ReportWire

Tag: Genetics

  • When bugs swipe left

    When bugs swipe left

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    Newswise — It’s almost Valentine’s Day, and love is in the air. Or in the waxy coating on your skin, if you are a vinegar fly. That’s where flies encounter pheromones that play an important role in regulating sexual attraction.

    Flies use pheromones to ensure that they court and mate with members of the same species. As new fly species split off from a common ancestor, but continue to share the same environment, they need a way to rapidly diversify their pheromones to suppress inter-species mating. When members of two related species stop finding each other attractive, this helps prevent interbreeding.

    But it’s more complicated than “she loves me, she loves me not.“

    Because the perception and production of pheromones are mediated by different tissues and cellular pathways, evolving new mating pheromones requires a coordinated evolution of both the genes responsible for sensing the pheromones as well as the genes that produce them.

    A new study in iScience led by Yehuda Ben-Shahar at Washington University in St. Louis identifies a link between the genetic instructions for the production and perception of sex pheromones. The research was conducted in collaboration with Jocelyn Millar from the University of California, Riverside.

    Researchers reported that a single protein called Gr8a is expressed in different organs in male and female flies and appears to play an inhibitory role in mating decision-making. The findings point to one of the ways that flies could put up behavioral barriers to protect against mating with the wrong kind of partner.

    “Mating pheromones often show rapid evolution,” said Ben-Shahar, a professor of biology in Arts & Sciences. “Because pheromonal communication requires a very robust and specific structural recognition of chemicals used as pheromones by the proteins that bind them in sensory neurons (chemoreceptors), it means that major molecular changes in either the receptor or the pheromone would reduce sexual attraction between males and females.”

    Ben-Shahar and his team found that Gr8a was expressed in tissues in fly mouthparts, including the proboscis, as well as in taste neurons in the forelegs of both males and females. They also found Gr8a in cells in the abdomens of males. This was important because it provided Ben-Shahar and his team the first hint that a gene that had been previously identified as a sensory chemoreceptor must also have non-neuronal functions.

    “Our findings provide a relatively simple molecular explanation for how signal production and perception are tied together in vinegar flies,” Ben-Shahar said. “A single pleiotropic protein can function as both a receptor for pheromones in sensory neurons, as well as contribute to their production in the pheromone-producing cells (oenocytes) of males, by way of a less-understood process.”

    In one of the experiments that Ben-Shahar and his team conducted, the scientists took flies that were mutant for the Gr8a receptor and reconstituted them using input from a different vinegar fly species. This experiment showed that introducing Gr8a from another species was enough to change the overall pheromone profile of the animal.

    The scientists still have not pinpointed exactly how the chemoreceptor affects the way the signal is produced, but they do know that it causes quantitative and qualitative differences in pheromones. And even small changes in pheromones could be enough to keep closely related flies from finding each other attractive — and change their mate choice behaviors.

    The question of how closely related species evolve and maintain behavioral mating barriers is one that has implications for several different basic and applied biological research fields.

    “Based on what we have observed, mutations in a single gene could provide a molecular path for a pheromonal communication system to evolve while still maintaining the functional coupling between a pheromone and its receptor,” Ben-Shahar said. “Our research uncovers a potential avenue for pheromonal systems to rapidly evolve when new species arise.”

    —

    This work was supported by National Science Foundation grants 1322783, 1754264 and 1707221, and National Institutes of Health (NIH) grant NS089834.

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    Washington University in St. Louis

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  • People with additional X or Y chromosome at increased risk for dangerous blood clots

    People with additional X or Y chromosome at increased risk for dangerous blood clots

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    Newswise — DANVILLE, Pa. – People with an additional X or Y chromosome—a genetic condition known as supernumerary sex chromosome aneuploidy—have an increased risk of developing blood clots known as venous thromboembolism (VTE), a Geisinger study found.

    The results were published in the Journal of the American Medical Association (JAMA).

    VTE, which is often fatal, affects an estimated 900,000 people in the United States each year, and is a frequent complication for patients in intensive care and those with medical conditions such as cancer and COVID-19. VTE includes deep vein thrombosis (a blood clot in a deep vein, usually in the leg) and pulmonary embolism (a blood clot in the lung).

    The Geisinger research team, led by Matthew Oetjens, Ph.D., assistant professor at Geisinger’s Autism & Developmental Medicine Institute, analyzed genetic and electronic health record data on two groups of patients—642,544 in all—enrolled in Geisinger’s MyCode Community Health Initiative and the UK Biobank, another large population study based in the United Kingdom. They found that approximately one in 500 Geisinger patients have an additional X or Y chromosome in their genome beyond the typical two found in females (XX) and males (XY). Those with an additional X or Y chromosome had a risk for VTE that was four to five times higher than expected.

    “An additional X or Y chromosome is more common than many people think, but it does not often receive clinical attention,” Dr. Oetjens said. “Our study shows that there are underappreciated health risks associated with these disorders that could change medical care if known in advance.”

    “VTE is a life-threatening, but preventable disease,” said Alex Berry, Ph.D., staff scientist at Geisinger and first author of the study. “It is important to identify individuals at high risk for VTE to minimize unnecessary illness and death.”

    The analysis also suggests that the loss of an X or Y chromosome, known as Turner syndrome, is not associated with a higher risk of blood clots. Further research is needed to understand the medical implications of this association, the research team wrote.

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    About Geisinger
    Geisinger is committed to making better health easier for the more than 1 million people it serves. Founded more than 100 years ago by Abigail Geisinger, the system now includes 10 hospital campuses, a health plan with more than half a million members, a Research Institute and the Geisinger Commonwealth School of Medicine. With nearly 24,000 employees and more than 1,700 employed physicians, Geisinger boosts its hometown economies in Pennsylvania by billions of dollars annually. Learn more at www.geisinger.org, or connect with us on Facebook, Instagram, LinkedIn and Twitter.

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    Geisinger Health System

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  • Unbelievable facts

    Unbelievable facts

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  • Family tree secrets: Island tree populations older, more diverse than expected

    Family tree secrets: Island tree populations older, more diverse than expected

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    Newswise — Tsukuba, Japan—It’s often assumed that island plant and animal populations are just the simple, fragile cousins of those on the mainland. But now, researchers from Japan have discovered that island populations may be a lot tougher and more complex than previously thought.

    In a recently published study, a research group led by the University of Tsukuba has revealed that the northernmost island populations of Siebold’s beech, Fagus crenata, are older and genetically more diverse than expected.

    Island and mainland populations often differ as a result of islands’ geographical isolation, which is often assumed to restrict the genetic diversity of their populations. However, a number of studies on land plants have shown that island populations have considerable genetic diversity despite their remoteness, indicating that the processes underlying their diversity are more complex than previously thought.

    “Although many island populations have existed for thousands of years or longer, the origins of some of them are still unknown,” says Professor Yoshiaki Tsuda, the main author of the study. “This includes Japan’s northernmost island populations of the native species F. crenata.”

    The research group investigated populations of F. crenata on Okushiri Island in the Japan Sea, which is thought to have broken away from the mainland in the Middle Pleistocene (the Ice Age, which occurred 2.58 million to 11,700 years ago), and remained separate ever since. The northward spread of this species began on the mainland approximately 6,000 years ago, after the last glacial maximum (LGM). The researchers studied the genetics of the island’s populations and those of nearby regions, and found that the island’s populations had high genetic diversity, and may not have arisen from a single colonization event.

    The Okushiri Island populations had a comparable number of private alleles (genetic sequences that are present in a single population and essentially absent in other populations) to the populations studied on nearby Hokkaido, which points to the existence of relict populations on Okushiri Island. A relict is a population of organisms that was more widespread or more diverse in the past in a restricted area.

    Taken together with palaeoecological and vegetation studies, as well as the island’s geology, these results indicate that F. crenata persisted in cryptic refugia (places where climatically sensitive species can survive regardless of incompatibility with the regional climate) on the island.

    “Our evidence indicates that populations of this species already existed on Okushiri Island prior to the LGM, and persisted there for longer than previously thought,” explains Professor Tsuda. The results of this study contribute to a growing body of evidence that island plant populations are more genetically diverse than previously estimated, which has implications for research and management of island species conservation, and the study of gene flow between island and mainland populations.

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    This study was supported by JSPS KAKENHI (JP17K07852 and JP20K06152) and Core-to-Core Program (Asia-Africa Science Platforms: JPJSCCB20220007) from the Japan Society for the Promotion of Science and the 27th Pro Natura Fund Grant Program from the Pro Natura Foundation Japan.
     

    Original Paper

    The article, “Possible northern persistence of Siebold’s beech, Fagus crenata, at its northernmost distribution limit on an island in Japan Sea: Okushiri Island, Hokkaido,” was published in Frontiers in Plant Science at DOI: 10.3389/fpls.2022.990927

    Correspondence

    Associate Professor TSUDA Yoshiaki
    Faculty of Life and Environmental Sciences, University of Tsukuba

    Related Link

    Faculty of Life and Environmental Sciences
    Sugadaira Research Station, Mountain Science Center

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    University of Tsukuba

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  • New hope for treatment of rare metabolic disease

    New hope for treatment of rare metabolic disease

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    Newswise — X-linked adrenoleukodystrophy (X-ALD) is the most common of a group of around 50 rare diseases of the white matter of the brain, the so-called leukodystrophies. The genetic damage in X-ALD is due to a defect in the X chromosome. Affected men suffer from progressive paralysis of the legs, deterioration of balance and sensory disturbances, and develop incontinence and sexual dysfunction. Despite inheritance via the X chromosome, female gene carriers can also be affected. About 30 per cent of boys and 60 per cent of male adults develop encephalitis, which is fatal within two to three years. Worldwide, the disease affects about one person in 20,000 births.

    Now, for the first time, scientists from all relevant leukodystrophy centres in Europe and the US have jointly succeeded in obtaining controlled trial data for X-linked adrenoleukodystrophy. Of the 116 patients, 77 received the drug leriglitazone and 39 a placebo. The drug had already shown in preclinical studies that it can prevent neurodegeneration and offer protection against the life-threatening inflammation of the brain. “Our clinical trial has in fact also shown that none of the patients who took the drug were affected by brain inflammation. In contrast, among the participants who were given a placebo, 15 per cent developed this life-threatening form of the disease within two years,” explains study leader and first author Dr Wolfgang Köhler, head of the leukodystrophy outpatient clinic at the Department of Neurology at Leipzig University Hospital.

    The actual aim of the study had been to show that the drug would prevent gait disorders in X-ALD patients from worsening over the course of two years. “This worked particularly well in those who were treated early. The more advanced the gait disorder, the less apparent the effect. Overall, there was no significant difference, so the actual aim of the study was not achieved,” explains Dr Köhler. Nevertheless, many points indicated a clinical effect of the new drug: besides the indication that brain inflammation could be prevented, other effects included improvements in neurological conditions such as balance disorders, which had a positive impact on quality of life.

    Note on financing:

    The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) is currently reviewing the marketing authorisation application of the Spanish pharmaceutical company Minoryx for the drug leriglitazone for the treatment of adult male patients with X-ALD. This study was sponsored by Minoryx.

    More information on this topic:

    All participants in the study currently have the option to continue treatment with leriglitazone for a total of five years as part of an open-label extension study. In addition, follow-up studies are planned in patients with pre-existing involvement of the brain. “This gives us hope that we will also be able to effectively treat patients with advanced, inflammatory brain involvement with a drug in the future, especially those whom we can no longer help with a stem cell transplant. This is only possible at a very early stage of brain inflammation,” explains Dr Köhler.

    A centre for myelin disorders, which include leukodystrophy and multiple sclerosis, is to be established at Leipzig University Hospital before the end of this year, and will be the first of its kind in Germany. “With such rare diseases, it is of utmost importance to bring together the excellence of different areas of treatment and research in order to jointly gain new insights and make further progress,” says initiator Dr Köhler.

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    Universitat Leipzig

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  • CHOP Researchers Develop New, More Accurate Computational Tool for Long-Read RNA Sequencing

    CHOP Researchers Develop New, More Accurate Computational Tool for Long-Read RNA Sequencing

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    Newswise — Philadelphia, January 20, 2023—On the journey from gene to protein, a nascent RNA molecule can be cut and joined, or spliced, in different ways before being translated into a protein. This process, known as alternative splicing, allows a single gene to encode several different proteins. Alternative splicing occurs in many biological processes, like when stem cells mature into tissue-specific cells. In the context of disease, however, alternative splicing can be dysregulated. Therefore, it is important to examine the transcriptome – that is, all the RNA molecules that might stem from genes – to understand the root cause of a condition.

    However, historically it has been difficult to “read” RNA molecules in their entirety because they are usually thousands of bases long. Instead, researchers have relied on so-called short-read RNA sequencing, which breaks RNA molecules and sequence them in much shorter pieces – somewhere between 200 to 600 bases, depending on the platform and protocol. Computer programs are then used to reconstruct the full sequences of RNA molecules. Short-read RNA sequencing can give highly accurate sequencing data, with a low per-base error rate of approximately 0.1% (meaning one base is incorrectly determined for every 1,000 bases sequenced). Nevertheless, it is limited in the information that it can provide due to the short length of the sequencing reads. In many ways, short-read RNA sequencing is like breaking a large picture into many jigsaw pieces that are all the same shape and size and then trying to piece the picture back together.

    Recently, “long-read” platforms that can sequence RNA molecules over 10,000 bases in length end-to-end have become available. These platforms do not require RNA molecules to be broken up before they are sequenced, but they have a much higher per-base error rate, typically between 5% to 20%. This well-known limitation has severely hampered the widespread adoption of long-read RNA sequencing. In particular, the high error rate has made it difficult to determine the validity of novel, previously unknown RNA molecules discovered in a particular condition or disease.

    To circumvent this problem, researchers at Children’s Hospital of Philadelphia (CHOP) have developed a new computational tool that can more accurately discover and quantify RNA molecules from these error-prone long-read RNA sequencing data. The tool, called ESPRESSO (Error Statistics PRomoted Evaluator of Splice Site Options), was reported today in Science Advances.

    “Long-read RNA sequencing is a powerful technology that will allow us to uncover RNA variation in rare genetic diseases and other conditions, like cancer,” said Yi Xing, PhD, director of the Center for Computational and Genomic Medicine at CHOP and senior author of the study. “We are probably at an inflection point in how we discover and analyze RNA molecules. The transition from short-read to long-read RNA sequencing represents an exciting technological transformation, and computational tools that reliably interpret long-read RNA sequencing data are urgently needed.”

    ESPRESSO can accurately discover and quantify different RNA molecules from the same gene – known as RNA isoforms – using error-prone long-read RNA sequencing data alone. To do so, the computational tool compares all long RNA sequencing reads of a given gene to its corresponding genomic DNA, and then uses the error patterns of individual long reads to confidently identify splice junctions – places where the nascent RNA molecule has been cut and joined – as well as their corresponding full-length RNA isoforms. By finding areas of perfect matches between long RNA sequencing reads and genomic DNA, as well as borrowing information across all long RNA sequencing reads of a gene, the tool is able to identify highly reliable splice junctions and RNA isoforms, including those that have not been previously documented in existing databases. 

    The researchers evaluated the performance of ESPRESSO using simulated data and data on real biological samples. They found that ESPRESSO performs better than multiple currently available tools, both in terms of discovering RNA isoforms and quantifying them. The researchers also generated and analyzed over 1 billion long RNA sequencing reads covering 30 human tissue types and three human cell lines, providing a useful resource for studying human transcriptome variation at the resolution of full-length RNA isoforms. 

    “ESPRESSO addresses a long-standing problem of long-read RNA sequencing and could usher in new opportunities of discovery,” Dr. Xing said. “We envision that ESPRESSO will be a useful tool for researchers to explore the RNA repertoire of cells in various biomedical and clinical settings.”

    This work was supported in part by the Immuno-Oncology Translational Network (IOTN) of the National Cancer Institute’s Cancer Moonshot Initiative (U01CA233074), other National Institutes of Health funding (R01GM088342, R01GM121827, and R56HG012310), along with a National Institutes of Health T32 Training Grant in Computational Genomics (T32HG000046). 

    Gao et al. “ESPRESSO: Robust discovery and quantification of transcript isoforms from error-prone long-read RNA-seq data,” Science Advances, January 20, 2023, DOI: 10.1126/sciadv.abq5072

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    About Children’s Hospital of Philadelphia: A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as a new inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

     

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    Children’s Hospital of Philadelphia

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  • Beyond Mendel: FinnGen study sheds new light on well-established theories of genetic inheritance

    Beyond Mendel: FinnGen study sheds new light on well-established theories of genetic inheritance

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    Newswise — A large-scale biobank-based study performed in Finland has discovered several new disease genes as well as new insights on how known genetic factors affect disease. The study highlights an underappreciated complexity in the dosage effects of genetic variants.

    An international team of scientists led by researchers at the University of Helsinki and the Broad Institute of MIT and Harvard examined the effects of 44,370 genetic variants on more than 2000 diseases in almost 177,000 Finnish biobank participants. The study focused on so-called coding genetic variants, i.e. variants that are known to change the protein product of the gene. 

    The results of the study, published in Nature on January 18, 2023, convey that the reality of genetic inheritance is more complex than the Mendelian inheritance laws taught in biology classes all around the world.

    What is special about the study, apart from the size of the data set, is that the team  searched at scale specifically for diseases that one only gets if one inherited a dysfunctional genetic variant from both parents (recessive inheritance). 

    “Researchers usually only search for additive effects when they try to find common genetic variants that influence disease risk. It is more challenging to identify recessively inherited effects on diseases as you need very large sample sizes to find the rare occasions where individuals have two dysfunctional variants”, explains Dr Henrike Heyne, first author of the study from the Institute for Molecular Medicine Finland FIMM, University of Helsinki (now group leader at HPI, Germany). 

    However, the extensive FinnGen study sample, collected from Finland, offers an ideal setting for such studies. The Finnish population has experienced several historical events that have led to a reduction of the population size and also been relatively isolated from other European populations. For this reason, a subset of dysfunctional and therefore potentially disease-causing genetic variants are present at higher frequencies, making the search for new rare disease associations of recessive inheritance easier.

    Acknowledging this benefit, the researchers performed genome-wide association studies (GWAS) on 2,444 diseases derived from national healthcare registries, testing both additive and recessive inheritance models. 

    As a result, the team was able to detect known and novel recessive associations across a broad spectrum of traits such as retinal dystrophy, adult-onset cataract, hearing loss and female infertility that would have been missed with the traditional additive model.

    “Our study showed that the search for recessive effects in genome-wide association studies can be worthwhile, especially if somewhat rarer genetic variants are included, as is the case in the FinnGen study”, says Henrike Heyne. 

    In addition, the dataset has provided a new perspective on the inheritance of known disease variants. For rare disease genes, inheritance is traditionally almost exclusively described as recessive or dominant. The study shows, however, that the reality is somewhat more diverse. 

    The researchers found, for example, that some variants that are known to cause genetic disease with recessive inheritance also have some attenuated effects when only one disease-causing variant is present, which other studies confirm. They also find genetic variants with beneficial effects (protecting from heart arrhythmia or protecting from hypertension) in genes that are associated with severe disease. 

    These results demonstrate that the so-called Mendelian laws based on the experiments with peas done in 1856, in a monastery garden near Brno (today Czech Republic) by the monk Gregor Mendel do not fully capture all aspects of inheritance of rare diseases.

    “With the increased usage of carrier screening in the general population, whereby many individuals are learning that they are carriers for multiple pathogenic variants, understanding which of those variants may have mild health effects could be incredibly important for these individuals”, says Heidi Rehm, an author on the paper and Professor of Pathology at Massachusetts General Hospital and Medical Director of the Broad Clinical Lab. 

    The study could contribute to the integration of the traditionally separate but more and more overlapping scientific fields that study either the effect of rare genetic variants on rare disease or the effect of common genetic variants on common disease. The results demonstrate how large biobank studies, particularly in founder populations such as Finland, can broaden our understanding of the sometimes more complex dosage effects of genetic variants on disease.

    “This study highlights the importance of integrating the large-scale biobank approach with detailed insights that emerge from rare disease studies. A more complete understanding of the role of genetic variation in each gene only emerges when we take account of all of the perspectives and insights from diverse study designs”, says Mark Daly, senior author on the paper and Director of the Institute for Molecular Medicine Finland (FIMM) and faculty member at Massachusetts General Hospital and the Broad Institute.

    Original publication: Mono- and biallelic variant effects on disease at biobank scale. H. O. Heyne, J. Karjalainen, K. J. Karczewski, S. M. Lemmelä, W. Zhou, FinnGen, A. S. Havulinna, M. Kurki, H. L. Rehm, A. Palotie, M. J. Daly. Nature 2023, DOI: 10.1038/s41586-022-05420-7. 

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    University of Helsinki

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  • KRISS Develops Dried Blood Spot Certified Reference Materials for Newborn Screening

    KRISS Develops Dried Blood Spot Certified Reference Materials for Newborn Screening

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    Newswise — As baby underwent a newborn screening test for inherited metabolic disorders within seven days of birth. The test checks for risk factors such as hypothyroidism, phenylketonuria, maple syrup urine disease, which can lead to developmental disabilities if not detected in their early stage. Every year, one in every 1,000 newborns are diagnosed with inherited metabolic disorders.

    The Korea Research Institute of Standards and Science (KRISS, President Hyun-Min Park) has developed Certified Reference Materials (CRMs)* that can enhance the reliability of using dried blood spot testing for newborn screening.

     * CRM: A reference material that serves as a standard in determining the accuracy of measurements and analytical methods

    DBS is a sample obtained by drying a drop of blood from the finger or heel on a piece of filter paper. This approach is used for screening rather than actual diagnosis, as it is less accurate than venous blood sample tests. Its common applications include newborn screening for inherited metabolic disorders and doping control during Olympics.

    The proposed CRM provides eight certified values and 10 reference values for amino acids, glucose, galactose, and acylcarnitines, which are diagnostic markers of inherited metabolic disorders in newborns. This allows accurate measurement of the amount of target compounds in the DBS.

    The lack of reference values has made it difficult for DBS testing to be considered reliable for medical decision. In addition, there has been a problem with measurement bias caused by the need to retrieve portions of blood spots using a paper puncher.

    The KRISS Biodiagnostics Analysis Team found that a 0.4 mm bias in diameter led to a 0.78 μL (one millionth of a liter) difference in sample volume.

    The research team controlled the sample volume to 50 μL during the CRM manufacturing stage, and proposed bias-free measurements as certified values, thereby successfully creating CRMs with complete measurement traceability to the International System of Units. This is the first-ever development of DBS CRMs.

    Dr. Ji-Seon Jeong, a principal researcher at KRISS, said, “DBS has come under the spotlight as a convenient way of blood sampling, which satisfies the high demand for remote healthcare and home sampling in the days of the pandemic. Our study has laid the foundation to improve the reliability in DBS sample measurement, opening the door for DBS to become an effective tool not only in screening but also diagnosis.”

    KRISS plans to develop more CRMs for other diagnostic markers used in newborn screening.

     

     

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    As the representative institute in the national measurement standards, the Korea Research Institute of Standards and Science (KRISS) has been setting the highest measurement standards and ensuring their international equivalence since its inception in 1975. Thereby, we help build solid foundations for the national development in science and technology and for industrial advancements

     

    Funded by KRISS, the study was published in the world-leading journal Analytical Chemistry (IF: 8.008) in July.

     

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    National Research Council of Science and Technology

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  • Combining multiple maps reveal new genetic risk factors for blindness

    Combining multiple maps reveal new genetic risk factors for blindness

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    Newswise — Combining a map of gene regulatory sites with disease-associated loci has uncovered a new genetic risk factor of adult-onset macular degeneration (AMD), according to a new study publishing January 17th in the open access journal PLOS Biology by Ran Elkon and Ruth Ashery-Padan of Tel Aviv University, Israel, and colleagues. The finding advances the understanding of the leading cause of visual impairment in adults.

    AMD is caused by dysfunction in the retinal pigmented epithelium (RPE), a layer of tissue sandwiched between the photoreceptors that receive light, and the choriocapillaris, which nourishes the retina. Because of the central importance of the RPE in AMD, the authors began by exploring a transcription factor (a protein that regulates specific genes) called LHX2 which, based on the team’s analysis of mouse mutants, is central to RPE development. Knocking down LHX2 activity in RPE derived from human stem cells, they found that most affected genes were down-regulated, indicating that LHX2’s role was likely that of a transcriptional activator, binding to regulatory sites on the genome to increase activity of other genes.

    The authors found that one affected gene, called OTX2, collaborated with LHX2 to regulate many genes in the RPE. By mapping the genomic sites that OTX2 and LHX2 could bind to, they showed that 68% of those that bound LHX2 were also bound by OTX2 (864 sites in all), suggesting they likely work together to promote the activity of a large suite of genes involved in RPE development and function.

    A common method for finding genes that may contribute to a disease is to perform a genome-wide association study (GWAS), which identifies genome sequence differences between individuals (termed single nucleotide polymorphisms, or SNPs) that co-occur with disease. Numerous such studies have previously been done in AMD. However, a GWAS by itself cannot uncover a causal mechanism. Here, the authors compared their LHX2/OTX2 binding data to GWAS data in order to home in on variations that affected binding of the transcription factors, and thus may contribute to disease.

    One such binding site was located within the promoter region of a gene called TRPM1, which had been previously linked to AMD, and found that the sequence variant at that site altered the binding strength of LHX2; the so-called C version bound it more strongly than the T version, and activity of the TRPM1 gene was higher when the C allele was present instead of the T allele.

    The results of the study indicate that the previously known increased risk of AMD from the variant identified in the GWAS was due to reduction in binding of the LHX2 transcription factor to the TRPM1 gene promoter, with a consequent reduction in activity of this gene. The gene encodes a membrane ion channel, and previous studies have shown that mutations in the gene also cause visual impairment.

    “Our study exemplifies how delineation of tissue-specific transcriptional regulators, their binding sites across the genome, and their downstream gene-regulatory networks can provide insights into a complex disease’s pathology,” the authors said.

    Ashery-Padan adds, “The findings reveal a regulatory module consisting of LHX2 and OTX2 that controls the development and maintenance of the retinal pigmented epithelium, an important tissue of visual function. The genomic analyses further link the genomic regions bound by the two developmental factors to the genetics of the common, multifactorial blinding disease age-related macular degeneration (AMD).”

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    In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001924

    Press-only preview: https://plos.io/3GK3PF3

     

    Citation: Cohen-Gulkar M, David A, Messika-Gold N, Eshel M, Ovadia S, Zuk-Bar N, et al. (2023) The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration. PLoS Biol 21(1): e3001924. https://doi.org/10.1371/journal.pbio.3001924

    Author Countries: Israel

    Funding: see manuscript

    Competing interests: The authors have declared that no competing interests exist.

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  • Using paleogenomics to elucidate 10,000 years of immune system evolution

    Using paleogenomics to elucidate 10,000 years of immune system evolution

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    Newswise — Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.

    In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.

    To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia – a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.

    By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under “positive” natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes – which are responsible for antiviral activity – and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this “acceleration” in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.

    At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to “negative” selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.

    Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders – including Crohn’s disease – became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. “These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases,” explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).

    The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.

    As well as the institutions mentioned above, this research was supported by the French Foundation for Medical Research (FRM), the Allianz-Institut de France Foundation and the Fondation de France.

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  • Evolution of uniquely human DNA was a balancing act, study concludes

    Evolution of uniquely human DNA was a balancing act, study concludes

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    Newswise — SAN FRANCISCO, CA—January 13, 2023—Humans and chimpanzees differ in only one percent of their DNA. Human accelerated regions (HARs) are parts of the genome with an unexpected amount of these differences. HARs were stable in mammals for millennia but quickly changed in early humans. Scientists have long wondered why these bits of DNA changed so much, and how the variations set humans apart from other primates.

    Now, researchers at Gladstone Institutes have analyzed thousands of human and chimpanzee HARs and discovered that many of the changes that accumulated during human evolution had opposing effects from each other.

    “This helps answer a longstanding question about why HARs evolved so quickly after being frozen for millions of years,” says Katie Pollard, PhD, director of the Gladstone Institute of Data Science and Biotechnology and lead author of the new study published today in Neuron. “An initial variation in a HAR might have turned up its activity too much, and then it needed to be turned down.”

    The findings, she says, have implications for understanding human evolution. In addition—because she and her team discovered that many HARs play roles in brain development—the study suggests that variations in human HARs could predispose people to psychiatric disease.

    “These results required cutting-edge machine learning tools to integrate dozens of novel datasets generated by our team, providing a new lens to examine the evolution of HAR variants,” says Sean Whalen, PhD, first author of the study and senior staff research scientist in Pollard’s lab.

    Enabled by Machine Learning

    Pollard discovered HARs in 2006 when comparing the human and chimpanzee genomes. While these stretches of DNA are nearly identical among all humans, they differ between humans and other mammals. Pollard’s lab went on to show that the vast majority of HARs are not genes, but enhancers— regulatory regions of the genome that control the activity of genes.

    More recently, Pollard’s group wanted to study how human HARs differ from chimpanzee HARs in their enhancer function. In the past, this would have required testing HARs one at a time in mice, using a system that stains tissues when a HAR is active.

    Instead, Whalen input hundreds of known human brain enhancers, and hundreds of other non-enhancer sequences, into a computer program so that it could identify patterns that predicted whether any given stretch of DNA was an enhancer. Then he used the model to predict that a third of HARs control brain development.

    “Basically, the computer was able to learn the signatures of brain enhancers,” says Whalen.

    Knowing that each HAR has multiple differences between humans and chimpanzees, Pollard and her team questioned how individual variants in a HAR impacted its enhancer strength. For instance, if eight nucleotides of DNA differed between a chimpanzee and human HAR, did all eight have the same effect, either making the enhancer stronger or weaker?

    “We’ve wondered for a long time if all the variants in HARs were required for it to function differently in humans, or if some changes were just hitchhiking along for the ride with more important ones,” says Pollard, who is also chief of the division of bioinformatics in the Department of Epidemiology and Biostatistics at UC San Francisco (UCSF), as well as a Chan Zuckerberg Biohub investigator.

    To test this, Whalen applied a second machine learning model, which was originally designed to determine if DNA differences from person to person affect enhancer activity. The computer predicted that 43 percent of HARs contain two or more variants with large opposing effects: some variants in a given HAR made it a stronger enhancer, while other changes made the HAR a weaker enhancer.

    This result surprised the team, who had expected that all changes would push the enhancer in the same direction, or that some “hitchhiker” changes would have no impact on the enhancer at all.

    Measuring HAR Strength

    To validate this compelling prediction, Pollard collaborated with the laboratories of Nadav Ahituv, PhD, and Alex Pollen, PhD, at UCSF. The researchers fused each HAR to a small DNA barcode. Each time a HAR was active, enhancing the expression of a gene, the barcode was transcribed into a piece of RNA. Then, the researchers used RNA sequencing technology to analyze how much of that barcode was present in any cell—indicating how active the HAR had been in that cell.

    “This method is much more quantitative because we have exact barcode counts instead of microscopy images,” says Ahituv. “It’s also much higher throughput; we can look at hundreds of HARs in a single experiment.”

    When the group carried out their lab experiments on over 700 HARs in precursors to human and chimpanzee brain cells, the data mimicked what the machine learning algorithms had predicted.

    “We might not have discovered human HAR variants with opposing effects at all if the machine learning model hadn’t produced these startling predictions,” said Pollard.

    Implications for Understanding Psychiatric Disease

    The idea that HAR variants played tug-of-war over enhancer levels fits in well with a theory that has already been proposed about human evolution: that the advanced cognition in our species is also what has given us psychiatric diseases.

    “What this kind of pattern indicates is something called compensatory evolution,” says Pollard. “A large change was made in an enhancer, but maybe it was too much and led to harmful side effects, so the change was tuned back down over time—that’s why we see opposing effects.”

    If initial changes to HARs led to increased cognition, perhaps subsequent compensatory changes helped tune back down the risk of psychiatric diseases, Pollard speculates. Her data, she adds, can’t directly prove or disprove that idea. But in the future, a better understanding of how HARs contribute to psychiatric disease could not only shed light on evolution, but on new treatments for these diseases.

    “We can never wind the clock back and know exactly what happened in evolution,” says Pollard. “But we can use all these scientific techniques to simulate what might have happened and identify which DNA changes are most likely to explain unique aspects of the human brain, including its propensity for psychiatric disease.”

    ###

    About the Study

    The paper “Machine learning dissection of human accelerated regions in primate neurodevelopment,” was published in the journal Neuron on January 13, 2023.

    Other authors are Kathleen Keough, Alex Williams, Md. Abu Hassan Samee, and Sean Thomas of Gladstone; Fumitaka Inoue, Hane Ryu, Tyler Fair, Eirene Markenscoff-Papadimitrious, Beatriz Alvarado, Orry Elor, Dianne Laboy Cintron, Erik Ullian, Arnold Kriegstein, and John Rubenstein of UC San Francisco; Martin Kircher, Beth Martin, and Jay Shendure of University of Washington; and Robert Krencik of Houston Methodist Research Institute.

    The work was supported by the Schmidt Futures Foundation and the National Institutes of Health (DP2MH122400-01, R35NS097305, FHG011569A, R01MH109907, U01MH116438, UM1HG009408, UM1HG011966, 2R01NS099099).

    About Gladstone Institutes

    To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco.

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  • Paving the way toward a cure? Study reports new insights into role of proteins in HIV latency

    Paving the way toward a cure? Study reports new insights into role of proteins in HIV latency

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    Newswise — Understanding HIV latency at the molecular level is crucial for efforts to eliminate the viral scourge that causes AIDS. Latent infected cell reservoirs—where the human immunodeficiency virus (HIV) hides and persists in the bodies of infected patients in a kind of silent standby mode—are the reason why antiretroviral treatments never wipe out the virus.

    In a nutshell, these latent reservoirs of HIV act as the biggest obstacle to curing the disease. 

    Now, in a rigorous new study led by uOttawa Faculty of Medicine virologist Dr. Marc-André Langlois, researchers are describing an against-the-grain discovery that is a potential game changer in the field. It has the potential to show the way forward for HIV cure research.

    Published today in Nature Communications, the findings demonstrate that a family of host proteins long thought of as purely antiviral are sometimes also helping latent HIV find safe harbor in patients’ bodies.

    Using cutting-edge technology and methodical assays in this project started in 2016, Dr. Langlois and his collaborators describe the impact of host-encoded proteins called APOBEC3 (A3). These proteins possess the ability to potently mutate viral DNA and restrict retroviruses like HIV as well as other types of viruses. But his team’s latest findings suggest that these proteins can also play another role outside of their traditional evolutionary one – and it’s not always in a patient’s favor.

    “We’re showcasing a new mechanism by which HIV can become latent – and it can become latent through the action of our host proteins that are there to protect us. But in fact, these proteins can end up helping the virus maintain its stealthiness in the body,” says Dr. Langlois, a full professor at the uOttawa Faculty of Medicine and Chair in Pandemic Viruses and Preparedness Research.

    “This is an important finding because these proteins were always perceived of as protectors that were on our side. But our work shows there are instances where they appear to have unintended consequences, and one of these unintended consequences is helping HIV become latent. And HIV latency is the biggest hurdle to a cure,” he says.

    This raises major questions: Is the action of these proteins ultimately more beneficial or more counterproductive in the case of HIV, a virus that favors a latency phenotype? Can a drug be developed down the line to prevent the action of A3 proteins so the cellular and anatomical reservoir of latently infected cells is reduced?

    These are the kind of explorations that Dr. Langlois and his team will be examining moving forward.

    “Yes, we can keep HIV under tight control with antiretroviral drugs – and those drugs work wonderfully. But they’re not a cure. We are striving for a cure, and we think part of the countermeasures following an exposure will be to block the activity of A3 proteins to inhibit HIV latency,” says Dr. Langlois, who is also executive director of CoVaRR-Net, a network of interdisciplinary researchersnorth_eastexternal link created to assist the Canadian government’s strategy to address the threat of emerging SARS-CoV-2 variants. 

    “We’ve done the first demonstration that this mechanism—something that wasn’t on the radar and goes against mainstream thought—is really happening. So this is the first layer of evidence, and we’ll be building on it with follow-up studies.”

    For this study, Dr. Langlois and his uOttawa Faculty of Medicine team focused on infection experiments. They provided samples to collaborators at the University of Western Ontario, who provided the “viral deep sequencing” expertise mapping where the virus inserts itself in the human genome after infection. The research was supported by a Canadian Institutes of Health Research (CIHR) grant.

    Now demonstrated in vitro in the lab, and to some extent in patient samples, Dr. Langlois wants to take it to the next level with animal models. And while the overarching impact of the A3 proteins’ influence on HIV integration site profiles is unclear at this stage, his research team is committed to exploring potential answers.

    The stakes of this research are high. Since its emergence as a new immunodeficiency syndrome in the early 1980s, HIV-AIDs has been one of the globe’s most serious health challenges. There’s been remarkable progress battling the virus, yet there are over 38 million people living with HIV worldwide, and tens of millions of people have died of HIV-related illnesses since the epidemic began.

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  • Researchers receive grant to study how fungal pathogens become drug-resistant

    Researchers receive grant to study how fungal pathogens become drug-resistant

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    Newswise — A pair of Clemson University researchers are collaborating to discover why fungal pathogens become drug resistant.

    Genetics and Biochemistry Associate Professor Lukasz Kozubowski and Chemistry Professor Julia Brumaghim are studying how the fungal pathogen Cryptococcus neoformans develops resistance to azole compounds, a class of fungicides that are widely used in agriculture for crop protection and as a treatment for life-threatening human fungal infections. They received a $492,000 National Science Foundation grant for the work.

    Only three types of antifungal drugs exist, so drug resistance can severely limit treatment options.

    Most azole compounds work by inhibiting fungi rather than killing them, which makes the drugs safer for humans, said Kozubowski, co-principal investigator on the project. That’s because both humans and fungi are eukaryotic. Therefore, drugs designed to kill fungi may also harm their human hosts. Eukaryotes are single-celled or multicellular organisms whose cells contain a distinct, membrane-bound nucleus.

    Chance of drug resistance

    Conversely, while fungi-inhibiting drugs are safer for humans, their use also increases the chance of drug resistance.

    “We know resistance to azoles is a fact,” Kozubowski explained. “Apparently, the drugs can somehow stimulate the development of resistance. It is counterintuitive: You may think of a drug as killing or inhibiting the pathogen, but the drugs have some propensity to stimulate the development of resistance to the same drugs. So what they are supposed to kill, the drugs are actually stimulating the cells to develop a resistance to it.”

    It’s rare that a fungal cell isn’t killed or inhibited by antifungal treatment — and that adds a complication for the scientists.

    “The problem with resistance is that it’s quite an elusive target when it comes to understanding because essentially what we are after is an event that happens maybe one in a million times,” Kozubowski said. “You have a population of millions of cells, and unfortunately, if the drug doesn’t kill them all, there will always be that lucky cell, that one in a million, that develops something that causes resistance.”

    Drug resistance is also a problem with antibiotics, Kozubowski noted. 

    Emerging problem

    Fungal drug resistance is an emerging problem that is also growing in scope, adding to the urgency of the Clemson scientists’ work. “It’s not a last-year emerging, but in the past decades, we’ve been experiencing drug-resistant fungal infections. That’s true for bacterial infections as well,” Kozubowski said.

    Ultimately, he said the researchers’ goal is to better understand how drugs such as the azole compounds stimulate the mechanism of drug resistance. A top suspect: damaged DNA.

    Enter Brumaghim, the project’s principal investigator, who said she became interested in the project because her work focuses on how cellular DNA becomes damaged, which complements Kozubowski’s research.

    “I got involved in the project because I found out [Kozubowski] was working on how these compounds generate reactive oxygen species like the radical species that can damage DNA,” Brumaghim recalled. 

    Reactive oxygen species are unstable molecules that contain oxygen and easily react with other molecules in a cell. 

    “He said, ‘this is the mechanism, but we know nothing about how this could happen.’ And that’s what I do. We look at how metals generate these radical species that damage DNA,” Brumaghim said

    Then, the question facing Brumaghim and Kozubowski was, “what happens if you have more damage [to cellular DNA] than can be repaired,” Brumaghim said. “Then you get into trouble. If a cell cannot replicate its DNA sufficiently, it will die. It’s called ‘programmed cell death.’… The alternative to that is when you have mutations to the DNA, and the cell would be better off dying, but it doesn’t — that leads to cancer. Or with fungi, it leads to drug resistance — or that’s what we think.”Kozubowski described the interdepartmental collaboration as a “natural match.” 

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  • Arrest of Idaho students murder suspect brings ‘a great sense of relief’ to university campus before a return to classes this week, provost says | CNN

    Arrest of Idaho students murder suspect brings ‘a great sense of relief’ to university campus before a return to classes this week, provost says | CNN

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    CNN
     — 

    Following the stabbing deaths of four students in November, the tight-knit University of Idaho community was shaken for weeks, but the recent arrest of a suspect may allow the campus to regain a sense of security as students return to classes this week.

    “I think I speak for many in our community that there’s a great sense of relief, but it’s bittersweet because this is still a horrible tragedy,” the university’s provost and executive vice president Torrey Lawrence told CNN Friday.

    Bryan Kohberger, 28, is charged with the murders of students Kaylee Goncalves, 21; Madison Mogen, 21; Xana Kernodle, 20; and Ethan Chapin, 20, who were found brutally stabbed to death in an off-campus home in Moscow, Idaho, on November 13.

    The gruesome killings rattled the campus community and city of Moscow, which had not seen a murder since 2015. Anxieties only worsened as weeks passed without a named suspect, leading some students to leave campus and complete the semester remotely.

    Classes resume on Wednesday following the winter break, and though students who are still uncomfortable being on campus have the option to attend remotely, most students are planning to return, Lawrence said.

    “The timing of this for our students was probably good,” the provost said, adding, “Hopefully we can really just be focused on classes starting and on that student experience that we provide.”

    Security will remain heightened on campus, he said, though some measures such as a state patrol presence are no longer in place.

    Still, the “very peaceful, safe community” students enjoyed before the killings has experienced a “loss of innocence,” he said.

    Kohberger, who is the sole suspect, was pursuing a PhD in criminal justice at nearby Washington State University at the time of the killings and lived just minutes from the scene of the killings, according to authorities.

    Investigators say phone records indicate Kohberger was near the victims’ home at least 12 times between June 2022 and the present day, according to an affidavit detailing the evidence against him. The records also show the suspect was near the residence on the morning of the killings, court documents say.

    DNA recovered from the the Kohberger family’s trash was linked to DNA found on a tan leather knife sheath found on the bed of one of the victims, according to the affidavit. The DNA in the trash is believed to belong to the biological father of the person whose DNA was found on the sheath, the document says.

    The suspect’s white Hyundai Elantra was also seen close the victims’ home around the time of the killings, according to investigators. Kohberger received a new license plate for the car five days after the killings, Washington state licensing records and court documents reveal.

    Kohberger had his initial court appearance in Idaho on Thursday and did not enter a plea at the hearing.

    Before Kohberger’s arrest, authorities noted that the suspect thoroughly cleaned his vehicle and was seen wearing surgical gloves repeatedly outside his family’s Pennsylvania home, a law enforcement source tells CNN.

    The source, who spoke on the condition of anonymity, was briefed on observations made by investigators during four days of surveillance leading up to Kohberger’s arrest at his family home.

    Kohberger “cleaned his car, inside and outside, not missing an inch,” according to the law enforcement source.

    A surveillance team assigned to Kohberger was tasked with two missions, according to multiple law enforcement sources: keep eyes on Kohberger so they could arrest him as soon as a warrant was issued, and try to obtain an object that would yield a DNA sample from Kohberger, which could then be compared to DNA evidence found at the crime scene.

    Kohberger was seen multiple times outside the Pennsylvania home wearing surgical gloves, according to the law enforcement source.

    In one instance prior to Kohberger’s arrest, authorities observed him leaving his family home around 4 a.m. and putting trash bags in the neighbors’ garbage bins, according to the source. At that point, agents recovered garbage from the Kohberger family’s trash bins and what was observed being placed into the neighbors’ bins, the source said.

    The recovered items were sent to the Idaho State Lab, per the source.

    Last Friday, a Pennsylvania State Police SWAT team then moved in on the Kohberger family home, breaking down the door and windows in what is known as a “dynamic entry” – a tactic used in rare cases to arrest “high risk” suspects, the source added.

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  • Tip Sheet: New genetic risk factors identified for colorectal cancer, new challenge trial on a tuberculosis vaccine — and 2022 news highlights

    Tip Sheet: New genetic risk factors identified for colorectal cancer, new challenge trial on a tuberculosis vaccine — and 2022 news highlights

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    Newswise — SEATTLE — Jan. 6, 2023 — Below are summaries of recent Fred Hutchinson Cancer Center research findings and other news.

    Interested in news you may have missed in 2022 from Fred Hutch? Check out our year in review for news highlights.

    Cancer research

    Large-scale study led by Fred Hutch finds new genetic risk factors for colorectal cancer, paving the way for better screening, prevention A comprehensive analysis of more than 100,000 colorectal cancer cases, led by researchers at the Fred Hutch, including Dr. Ulrike Peters, with 200 scientific collaborators worldwide, has identified more than 100 new genetic risk factors strongly linked with the disease. These findings published in Nature Genetics could help clinicians better determine who’s at highest risk for colorectal cancer so they can receive early screening.

    What’s new in breast cancer research? SABCS 2022 delivers plenty Scientists from Fred Hutch d new findings at the 45th annual meeting of the San Antonio Breast Cancer Symposium. Findings included data on new imaging tracers, analysis of treatment-related side effects like neuropathy and identifying gaps in metastatic cancer care. The meeting also highlighted efforts by patient advocates to address health disparities and gaps in research, such as in lobular breast cancer.

    Tracking prostate cancer dynamics New work published in eLife gives scientists a detailed look at individual cells as prostate cancer develops and turns treatment-resistant in mouse models of the disease. The project, led by Dr. Andrew Hsieh, aims to better understand the molecular underpinnings of cancer progression and resistance to androgen-deprivation therapy. 

    Infectious disease

    Could a 100-year-old TB vaccine help scientists find a better one? Bacillus Calmette-Guerin (BCG) is a vaccine made of living bacteria to prevent tuberculosis (TB) and the most widely used vaccine on the planet. Led by Dr. Jim Kublin, researchers at Fred Hutch have begun a new 10-person challenge trial that will study how immune systems respond to BCG and to isoniazid, a drug used to treat TB. 

    Awards and other news

    Eight Fred Hutch teams win Evergreen Fund awards Eight research teams at Fred Hutch will receive in-house grants this year from the Evergreen Fund, a unique program to boost scientific projects deemed promising enough in their early stages to attract potential commercial partners later on. Research includes continued work on developing laboratory-designed antibodies, a monoclonal antibody drug to block necrosis and many others.

    Leader in apheresis and cellular therapy, Dr. Michael Linenberger, retires Dr. Michael Linenberger, a professor in the Clinical Research Division and holder of the Robert and Phyllis Henigson Endowed Chair, retired after working in the Fred Hutch clinic, formerly Seattle Cancer Care Alliance, since it opened in 2001. Linenberger has played a major role in the development of evidence-based guidelines and best practices for the safe, efficient and effective use of apheresis in the clinic.

    A giant in BMT survivorship retires Dr. Mary Flowers, longtime medical director of Fred Hutch’s Long-Term Follow-Up program, a comprehensive survivorship program for blood and marrow transplant recipients, is retiring from Fred Hutch. When Flowers began working at the LTFU program, the clinic saw five patients a week. That number has increased more than six-fold since then, now tracking 6,500 patients post-transplant, including a 47-year survivor.

    Science spotlight Science Spotlight is a monthly installment of articles written by postdoctoral fellows at Fred Hutch that summarize new research papers from Hutch scientists.

    # # #

    Fred Hutchinson Cancer Center unites comprehensive care and advanced research to provide the latest cancer treatment options and accelerate discoveries that prevent, treat and defeat cancer and infectious diseases worldwide.

    Based in Seattle, Fred Hutch is an independent, nonprofit organization and the only National Cancer Institute-designated cancer center in Washington. We have earned a global reputation for our track record of discoveries in cancer, infectious disease and basic research, including important advances in bone marrow transplantation, HIV/AIDS prevention, immunotherapy and COVID-19 vaccines. Fred Hutch operates eight clinical care sites that provide medical oncology, infusion, radiation, proton therapy and related services and has network affiliations with hospitals in four states. Fred Hutch also serves as UW Medicine’s cancer program.

    Please note that our organization was renamed Fred Hutchinson Cancer Center in April 2022, following the merger of long-time partners, Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance.

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  • More than two billion are infected with this disease; Vitamin D can help

    More than two billion are infected with this disease; Vitamin D can help

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    Newswise — Sarcomas are cancer tumours found in e.g. the bones, muscles or fatty tissue. It is a rare type of cancer seen in only one per cent of cancer patients. It is complex and difficult to treat.

    However, a new study may have found a new treatment that can help the sickest sarcoma patients.

    “We have learned that sarcoma patients whose cancer cells have a high expression of the cep135 protein are worse off. But inhibiting a gene called plk1 also inhibits growth of the sarcoma cells, and this suggests that we can target the treatment of the sickest sarcoma patients,” says Associate Professor Morten Scheibye-Knudsen from the Center for Healthy Aging at the Department of Cellular and Molecular Medicine, who is responsible for the new study.

    Methods for identifying sarcoma patients’ prognoses are already available, as are different forms of treatment. But the new study has identified a new method.

    “This is a new way of stratifying and possibly a new and better way of treating sarcoma. And the introduction of yet another method is always good news to patients. Because no two cancers are alike. Ideally, treatment should always be tailored to the individual patient,” Morten Scheibye-Knudsen stresses.

    He hopes other researchers with access to the necessary test facilities will study his results in more detail and eventually design a new treatment. If the method turns out to work, he believes a new treatment may be available to patients in five to 10 years.

    Grey hair, wrinkles and loss of fatty tissue at an early age

    Morten Scheibye-Knudsen and his colleagues started out by studying patients suffering from the rare neurological disorders Werner’s syndrome, Nijmegen breakage syndrome and Ataxia-telangiectasia syndrome.

    These patients experience symptoms of early ageing such as grey hair, wrinkles and loss of fatty tissue – and they have a high risk of developing cancer at an early age.

    “Age-associated diseases such as cancer is one of my main areas of interest as a researcher at the Center for Healthy Aging. As we grow older, a lot of things happen to the body, and determining causality can be difficult. But in people suffering from e.g. Werner’s syndrome it is easier to see which genes are responsible for which processes. This gives us a molecular handle, so to speak,” says Morten Scheibye-Knudsen.

    In order to establish why these patients develop cancer at an early age, the researchers compared gene expressions across the three disorders. Here they worked together with the company Insilico Medicine, whose large Pandaomics platform made it possible to identify gene mutations in thousands of different disorders. It turned out that cep135 is a common denominator for the cancer genes of the three disorders.

    “This made us study the gene expressions of various cancers, and we learned that cep135 is associated with high mortality in i.a. sarcoma, but also in bladder cancer. Sarcoma was particularly interesting, as many Werner’s syndrome patients develop sarcoma,” explains Morten Scheibye-Knudsen.

    Finally, the researchers sought to find ways to inhibit the sarcoma. Cep135 is not a useful target, as it is a so-called structural protein, which are difficult to target. Instead, the researchers learned that by inhibiting the plk1 gene they were able to target the sarcoma.

    “The study indicates that we can use genetic diseases that exhibit accelerated aging to identify new treatment targets. In this study, we investigated cancer, but the method can in principle be used for all age-related diseases such as dementia, cardiovascular diseases and others,” says Morten Scheibye-Knudsen.

    Read the entire study, ”High-confidence cancer patient stratification through multiomics investigation of DNA repair disorders”, in CDDpress.

    What are sarcomas?

    Sarcomas are cancer tumours found in i.a. the bones, muscles or fatty tissue. There are two main types: bone sarcoma and soft tissue sarcoma (muscles, fatty tissue, connective tissue, blood vessels and neurilemma).

    Sarcoma affects one per cent of cancer patients. In Denmark, around 45 people are diagnosed with bone sarcoma each year and 220 with soft tissue sarcoma. Adults diagnosed with bone sarcoma have a 60-per cent five-year survival rate, while adults diagnosed with bone sarcoma have a 50-70-per cent five-year survival rate.

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    University of Copenhagen, Faculty of Health and Medical Sciences

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  • Beyond the average cell

    Beyond the average cell

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    Newswise — Nobody wants to be average.

    But for a long time, scientists have found it convenient to think of bacterial cells as just that: “average.”

    Researchers have traditionally relied on population-level strategies to understand fundamental aspects of bacterial physiology. These population-level approaches describe the behavior of idealized average cells, and they serve as the foundation for prevailing models of bacterial growth.

    Models based on an average cell are useful, but they may not accurately describe how individual cells really work. New possibilities opened up with the advent of single-cell live imaging technologies. Now it is possible to peer into the lives of individual cells. In a new paper in PLOS Genetics, a team of biologists and physicists from Washington University in St. Louis and Purdue University used actual single-cell data to create an updated framework for understanding the relationship between cell growth, DNA replication and division in a bacterial system.

    Petra Levin, the George William and Irene Koechig Freiberg Professor of Biology in Arts & Sciences at Washington University, an author of the new paper, has a keen interest in single-cell biology. In her research work, Levin has made seminal contributions to our understanding of bacterial cell growth.

    A chance encounter at the Aspen Center for Physics led to a collaboration with Srividya Iyer-Biswas, a physicist at Purdue University with expertise in both first-principles-based physics theory and high-precision single cell experiments.

    Taking advantage of the Zoom era brought on by the early days of the pandemic, Levin and Iyer-Biswas developed their virtual collaboration to revisit some of the “beautiful, classic models of the bacterial cell cycle,” as Levin describes them.

    They found exciting bits were missing.

    What was the problem? The models counted on the behavior of an “average” cell within a population. But using the average to infer what an actual cell does can be misleading.

    “Imagine each bacterium as singing its own whimsical tune, following its own rhythm,” Iyer-Biswas said. “The collective — a population of millions of cells — has its own music, where no single voice especially stands out, but a song nonetheless emerges. From hearing just the collective rendition, how could one possibly uncover what precisely an individual’s song might be? That is the problem we were faced with.”

    “What is true for the average cell is not necessarily true for the individual cell. Bacteria are just like us in this regard!” Levin added.

    For this new paper, Levin and Iyer-Biswas worked together with Sara Sanders, a postdoctoral scientist in the Levin lab who recently moved to the National Institutes of Health (NIH), and Kunaal Joshi, a PhD student in the Iyer-Biswas lab, to tackle one basic question.

    They wanted to figure out how these “whimsical” individual bacterial cells — or, as a more typical physicist might say, these stochastic cells — manage to exquisitely coordinate DNA replication with growth and division, so that overall events happen in the right sequence despite the “noisiness” of each process.

    To answer the question, the authors carefully looked at single-cell growth data from the model organism Escherichia coli collected by the Jun laboratory at the University of California, San Diego. They then constructed a minimal mathematical model that captured complex, stochastic behaviors of individual cells and accurately matched individual cell data.

    Based on average cell behavior, others had come to view the basic cell cycle steps of DNA replication and cell division as dependent on each other. But that wasn’t how Levin and Sanders saw it.

    “Decades of genetic and molecular studies indicate that although DNA replication and division are clearly coordinated, they are not dependent on one another,” Levin said. “As long as there are mechanisms to prevent division across uncopied chromosomes, or fix the situation in the unlikely event that does happen, everything is fine. E. coli does not have cell cycle checkpoints like eukaryotic cells do.”

    Meanwhile, Iyer-Biswas and Joshi realized that there was a simple way to understand the individual cell data. Each cell has three independent (stochastic) timers (equivalent to the whimsical tune from above) that start ticking each time DNA replication begins, and whose orchestration determines the sequence of cell cycle events.

    Starting from this simple idea, Joshi discovered he could predict the sequence of DNA replication initiation, the end of DNA replication and division based on when the three timers independently go off and reset. His predictions matched exquisitely with the extant data on individual cell DNA replication and cell division in many different growth conditions.

    By describing a stochastic, not deterministic, relationship between DNA replication and cell division, the authors have shifted how scientists understand a basic process in cell biology.

    “Our ultimate goal is to build a community around high-precision approaches in biology that seamlessly integrate theory and experiment,” Iyer-Biswas said. “A more immediate goal is to transcend system-specific details and provide a unifying framework also applicable to other bacterial species.”

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    Washington University in St. Louis

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  • Study reveals average age at conception for men versus women over past 250,000 years

    Study reveals average age at conception for men versus women over past 250,000 years

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    Newswise — BLOOMINGTON, Ind. — The length of a specific generation can tell us a lot about the biology and social organization of humans. Now, researchers at Indiana University can determine the average age that women and men had children throughout human evolutionary history with a new method they developed using DNA mutations.

    The researchers said this work can help us understand the environmental challenges experienced by our ancestors and may also help us in predicting the effects of future environmental change on human societies.

    “Through our research on modern humans, we noticed that we could predict the age at which people had children from the types of DNA mutations they left to their children,” said study co-author Matthew Hahn, Distinguished Professor of biology in the College of Arts and Sciences and of computer science in the Luddy School of Informatics, Computing and Engineering at IU Bloomington. “We then applied this model to our human ancestors to determine what age our ancestors procreated.”

    According to the study, published today in Science Advances and co-authored by IU post-doctoral researcher Richard Wang, the average age that humans had children throughout the past 250,000 years is 26.9. Furthermore, fathers were consistently older, at 30.7 years on average, than mothers, at 23.2 years on average, but the age gap has shrunk in the past 5,000 years, with the study’s most recent estimates of maternal age averaging 26.4 years. The shrinking gap seems to largely be due to mothers having children at older ages.

    Other than the recent uptick in maternal age at childbirth, the researchers found that parental age has not increased steadily from the past and may have dipped around 10,000 years ago because of population growth coinciding with the rise of civilization.

    “These mutations from the past accumulate with every generation and exist in humans today,” Wang said. “We can now identify these mutations, see how they differ between male and female parents, and how they change as a function of parental age.”

    Children’s DNA inherited from their parents contains roughly 25 to 75 new mutations, which allows scientists to compare the parents and offspring, and then to classify the kind of mutation that occurred. When looking at mutations in thousands of children, IU researchers noticed a pattern: The kinds of mutations that children get depend on the ages of the mother and the father.

    Previous genetic approaches to determining historical generation times relied on the compounding effects of either recombination or mutation of modern human DNA sequence divergence from ancient samples. But the results were averaged across both males and females and across the past 40,000 to 45,000 years.

    Hahn, Wang and their co-authors built a model that uses de novo mutations — a genetic alteration that is present for the first time in one family member as a result of a variant or mutation in a germ cell of one of the parents or that arises in the fertilized egg during early embryogenesis — to separately estimate the male and female generation times at many different points throughout the past 250,000 years.

    The researchers were not originally seeking to understand the relationship of gender and age at conception over time; they were conducting a broader investigation about the number of mutations passed from parents to children. They only noticed the age-based mutation patterns while seeking to understand differences and similarities between these pattens in humans versus other mammals, such as cats, bears and macaques.

    “The story of human history is pieced together from a diverse set of sources: written records, archaeological findings, fossils, etc.,” Wang said. “Our genomes, the DNA found in every one of our cells, offer a kind of manuscript of human evolutionary history. The findings from our genetic analysis confirm some things we knew from other sources (such as the recent rise in parental age), but also offer a richer understanding of the demography of ancient humans. These findings contribute to a better understanding of our shared history.”

    Additional contributors to this research were Samer I. Al-Saffar, a graduate student at IU at the time of the study, and Jeffrey Rogers of the Baylor College of Medicine.

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    Indiana University

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  • Idaho suspect in student murders thoroughly cleaned vehicle, also seen wearing surgical gloves multiple times outside family home, source says | CNN

    Idaho suspect in student murders thoroughly cleaned vehicle, also seen wearing surgical gloves multiple times outside family home, source says | CNN

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    CNN
     — 

    The man accused of murdering four University of Idaho students in November had thoroughly cleaned the interior and exterior of his car and was also seen wearing surgical gloves multiple times before being apprehended, a law enforcement source tells CNN.

    Bryan Kohberger, 28, is currently the sole suspect in the gruesome stabbings of students Kaylee Goncalves, 21; Madison Mogen, 21; Xana Kernodle, 20; and Ethan Chapin, 20, who were found dead inside their off-campus house in Moscow, Idaho, on November 13.

    Kohberger, who was pursuing a PhD in criminal justice at Washington State University at the time of the killings, “cleaned his car, inside and outside, not missing an inch,” according to the law enforcement source.

    The source, who spoke on the condition of anonymity, was briefed on observations made by investigators during four days of surveillance leading up to Kohberger’s arrest at his family’s Pennsylvania home on December 30.

    As Kohberger now remains behind bars in Idaho awaiting his January 12 status hearing, new details have emerged elucidating some of the suspect’s movements in the days leading up to his arrest.

    A surveillance team assigned to Kohberger was tasked with two missions, according to multiple law enforcement sources: keep eyes on Kohberger so they could arrest him as soon as a warrant was issued, and try to obtain an object that would yield a DNA sample from Kohberger, which could then be compared to DNA evidence found at the crime scene.

    Kohberger was seen multiple times outside the Pennsylvania home wearing surgical gloves, according to the law enforcement source.

    In one instance prior to Kohberger’s arrest, authorities observed him leaving his family home around 4 a.m. and putting trash bags in the neighbors’ garbage bins, according to the source. At that point, agents recovered garbage from the Kohberger family’s trash bins and what was observed being placed into the neighbors’ bins, the source said.

    The recovered items were sent to the Idaho State Lab, per the source.

    Last Friday, a Pennsylvania State Police SWAT team then moved in on the Kohberger family home, breaking down the door and windows in what is known as a “dynamic entry” – a tactic used in rare cases to arrest “high risk” suspects, the source added.

    On Thursday, Kohberger had his initial court appearance in Idaho after he was booked into the Latah County jail Wednesday night following his extradition from Pennsylvania.

    Kohberger is charged with four counts of first-degree murder and one count of burglary. He did not enter a plea at the hearing.

    Steve Goncalves, whose daughter Kaylee was among those killed, he told CNN’s JIm Sciutto in an interview that aired Friday morning.

    “Nobody understands exactly why but he was stalking them, he was hunting them,” Goncalves said. “He was a person looking for an opportunity and it just happened to be in that house. And that’s hard to take.

    “She had her phone right next to her and she couldn’t call 911. So these were just girls that went to sleep that night and a coward, you know, a hunter that went out and he picked his little opponent that was girls, that’s probably why the house was targeted.”

    Goncalves was in the courtroom for Kohberger’s appearance.

    “He knows I want him to look me in the eye. So he didn’t. He didn’t give me that opportunity,” Goncalves said. “He’s scared to look at me in the eyes and start to understand what’s about to happen to him. You know, he picked the wrong family.”

    Authorities spent nearly two months investigating before they were able to name publicly a suspect, a task that grabbed national attention and rattled the victims’ loved ones as well as the community – which had not recorded a murder in years.

    Still, the public’s view of the case remains mired with questions. As of late Thursday, it remains unclear what motivated the killings. It’s also unclear how the suspect entered the house after authorities said there was no sign of forced entry or why two roommates who were inside the residence at the time of the killings survived the attacks.

    Here’s how investigators narrowed the search to Kohberger:

    • DNA: Trash recovered from Kohberger’s family home revealed that the “DNA profile obtained from the trash” matched a tan leather knife sheath found “laying on the bed” of one of the victims, according to a probable cause affidavit released Thursday. The DNA recovered from the trash “identified a male as not being excluded as the biological father” of the suspect whose DNA was found on the sheath. “At least 99.9998% of the male population would be expected to be excluded from the possibility of being the suspect’s biological father,” the affidavit said.
    • Phone records: Authorities found the suspect’s phone was near the victims’ Moscow, Idaho, home at least a dozen times between June 2022 to the present day, according to the affidavit. The records also reveal Kohberger’s phone was near the crime scene hours after the murders that morning between 9:12 a.m. and 9:21 a.m, the document says. The killings were not reported to authorities until just before noon.
    • A white sedan: A Hyundai Elantra was seen near the victims’ home around the time of their killings. Officers at Washington State University identified a white Elantra and later learned it was registered to Kohberger. The same car was also found at the suspect’s Pennsylvania family home when he was arrested last Friday. The suspect’s university is about a 10-minute drive from the Idaho crime scene.

    One of two roommates who were not harmed in the attacks said she saw a masked man dressed in black inside the house on the morning of the killings, according to the probable cause affidavit.

    Identified as D.M. in the court document, the roommate said she “heard crying” in the house that morning and also heard a man’s voice say, ‘It’s OK, I’m going to help you.’” D.M. said she then saw a “figure clad in black clothing and a mask that covered the person’s mouth and nose walking towards her,” the affidavit continued.

    “D.M. described the figure as 5’ 10” or taller, male, not very muscular, but athletically built with bushy eyebrows,” the affidavit says. “The male walked past D.M. as she stood in a ‘frozen shock phase.’

    “The male walked towards the back sliding glass door. D.M. locked herself in her room after seeing the male,” the document says, adding the roommate did not recognize the male.

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  • Key takeaways from court documents in case against Bryan Kohberger and some questions that remain | CNN

    Key takeaways from court documents in case against Bryan Kohberger and some questions that remain | CNN

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    CNN
     — 

    DNA allegedly found on a knife sheath recovered at the murder scene.

    A roommate described a masked figure with “bushy eyebrows.”

    Phone records showed the suspect was near the victims’ residence numerous times in the months before the killings.

    Nearly two months after the killings of four University of Idaho students captivated the country and sowed fear in the small community of Moscow, Idaho, an affidavit released Thursday offered a look at the investigative work that went into identifying Bryan Kohberger as the suspect.

    The 28-year-old PhD student in criminal justice was extradited to Idaho Wednesday from his home state of Pennsylvania. Facing four counts of first-degree murder and one count of burglary, Kohberger did not enter a plea during his initial court appearance Thursday.

    The suspect was arrested in Pennsylvania December 30, nearly seven weeks after Kaylee Goncalves, 21; Madison Mogen, 21; Xana Kernodle, 20; and Ethan Chapin, 20, were found fatally stabbed in an off-campus home.

    Here are key takeaways from the court documents – which include the probable cause affidavit used to support Kohberger’s arrest and obtain a warrant – and some questions that remain.

    Trash recovered from the Pennsylvania home of Kohberger’s family late last month and sent to the Idaho State Lab for DNA testing revealed that the “DNA profile obtained from the trash” matched a tan leather knife sheath found “laying on the bed” of one of the victims, according to the probable cause affidavit.

    The DNA in the trash “identified a male as not being excluded as the biological father” of the suspect whose DNA was found on the sheath.

    “At least 99.9998% of the male population would be expected to be excluded from the possibility of being the suspect’s biological father,” the affidavit said.

    One of two roommates who were not harmed told investigators she saw a masked man dressed in black in the house the morning of the attack, according to the probable cause affidavit.

    Identified in the document as D.M., the roommate said she “heard crying” in the house that morning and a male voice saying, ‘It’s OK, I’m going to help you.’”

    D.M. told investigators she saw a “figure clad in black clothing and a mask that covered the person’s mouth and nose walking towards her,” according to the affidavit.

    “D.M. described the figure as 5’ 10” or taller, male, not very muscular, but athletically built with bushy eyebrows,” the affidavit said. “The male walked past D.M. as she stood in ‘frozen shock.’”

    “The male walked towards the back sliding glass door. D.M. locked herself in her room after seeing the male,” according to the document, which said the roommate did not recognize the male.

    Authorities reviewed local surveillance footage and were drawn to a white sedan, later identified as a Hyundai Elantra, according to the affidavit.

    The vehicle was seen in the area around the home where the killings took place.

    By November 25, local law enforcement had been notified to be on the lookout for the vehicle, the affidavit said.

    Days later, officers at nearby Washington State University, where the suspect was a PhD student in criminal justice, identified a white Elantra and found it was registered to Kohberger.

    Kohberger’s driver’s license information was consistent with the description the unharmed roommate gave investigators, according to the affidavit.

    The document specifically noted Kohberger’s height and weight – 6 feet and 185 pounds – and that he has bushy eyebrows.

    Kohberger received a new license plate for his Elantra five days after the killings, the affidavit said, citing records from the Washington State Department of Licensing.

    At the time of Kohberger’s arrest last week, a white Elantra was found at his parents’ house in Pennsylvania, according to Monroe County Chief Public Defender Jason LaBar, who said Kohberger had gone home for the holidays.

    Phone records show Kohberger’s phone was near the victims’ residence at least 12 times since June, according to the court documents.

    “All of these occasions, except for one, occurred in the late evening and early morning hours of their respective days.”

    Additionally, records show Kohberger’s phone was near the murder scene – 1122 King Road – between 9:12 a.m. and 9:21 a.m. – hours after the killings, according to the court documents.

    A review of phone records showed Kohberger’s phone left his home at approximately 9 a.m. and traveled to Moscow, the affidavit said, and that the same phone traveled “back to the area of the Kohberger Residence … arriving to the area at approximately 9:32 a.m.”

    Kohberger applied for an internship with the Pullman Police Department in Washington in the fall of 2022, court documents show.

    “Pursuant to records provided by a member of the interview panel for Pullman Police Department, we learned that Kohberger’s past education included undergraduate degrees in psychology and cloud-based forensics,” according to an affidavit.

    “These records also showed Kohberger wrote an essay when he applied for an internship with the Pullman Police Department in the fall of 2022. Kohberger wrote in his essay he had interest in assisting rural law enforcement agencies with how to better collect and analyze technological data in public safety operations.”

    Nearly two months after the killings, however, a number of questions remain.

    It’s not clear why the unharmed roommate did not immediately call 911, or why the roommates were spared.

    The motive for the crime also remains a mystery, and police have said they are still looking for the murder weapon.

    The documents released Thursday shed no light on whether Kohberger had any other reason to be in the area at the time of the killings.

    Why wasn’t Kohberger arrested until more than six weeks after the victims were found dead?

    And authorities have not said publicly whether Kohberger knew any of the victims.

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