA segments, these uridine-rich linkers are neither folded into a helix nor they are involved in extensive contacts with ribosomal proteins. Instead, they adopt a solvent-exposed and fully unfolded structure in which rRNA strands are stretched into an almost straight line. This stretched conformation explains how E. cuniculi can use just 12 RNA bases to fill the 33 -long gap between rRNA helices H16 and H18while other species require at least twice as many rRNA bases to fill this gap.

Thus, we could show that at the expense of energetically unfavorable folding, microsporidian parasites have invented a strategy to reduce even those rRNA segments that remain widely conserved across species from the three domains of life. Apparently, by accumulating mutations that transform rRNA helices into short poly-U linkers, E. cuniculi could evolve unusual rRNA segments that comprise the minimum possible number of nucleotides that is required to connect distant segments of rRNA. This helps explain how microsporidia have accomplished the phenomenal reduction of their essential molecular structure without losing its structural and functional integrity.

Another anomalous feature of E. cuniculi rRNA is the emerging of bulgeless rRNA (Fig.4). Bulges are non-base-paired nucleotides that flip out from RNA helices rather than being buried inside a helix41. Most rRNA bulges serve as a molecular glue by helping to bind adjacent ribosomal proteins or other rRNA segments. Some bulges serve as a hinge that allows rRNA helices to bend and adopt an optimal folding for productive protein synthesis41.

a rRNA bulges (S. cerevisiae numbering) that are missing in the structure of E. cuniculi ribosomes but present in most other eukaryotes b Comparison of the ribosome interior of E. coli, S. cerevisiae, H. sapiens and E. cuniculi illustrates that microsporidian parasites lack many ancient, highly conserved rRNA bulges. These bulges stabilize ribosome structure, therefore their absence in microsporidia suggests decreased stability of rRNA folding in microsporidian parasites. c Comparison with the P-stalk (L7/L12-stalk in bacteria) illustrates that the loss of rRNA bulges can occasionally co-occur with the emergence of new bulges in the vicinity of the lost ones. The helix H42 in 23S/28S rRNA possesses an ancient bulge (U1206 in S. cerevisiae), which is estimated to be at least 3.5 billion years old due to its conservation across the three domains of life. In microsporidia, this bulge has been eliminated; however, a new bulge (A1306 in E. cuniculi) has evolved in the vicinity of the lost one.

Strikingly, we observed that E. cuniculi ribosomes lack most of the rRNA bulges found in other species, including more than 30 bulges that are conserved in other eukaryotes (Fig.4a). This loss eliminates many contacts between ribosomal subunits and adjacent rRNA helices, occasionally creating large hollow voids within the ribosome interior, making E. cuniculi ribosomes more porous compared to the more conventional ribosomes (Fig.4b). Notably, we found that most of these bulges are also lost in the previously determined structures of V. necatrix and P. locustae ribosomes, which was overlooked by previous structural analyses31,32.

Occasionally, the loss of rRNA bulges is accompanied by the evolution of new bulges near the lost ones. For example, the ribosomal P-stalk contains a bulge U1208 (in S. cerevisiae) that is conserved from E. coli to humans and is therefore estimated to be 3.5 billion years old. During protein synthesis, this bulge helps the P-stalk to move between open and closed conformations so that the ribosome can recruit translation factors and deliver them to the active site42. In E. cuniculi ribosomes this bulge is missing; however, a new bulge (G883) is located just three base pairs away, possibly helping restore the optimal flexibility of the P-stalk (Fig.4c).

Our finding of bulgeless rRNA shows that rRNA minimization is not limited to the loss of rRNA elements on the surface of the ribosome but may affect the very core of the ribosome, creating a parasite-specific molecular defect that has not been observed in free-living species.

Having modelled canonical ribosomal proteins and rRNA, we found three segments of the cryo-EM map not accounted for by the conventional ribosome components. Two of these segments had a size of small molecules (Fig.5, Supplementary Fig.8). The first segment was sandwiched between ribosomal proteins uL15 and eL18 at a location normally occupied by the eL18 C-terminal truncated in E. cuniculi. Although we could not determine the identity of this molecule, the size and shape of this density island would be explained well by the presence of a spermidine molecule. Its binding to the ribosome is stabilized by microsporidia-specific mutations in protein uL15 (Asp51 and Arg56), which appear to increase the ribosome affinity to this small molecule as they allow uL15 to wrap around this small molecule in the ribosome structure (Supplementary Fig.8, Supplementary Data1, 2).

a The cryo-EM map indicates the presence of the extra-ribosomal nucleotide bound to the E. cuniculi ribosome. In the E. cuniculi ribosome this nucleotide occupies the same space as the 25S rRNA nucleotide A3186 (S. cerevisiae numbering) in most other eukaryotic ribosomes. b In the E. cuniculi ribosome structure, this nucleotide is being sandwiched between ribosomal proteins uL9 and eL20, stabilizing contacts between these two proteins. cd Analyses of eL20 sequence conservation in microsporidian species. A phylogenetic tree of microsporidian species (c) and a multiple sequence alignment of protein eL20 (d) illustrate that the nucleotide-binding residues F170 and K172 are conserved in most canonical microsporidia (aside from S. lophii), except for the early-branched microsporidia, in which the rRNA expansion ES39L is preserved. e The plot shows that the nucleotide-binding residues F170 and K172 are only found in eL20 from microsporidian parasites with highly reduced genomes and not in other eukaryotes. Overall, these data indicate that microsporidian ribosomes have evolved a nucleotide-binding site that appears to bind AMP molecules and use them to stabilize proteinprotein interactions in the ribosome structure. The high degree of conservation of this binding site among microsporidia and its absence in other eukaryotes indicates that this site may provide a selective advantage for microsporidia survival. Therefore, the nucleotide-binding pocket in microsporidian ribosomes appears not to be a vestigial feature or the ultimate form of rRNA degeneration, as previously suggested32, but a useful evolutionary innovation that allows microsporidian ribosomes to directly bind small molecules, utilizing them as molecular building blocks for ribosome assembly. This finding makes microsporidian ribosomes the only known ribosomes that use single nucleotides as a structural building block. f A hypothetic evolutionary path of the nucleotide-binding acquisition.

The second small molecule density was located at the interface of ribosomal proteins uL9 and eL30 (Fig.5a). This interface was previously described in the structure of S. cerevisiae ribosomes as a binding site of the 25S rRNA nucleotide A3186 (part of the rRNA expansion segment ES39L)38. In P. locustae ribosomes, where ES39L is degenerated, this interface was shown to bind an unidentified single nucleotide31, and it was hypothesized that this nucleotide represents the ultimate form of rRNA reduction in which the ~130-230 base-long rRNA expansion ES39L was reduced to a single nucleotide32,43. Our cryo-EM maps confirmed the idea that the density can be accounted for by a nucleotide. However, the higher resolution of our structure revealed that this nucleotide is an extra-ribosomal molecule, likely AMP (Fig.5a, b).

We next asked whether the nucleotide-binding site has been evolved or preexisted in E. cuniculi ribosomes. Because the nucleotide-binding is primarily mediated by residues Phe170 and Lys172 in the ribosomal protein eL30, we assessed the conservation of these residues in 4,396 representative eukaryotes. Similar to the aforementioned case of uL15, we found that Phe170 and Lys172 residues are highly conserved only in canonical microsporidia, but are absent in other eukaryotes, including non-canonical microsporidia Mitosporidium and Amphiamblys in which the rRNA ES39L segment is not reduced44,45,46 (Fig.5ce).

Collectively, these data supported the idea that E. cuniculi, and possibly other canonical microsporidians, have evolved the ability to effectively trap abundant small metabolites in their ribosome structures in order to compensate for the rRNA and protein reduction. In doing so, they have evolved the unique ability to bind extra-ribosomal nucleotides, illustrating a previously unknown and ingenious ability of parasitic molecular structures to compensate their degeneration by trapping small abundant metabolites and using them as structural mimics of degenerated RNA and protein segments.

The third unmodeled segment of the cryo-EM map we found within the large ribosomal subunit. The relatively high resolution of our maps (2.6) revealed that this density belongs to a protein with a unique combination of bulky side chains residues, which allowed us to identify this density as a previously unknown ribosomal protein, which we termed msL2 (microsporidia-specific protein L2) (Methods, Fig.6). Our homology search revealed that msL2 is conserved in the microsporidian branch of Encephalitozoon and Ordospora species but is absent in other species, including other microsporidians. In the ribosome structure, msL2 occupies a void formed by the loss of the rRNA expansion ES31L. In this void, msL2 helps stabilize rRNA folding and likely compensates for the ES31L loss (Fig.6).

a Electron density and model of the microsporidia-specific ribosomal protein msL2 found in E. cuniculi ribosomes. b Most eukaryotic ribosomes, including 80S ribosomes of S. cerevisiae, possess the rRNA expansion ES19L, which has been lost in most microsporidian species. The previously determined structure of microsporidian ribosomes from V. necatrix showed that the loss of ES19L in these parasites was compensated by the evolution of a new ribosomal protein, msL1. In this study, we discovered that E. cuniculi ribosomes also evolved an additional RNA-mimicking ribosomal protein as an apparent compensation for the loss of ES19L. However, msL2 (currently annotated as hypothetical protein ECU06_1135) and msL1 have different structure and evolutionary origin. c This finding of the birth of evolutionary unrelated ribosomal proteins msL1 and msL2 illustrates that ribosomes can achieve an unprecedented level of compositional diversity, even within a small group of closely related species, if they accumulate a deleterious mutation in their rRNA. This finding may help shed light on the origin and evolution of mitochondrial ribosomes, which are known for their severely reduced rRNA and exceptional variability of protein composition among species.

We next compared msL2 protein with the previously described protein msL1the only known microsporidia-specific ribosomal protein that was found in V. necatrix ribosomes31. We wanted to test whether msL1 and msL2 are evolutionary related to each other. Our analysis showed that msL1 and msL2 occupy the same cavity in the ribosome structure, but have distinct primary and tertiary structure, suggesting their independent evolutionary origin (Fig.6). Thus, our finding of msL2 provided evidence that close groups of eukaryotic species can independently evolve structurally distinct ribosomal proteins to compensate for the loss of rRNA segments. This finding is remarkable because most cytoplasmic eukaryotic ribosomes have invariant protein content, comprising the same set of 81 families of ribosomal proteins47. The birth of msL1 and msL2 in distinct microsporidian branches in response to the loss of the rRNA expansion segments suggests that degeneration of parasitic molecular structures forces parasites to seek compensatory mutations that may eventually lead to gain of compositional diversity of these structures in distinct groups of parasites.

Finally, when our model building was complete, we compared the composition of E. cuniculi ribosomes with the composition that was predicted based on genome sequence27. Previously, the E. cuniculi genome was predicted to lack several ribosomal proteins, including eL14, eL38, eL41, and eS30 due to the apparent absence of their homologs in the E. cuniculi genome27,48. The loss of multiple ribosomal proteins was also predicted in most other intracellular parasites and endosymbionts with highly reduced genomes49. For example, while most free-living bacteria contain the same set of 54 families of ribosomal proteins, only 11 of these protein families have detectable homologs in each of the analyzed genomes of host-restricted bacteria49. Supporting this idea, the loss of ribosomal proteins was observed experimentally in microsporidians V. necatrix and P. locustae, which both lack proteins eL38 and eL4131,32.

Our structure revealed, however, that only eL38, eL41, and eS30 are in fact lost in E. cuniculi ribosomes. The protein eL14 was retained, and our structure revealed why this protein could not be detected through homology search (Fig.7). In E. cuniculi ribosomes, most of the eL14-binding site is lost due to degeneration of the rRNA expansion ES39L. In the absence of ES39L, eL14 loses most of its secondary structure, and only 18% of the eL14 sequence is identical between E. cuniculi and S. cerevisiae. This poor sequence conservation is remarkable because even S. cerevisiae and H. sapiensorganisms that are separated by 1.5 billion years of evolutionpossess more than 51% identical residues in eL14. This extraordinary loss of conservation explains why E. cuniculi eL14 is currently annotated as hypothetical protein M970_061160 rather than ribosomal protein eL1427.

a Microsporidian ribosomes have lost the rRNA expansion ES39L, which partially eliminated the binding site for ribosomal protein eL14. In the absence of ES39L, microsporidian protein eL14 underwent a loss of secondary structure, in which former rRNA-binding -helices degenerated to minimal-length loops. b Multiple sequence alignment shows that protein eL14 is highly conserved among eukaryotic species (where it shares 57% sequence identity between yeast and human homologs), but poorly conserved and divergent among microsporidia (where no more than 24% of residues are identical to eL14 homologs from S. cerevisiae or H. sapiens). This poor sequence conservation, along with changes in the secondary structure, explains why homologs of eL14 have never been found in E. cuniculi and why this protein was thought to have been lost in E. cuniculi. Instead, E. cuniculi eL14 was previously annotated as the hypothetical protein M970_061160. This observation reveals that the diversity of microsporidian genomes is currently overestimated: some genes that are currently thought to have been lost in microsporidia are actually retained, although in a highly diverged form; conversely, some genes that are thought to encode microsporidia-specific proteins (e.g., hypothetical protein M970_061160) do in fact encode highly divergent proteins that can be found in other eukaryotes.

This finding illustrates that rRNA degeneration can lead to drastic loss of sequence conservation in adjacent ribosomal proteins, rendering these proteins undetectable for homology search. Hence, we may overestimate the actual extent of molecular degeneration in organisms with small genomes because some proteins that are viewed as lost are in fact preserved, though in a highly altered form.

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Adaptation to genome decay in the structure of the smallest eukaryotic ribosome - Nature.com

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(THE CONVERSATION) For children suffering from rare diseases, it usually takes years to receive a diagnosis. This diagnostic odyssey is filled with multiple referrals and a barrage of tests, seeking to uncover the root cause behind mysterious and debilitating symptoms.

A new speed record in DNA sequencing may soon help families more quickly find answers to difficult and life-altering questions.

In just 7 hours, 18 minutes, a team of researchers at Stanford Medicine went from collecting a blood sample to offering a disease diagnosis. This unprecedented turnaround time is the result of ultra-rapid DNA sequencing technology paired with massive cloud storage and computing. This improved method of diagnosing diseases allows researchers to discover previously undocumented sources of genetic diseases, shining new light on the 6 billion letters in the human genome.

More than 7,000 rare diseases affect 300 million people worldwide, 50% of whom are children. Of these diseases, 80% have a genetic component. The onset of some rare genetic diseases can be swift and debilitating. Spotting symptoms and identifying the root cause is a race against the clock for many families.

Im a biotechnology and policy scholar who works on improving access to innovative health care technologies. Whether its simple and affordable tests or sophisticated and expensive gene therapies, medical breakthroughs need to reach populations around the world. I believe that ultra-rapid DNA sequencing is key to casting a wider net and providing a faster turnaround for diagnosing rare diseases.

A new Guinness World Record

The Human Genome Project, the first successful attempt to sequence a complete or whole human genome, took 13 years, from 1990 to 2003, and cost $2.7 billion. In 2014, the field of whole genome sequencing passed another major milestone by hitting the $1,000 price point. Every year, the cost of sequencing continues to fall, driven by engineering and computational innovation.

In their quest for a world record, Stanford researchers reached for a DNA sequencing platform from the company Oxford Nanopore Technologies, which developed a device that reads genomes by pulling large strands of DNA through pores comparable in size and composition to the openings in biological cell membranes. As a DNA strand passes through the pore, the device reads subtle electrical changes unique to each DNA letter, thus detecting the DNA sequence.

Thousands of these pores are distributed across a device called a flow cell. The researchers sequenced a single patients genome across 48 flow cells simultaneously, allowing them to read the entire genome in a record time of 5 hours, 2 minutes.

The ultra-rapid DNA sequencing generated terabytes of data, which was moved to a cloud-based storage system. In the cloud, algorithms scanned the genome, looking for tiny variations mutations within the DNA sequence that could help explain the origin of a genetic disease.

Rewriting the diagnostic odyssey

If a diseases origin is thought to reside in the genome, the standard medical way forward is to order a gene panel. This test sequences a list of predetermined genes for possible disease-causing mutations. Receiving test results usually takes two to three weeks but can take up to eight weeks, and can miss mutations in genes not on the list.

Shortening the sequencing and analysis process to seven hours and expanding the sequencing from a few genes to the entire genome could fundamentally alter the diagnostic odyssey. Ultra-rapid DNA sequencing has already made a difference in the lives of two children.

Matthew Junzman, a 13-year-old from Oregon, was rushed to Stanford Hospital and placed on life support. His heart was failing, and no one knew why. Doctors narrowed down the cause to two options: myocarditis, a reversible condition involving inflammation of the heart, or an untreatable genetic condition.

In the Stanford study, doctors performed an ultra-rapid DNA sequencing test, which quickly revealed that Matthew had a genetic condition. He was immediately placed on a transplant list and received a new heart three weeks later.

In the same study, a 3-month-old patient was admitted to the pediatric hospital suffering from seizures. Using the ultra-rapid DNA sequencing process, doctors quickly spotted a mutation in a gene that explained the seizures. Standard tests would have initially missed this diagnosis.

Disease diagnosis is a global problem

Advances in health care technology typically have a high price tag when they first become available. Corporate competition, cheaper materials and new generations of technology can help drive down costs. But infrastructure, political and regulatory hurdles all contribute to limiting global access.

While Oxford Nanopores technology is cheaper than several alternative sequencing devices, costs of equipment and materials are still prohibitively expensive for labs in many countries. Similarly, less than 20% of low- and middle-income countries have modern data infrastructure. This removes the possibility of cloud computing in many places.

Bringing ultra-rapid DNA sequencing to these countries will involve investing in regional efforts to support genomic research. For example, the Human Heredity & Health in Africa Initiative invests in scientific infrastructure and workforce development to study health and disease for African populations. Providing groups like these with the equipment and software needed for ultra-rapid DNA sequencing will ensure that rare diseases that are more common in African populations will not go unexplored.

There are no approved treatments for 95% of rare diseases. The limited number of individuals affected by a given rare disease makes it difficult to study symptoms and design clinical trials. Creating data-sharing systems and crafting regulations will be vital to allow people to safely share their personal information between countries. The European Joint Programme on Rare Diseases and the Global Alliance for Genomics & Health are making progress toward these goals, building bridges between rare disease communities around the world.

As ultra-rapid genome sequencing becomes a feature in hospitals across high-income countries, I believe its important to consider how the broader rare disease community will have access to these tools and benefit from the wave of new disease insight on the horizon.

[Understand new developments in science, health and technology, each week. Subscribe to The Conversations science newsletter.]

This article is republished from The Conversation under a Creative Commons license. Read the original article here: https://theconversation.com/record-breaking-rapid-dna-sequencing-promises-timely-diagnosis-for-thousands-of-rare-disease-cases-175480.

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Record-breaking rapid DNA sequencing promises timely diagnosis for thousands of rare disease cases - Jacksonville Journal-Courier

The Festival of Genomics and Biodata the UK's largest genomics event, with more than 7,000 attendees is a great place for the global genomics community to meet.

Researchers from The Institute of Cancer Research, London, were present, including Professor Paul Workman, Professor Clare Turnbulland Dr Anguraj Sadanandam, who gave talks at the conference that ran from 25-28 January 2022.

Professor Dame Sue Hill, Chief Scientific Officer for NHS England, delivered the introductory keynote and explained how NHS England plans to keep up the momentum in genomics.

As she described, the UK holds a world-leading position in genomics, having been heavily involved in the Human Genome Project in the early 2000s and committed to sequencing 100,000 whole human genomes from patients with rare diseases and common cancers back in 2012.

Fast-forward to today and the NHS has launched the NHS Genomic Medicine Serviceand a world-first whole genome sequencing service, hoping to become the first national health care system to offer whole genome sequencing as part of routine care.

Next, the NHS and Genomics England will focus on the Cancer 2.0 initiative a proof of concept to explore the use of long-read sequencing (LRS) technology in cancer.

Our genome is too long to be sequenced in one go. Scientists often use short-read sequencing technology, where short fragments of DNA are sequenced separately and then pieced together. Long-read sequencing enables faster sequencing of longer fragments.

The hope is that the Cancer 2.0 project will introduce new technologies like this to support earlier, faster diagnosis cutting waiting times from weeks to days in some cases.

Another priority for Genomics England is diversity in genomic data. In the next few years, they hope to enrich their genomic datasets, sequencing cohorts of diverse backgrounds.

The ICRs Professor Paul Workman, Harrap Professor of Pharmacology and Therapeutics, delivered another of the opening keynote speeches, focusing on 'drugging' the cancer genome.

It has been 21 years since the human genome was first sequenced and released, and that has had an enormous impact of cancer drug discovery and development, he said.

New understanding of cancer genomes helps researchers identify new targets for drug development, and even repurpose drugs that already exist. So, putting it simply, using our knowledge of genomics increases the probability of drug development success.

This is hugely important, since the cost of drug discovery and development is prohibitive it costs around 2.6 billion dollars for a drug to come to the market and reach patients. This means that any help to pinpoint drug candidates as accurately as possible is desirable.

Despite all the investment in cancer research and discovering new cancer drugs, oncology has one of the lowest approval rates, at around 5 per cent and it takes an average of 10.5 years for a cancer drug to go from phase I trials to regulatory approval. There are many reasons for this delay from patent to patient highlighted in our Drug access report, which shows its particularly hard for innovative drugs to get rapid approval.

But using genetics across the drug development pipeline to validate targets and find biomarkers, for example is one of the first steps to help drug discovery efforts and re-purposing opportunities, ultimately benefiting patients.

Professor Workman also highlighted the important role of chemical probes in biomedical research and drug discovery. More publications come out when a chemical probe is identified, he said. Chemical probes are key to understanding a proteins role in biology and disease, which helps scientists in drug target validation and discovery.

There is a long way to go when it comes to drug development, and collaboration is key, explained Professor Workman:

Only around 9 per cent of patients actually have molecular targets that allow them to benefit from personalised medicine. For at least 90 per cent of patients, despite their genome sequence being available, there isnt currently a drug that works for them.

It takes a village. It takes basic research, universities, research institutes, pharma, biotech, regulators working together to do this better.

Professor Clare Turnbull spoke about genomics for early detection and prevention of cancer focusing on breast cancer as an example.

The field of genomics helps us understand and estimate peoples risk of developing cancer, which in turn helps us detect the disease as early as possible, or even prevent it. But cancer susceptibility genomics is complex, and researchers are still working out how to use their knowledge in the clinic.

There are specific inherited gene changes, also known as variants, which significantly increase cancer risk on their own such as variants of the BRCA1, BRCA2 or PALB2 genes. However, for most people, their genetic predisposition to cancer comes from the combined risk of many different variants. To understand this risk, scientists use so-called polygenic risk scores, which provide a snapshot of an individuals genetic risk.

So what can we do if we know certain people are at increased risk of certain cancers? Firstly, risk varies across tumour subtypes, and interventions vary in efficacy depending on the tumour subtype too. But by using their understanding of susceptibility genes and risk, clinicians can attempt to detect disease sooner thanks to screening programmes, or even prevent it using measures such as surgical prevention, chemoprevention or even behavioural changes.

One of Professor Turnbulls projects, BRCA-DIRECT, is exploring the usefulness of a digital platform to deliver genetic susceptibility testing, aiming to extend genetic testing to all women with breast cancer.

Aside from all the knowledge we can gain from genetic and genomic data, there are whole different sets of data and knowledge that can be used to power personalised medicine. Multi-omics also involves data ranging from proteomics, which focuses on proteins, to metabolomics, which involves the analysis of metabolism by-products.

Dr Anguraj Sadanandam talked about multi-omics data and how, with the help of AI and machine learning, we can make sense of the breadth of data available. By combining and integrating the data using these powerful technologies, we can understand whole systems we can obtain a much fuller picture of what goes wrong in cancer.

One of the machine learning tools that Dr Sadanandam uses in his lab is PhenMap, which helps to identify cancer subtypes and biomarkers by integrating different multi-omics data sets. He has been using PhenMap to reimagine clinical diagnoses of pancreatic neuroendocrine tumours helping define new subtypes of the disease and stratify for potential treatment opportunities.

We have come a long way since the inception of the Human Genome Project, launched more than two decades ago. From machine learning tools to drug development and susceptibility genes, there is no doubt that genomic research is delivering on promises we have been hearing about for a while but there is still a lot to accomplish.

As the curtain was drawn on the Festivals sixth year, George Freeman MP, Minister for Science, Research and Innovation, thanked all the attendees for a great week, assuring the audience that this is only the beginning: We are in the foothills of what, I think, is the most exciting revolution in healthcare.

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Science Talk - Sequencing, drugging and interpreting genomes: Where is genomics going next? - The Institute of Cancer Research, London - The Institute...

SAN DIEGO, Feb. 02, 2022 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (BNGO), pioneer of optical genome mapping (OGM) solutions on the Saphyr system and provider of NxClinical, the leading software solutions for visualization, interpretation and reporting of genomic data, today announced the adoption of its Saphyr system by two genetics laboratory hubs (GLH) within the United Kingdoms (UK) National Health Service (NHS). The Newcastle upon Tyne Hospitals NHS Foundation Trust and the Birmingham Womens and Children NHS Foundation Trust intends to utilize the system to evaluate OGM against traditional cytogenetic methods.

The UKs NHS is one of the worlds largest healthcare systems and is working to create a world class healthcare system using cutting edge genomic technologies. These adoptions significantly increase the footprint for OGM in the UK, complementing previous Saphyr placements in Belfast City Hospital in Belfast, Northern Ireland and Kings College Hospital in London, England.

The Newcastle upon Tyne Hospitals NHS Foundation Trust leads the North East and Yorkshire Genomic Laboratory Hub and is a partnership of hospitals and labs serving millions of people in these regions. The Birmingham Womens and Children NHS Foundation Trust leads the Central and South Genomic Laboratory Hub and is a consortium of labs serving 12 million residents in West Midlands, Oxford and Wessex. Both labs intend to evaluate the potential of OGM to detect chromosomal aberrations in hematologic malignancies, genetic conditions and specific solid tumors.

OGM has the potential to streamline a number of areas by replacing multiple analysis modalities with a single process, said Polly Talley, FRCPath, scientific lead for HaemOnc at the North East and Yorkshire Genomic Laboratory Hub. This could offer efficiency and speed to our genome analysis capabilities, and we are keen to see what this technology can provide to our HaemOnc service. Ms. Talleys colleague, Jennie Bell, Deputy Director/Consultant Clinical Scientist with the Central & South Genomic Laboratory Hub and Director, West Midlands Regional Genetics Laboratory, noted, We were encouraged by the positive experience reported by other laboratories using OGM technology, which included good detection resolution for genomic structural variations, a high level of automation and genome-wide analysis.

Story continues

With these two new Saphyr placements in the UKs NHS, we continue to broaden our footprint and provide scientists and clinical researchers with the ability to develop a comprehensive, reliable and cost-effective solution for detecting chromosomal abnormalities in hematologic malignancies, genetic conditions and cancer research applications, commented Erik Holmlin, PhD, President and Chief Executive Officer of Bionano. We welcome these genomic laboratory hubs to the OGM community and look forward to working with them as we strive to transform the way the world sees the genome.

About Bionano Genomics

Bionano Genomics is a provider of genome analysis solutions that can enable researchers and clinicians to reveal answers to challenging questions in biology and medicine. The Companys mission is to transform the way the world sees the genome through OGM solutions, diagnostic services, and software. The Company offers OGM solutions for applications across basic, translational and clinical research. Through its Lineagen business, the Company also provides diagnostic testing for patients with clinical presentations consistent with autism spectrum disorder and other neurodevelopmental disabilities. Through its BioDiscovery business, the Company also offers an industry-leading, platform-agnostic software solution, which integrates next-generation sequencing and microarray data designed to provide analysis, visualization, interpretation and reporting of copy number variants, single-nucleotide variants, and absence of heterozygosity across the genome in one consolidated view. For more information, visit bionanogenomics.com, lineagen.com or biodiscovery.com.

Forward-Looking Statements of Bionano Genomics

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the ability and utility of OGM and Saphyr to analyze genomes in a comprehensive, reliable and cost-effective way, the potential for OGM to become part of the standard of care and NHS continued use of the Saphyr system. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape, including the introduction of competitive technologies or improvements in existing technologies; failure of future results to support those found by NHS and referenced in this press release; changes in our strategic and commercial plans; our ability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions, including NHS, to obtain funding to support adoption or continued use of our technologies; and the risks and uncertainties associated with our business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2020 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on managements assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations:Amy ConradJuniper Point+1 (858) 366-3243amy@juniper-point.com

Media Relations:Michael SullivanSeismic+1 (503) 799-7520michael@teamseismic.com

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Bionano Genomics Announces UK Footprint Expansion with Adoption of its Saphyr System for Optical Genome Mapping in Two Genetic Laboratory Hubs within...

image:PopHumanVar application view more

Credit: UAB

Throughout our evolutionary history, we have been subjected to persistent adaptive challenges: changes in environmental conditions as we left Africa and expanded to the rest of the planet; changes in diet as we replaced the hunting of wild animals and fruit picking with the domestication of animals and farming; and changes in encountering new pathogens when forming Neolithic settlements. Our adaptive responses to these selective pressures have left their signature in our genomes, something we can now identify and analyse in order to reconstruct our past.

In 2019, the research group Bioinformatics of Genomics Diversity from Universitat Autnoma de Barcelona (UAB) identified 2859 regions of the human genome that could be relevant to the understanding of human evolution, 873 of which had not been described before. The group, directed by Snia Casillas and Antonio Barbadilla, researchers at the Department of Genetics and Microbiology and at the Institute for Biotechnology and Biomedicine (IBB), thus provided a very valuable set of data to answer the question What makes us human?, and made it freely accessible through the PopHumanScan database.

The PopHumanScan catalogue was a first step in understanding which signatures had been left by selection on our genomes. Now, the research group has published the new interactive online resource PopHumanVar, which allows narrowing down these signatures, studying their origins and reconstructing the past of the human species. The new database makes it easier to explore and analyse the regions of the genome with evidence of having been the target of natural selection at a given point of our evolutionary history. This will help answering questions such as the functional causes of these mutations, when they occurred, and among which populations.

PopHumanVar collects, integrates and graphically represents functional and evolutionary genomic data from millions of genetic variants based on 2504 complete genomic sequences of 26 human populations from different parts of the world. Thanks to all the information collected, the database allows studying specific genomic regions with the aim of finding the mutations responsible for an adaptive event and discover when and where it first emerged. For example, PopHumanVar identifies the mutations responsible for well-known adaptive processes such as the EDAR gene in East Asian populations, involved in the development of hair follicles, teeth and sweat glands; the ACKR1 gene (DARC) in Africa, which plays a role in the inflammatory response and is associated with malaria resistance; and the one near the LCT gene in European populations, responsible for the digestion of lactose. Moreover, the application allows users to add and analyse their own data so that they can study adaptive processes in populations not included in the application.

The PopHumanVar application, which is the result of a study published by the researchers in the journal Nucleic Acid Research, represents a breakthrough in the study of human adaptation to different environments and big cultural changes during our expansion on Earth, and can be freely and easily accessed at: https://pophumanvar.uab.cat

The study that led to the creation of PopHumanVar is based on the international 1000 Genomes Project, the same one for which the UAB research group launched in 2018 PopHuman, the largest genome browser available on human genetic variation.

Nucleic Acids Research

Computational simulation/modeling

People

PopHumanVar: an interactive application for the functional characterization and prioritization of adaptive genomic variants in humans

19-Oct-2021

None declared

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.

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PopHumanVar: Reconstructing the evolutionary past of the human species - EurekAlert

Tuesday, February 1st 2022 - 09:55 UTC The data and analysis generated will provide public health staff a set of tools to assess the political answers to the pandemic

The British government and the Pasteur Institute of Montevideo, Uruguay, have announced they will be working jointly in an agreement that will help advance the genome-sequencing of Covid-19 project, through techniques under development in Uruguay, using British technology, and thus providing this capacity to several countries in the region.

The announcement was made during a meeting of James Dauris, Head of the Latin American Department, from the Foreign, Commonwealth and Development Office, currently visiting Uruguay, with the Director of the Pasteur Institute Montevideo, Carlos Batthyany, Uruguayan Health minister Daniel Salinas and Deputy minister Jose Luis Satdjian

Health minister Salinas said that through collaboration from both countries, the intention is for Uruguay to become a regional hub of scientific knowledge and added value. Many countries in Latin America and the Caribbean need a knowledge support plus labs, for the gnome-sequencing and the follow up of different plagues and viruses. We are betting on Uruguayan knowledge quality to provide them.

The data and analysis generated will provide public health staff a set of tools to assess the political answers to the pandemic, will supply an early alert system to face new variants, and guarantee the world scientific community will benefit through quality information, which for example, will help guarantee that vaccines continue to be the adequate for any new variants.

Dauris underlined that combating the pandemic has shown the importance of international collaboration. We are proud to work with the Pasteur Institute Montevideo to increase the capacity of making genome-sequencing in Uruguay, and thus support countries in the region in their fight against the pandemic

Pasteur Institute Montevideo chief Batthyany said that it was an honor for the Institute and we are very pleased to continue collaborating with the British Embassy, (as with other countries), with the purpose of improving the scientific networks in South America. We are analyzing the economic support offered by the British government to boost genome vigilance in real time in the region, measuring the capacity of the Institute to make such vigilance for Uruguay, besides other countries in the region

The project, involving some US$ 100,000 will be in charge of the Epidemiologic Vigilance Innovation Center, CIVE, to which the British government contributed funds for its foundation in 2020, together with the governments of France and the United States besides private organizations, corporations and citizens. The British Embassy and the Pasteur Institute Montevideo are drafting the agreement which they expect to have finalized and ready to sign very soon.

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Britain helping the Pasteur Institute of Montevideo with a Covid-19 genome-sequencing project - MercoPress