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Identifying changes in viral fitness using population genetic structure

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024年第28期121卷 e2410274121-e2410274121页

作者： Petros, Brittany A. Broad Inst MIT & Harvard Genom Ctr Infect Dis Cambridge MA 02142 USA Harvard Med Sch Hlth Sci & Technol Cambridge MA 02139 USA MIT Cambridge MA 02139 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA

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Somatic copy number variants in neuropsychiatric disorders

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CURRENT OPINION IN GENETICS & DEVELOPMENT 2021年 68卷 9-17页

作者： Maury, Eduardo A. Walsh, Christopher A. Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA 02115 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Harvard Med Sch Bioinformat & Integrat Genom Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PHD Program Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA

Copy number variants (CNVs) have been implicated in neuropsychiatric disorders, with rare-inherited and de novo CNVs (dnCNVs) having large effects on disease liability. Recent studies started exploring a class of dnCNVs that occur postzygotically, and are therefore present in some but not all cells of the body. Analogous to conditional mutations in animal models, the presence of risk mutations in a fraction of cells has the potential to enlighten how damaging mutations affect cell-type/cell-circuit specific pathologies leading to neuropsychiatric manifestations. Although mosaic CNVs appear to contribute to a modest fraction of risk (0.3-0.5%), expanding our insights about them with more sensitive experimental and statistical methods, has the potential to help clarify mechanisms of neuropsychiatric disease.

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Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA

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NATURE 2014年第7513期512卷 213-+页

作者： Hwang, William L. Deindl, Sebastian Harada, Bryan T. Zhuang, Xiaowei Harvard Univ Howard Hughes Med Inst Cambridge MA 02138 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ Dept Phys Cambridge MA 02138 USA

Imitation switch (ISWI)-family remodelling enzymes regulate access to genomic DNA by mobilizing nucleosomes(1). These ATP-dependent chromatin remodellers promote heterochromatin formation and transcriptional silencing(1) by generating regularly spaced nucleosome arrays(2-5). The nucleosome-spacing activity arises from the dependence of nucleosome translocation on the length of extranucleosomal linker DNA(6-10), but the underlying mechanism remains unclear. Here we study nucleosome remodelling by human ATP-dependent chromatin assembly and remodelling factor (ACF), an ISWI enzyme comprising a catalytic subunit, Snf2h, and an accessory subunit, Acf1 (refs 2, 11-13). We find that ACF senses linker DNA length through an interplay between its accessory and catalytic subunits mediated by the histone H4 tail of the nucleosome. Mutation of AutoN, an auto-inhibitory domain within Snf2h that bears sequence homology to the H4 tail(14), abolishes the linker-length sensitivity in remodelling. Addition of exogenous H4-tail peptide or deletion of the nucleosomal H4 tail also diminishes the linker-length sensitivity. Moreover, Acf1 binds both the H4-tail peptide and DNA in an amino (N)-terminal domain dependent manner, and in the ACF-bound nucleosome, lengthening the linker DNA reduces the Acf1-H4 tail proximity. Deletion of the N-terminal portion of Acf1 (or itshomologue in yeast) abolishes linker-length sensitivity in remodelling and leads to severe growth defects in vivo. Taken together, our results suggest a mechanism for nucleosome spacing where linker DNA sensing by Acf1 is allosterically transmitted to Snf2h through the H4 tail of the nucleosome. For nucleosomes with short linker DNA, Acf1 preferentially binds to the H4 tail, allowing AutoN to inhibit the ATPase activity of Snf2h. As the linker DNA lengthens, Acf1 shifts its binding preference to the linker DNA, freeing the H4 tail to compete Auto N off the ATPase and thereby activating ACF.

关键词： Chromatin remodelling Single-molecule biophysics Single-molecule biophysics Enzyme mechanisms

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Thymidine nucleotide metabolism controls human telomere length (vol 55, pg 568, 2023)

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NATURE GENETICS 2023年第7期55卷 1251-1251页

作者： Mannherz, William Agarwal, Suneet Boston Childrens Hosp Oncol & Stem Cell Program Div Hematol Boston MA 02115 USA Dana Farber Canc Inst Pediat Oncol Boston MA 02215 USA Harvard Med Sch Harvard Stem Cell Inst Harvard Initiat RNA Med Biol & Biomed Sci Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Dept Pediat Boston MA 02115 USA

Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR–Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR–Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.

关键词： Genetic engineering Haematological diseases High-throughput screening Stem-cell research

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Alterations in facial expressions in individuals at risk for psychosis: a facial electromyography approach using emotionally evocative film clips

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PSYCHOLOGICAL MEDICINE 2023年第12期53卷 5829-5838页

作者： Gupta, Tina Osborne, K. Juston Nadig, Ajay Haase, Claudia M. mittal, Vijay A. Univ Pittsburgh Dept Psychiat Pittsburgh PA 15213 USA Northwestern Univ Dept Psychol Evanston IL USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Northwestern Univ Sch Educ & Social Policy Evanston IL USA

Background Negative symptoms such as blunted facial expressivity are characteristic of schizophrenia. However, it is not well-understood if and what abnormalities are present in individuals at clinical high-risk (CHR) for psychosis. Methods This experimental study employed facial electromyography (left zygomaticus major and left corrugator supercilia) in a sample of CHR individuals (N = 34) and healthy controls (N = 32) to detect alterations in facial expressions in response to emotionally evocative film clips and to determine links with symptoms. Results Findings revealed that the CHR group showed facial blunting manifested in reduced zygomatic activity in response to an excitement (but not amusement, fear, or sadness) film clip compared to controls. Reductions in zygomatic activity in the CHR group emerged in response to the emotionally evocative peak period of the excitement film clip. Lower zygomaticus activity during the excitement clip was related to anxiety while lower rates of change in zygomatic activity during the excitement video clip were related to higher psychosis risk conversion scores. Conclusions Together, these findings inform vulnerability/disease driving mechanisms and biomarker and treatment development.

关键词： Clinical high-risk electromyography evocative film clips facial expressions negative symptoms schizophrenia

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Impulsivity and risk-seeking as Bayesian inference under dopaminergic control

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NEUROPSYCHOPHARMACOLOGY 2022年第2期47卷 465-476页

作者： Mikhael, John G. Gershman, Samuel J. Harvard Med Sch Program Neurosci Boston MA 02115 USA Harvard Med Sch MD PhD Program Boston MA 02115 USA Harvard Univ Dept Psychol 33 Kirkland St Cambridge MA 02138 USA Harvard Univ Ctr Brain Sci Cambridge MA 02138 USA MIT Ctr Brains Minds & Machines 77 Massachusetts Ave Cambridge MA 02139 USA

Bayesian models successfully account for several of dopamine (DA)'s effects on contextual calibration in interval timing and reward estimation. In these models, tonic levels of DA control the precision of stimulus encoding, which is weighed against contextual information when making decisions. When DA levels are high, the animal relies more heavily on the (highly precise) stimulus encoding, whereas when DA levels are low, the context affects decisions more strongly. Here, we extend this idea to intertemporal choice and probability discounting tasks. In intertemporal choice tasks, agents must choose between a small reward delivered soon and a large reward delivered later, whereas in probability discounting tasks, agents must choose between a small reward that is always delivered and a large reward that may be omitted with some probability. Beginning with the principle that animals will seek to maximize their reward rates, we show that the Bayesian model predicts a number of curious empirical findings in both tasks. First, the model predicts that higher DA levels should normally promote selection of the larger/later option, which is often taken to imply that DA decreases 'impulsivity,' and promote selection of the large/risky option, often taken to imply that DA increases 'risk-seeking.' However, if the temporal precision is sufficiently decreased, higher DA levels should have the opposite effect-promoting selection of the smaller/sooner option (higher impulsivity) and the small/safe option (lower risk-seeking). Second, high enough levels of DA can result in preference reversals. Third, selectively decreasing the temporal precision, without manipulating DA, should promote selection of the larger/later and large/risky options. Fourth, when a different post-reward delay is associated with each option, animals will not learn the option-delay contingencies, but this learning can be salvaged when the post-reward delays are made more salient. Finally, the Bayesian model pre

关键词： Cognitive neuroscience Reward Medicine/Public Health general Psychiatry Neurosciences Behavioral Sciences Pharmacotherapy Biological Psychology

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Neurosurgery elucidates somatic mutations

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SCIENCE 2023年第6677期382卷 1360-1362页

作者： Maury, Eduardo A. Walsh, Christopher A. Kahle, Kristopher T. Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02142 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA Broad Inst MIT & Harvard Program Neurosci Cambridge MA USA Boston Childrens Hosp Dept Neurosurg Boston MA USA Massachusetts Gen Hosp Dept Neurosurg Boston MA USA

Surgical innovation is helping to identify roles for somatic mutations in brain disorders Somatic variants are genomic alterations present in some cells of the body but not in others. In contrast to inherited germline variants, somatic variants are typically acquired during postzygotic cell divisions or from environmental factors. Somatic variants in a given tissue can also be highly dynamic, such as in the brain, where the number of clonal variants can change during aging and disease (1). Neuro-oncology has greatly benefited from the analyses of somatic mutations in tissue obtained from surgical biopsies or resections. Increased understanding of somatic mutations in brain tumors brought a revolution in prognostication and individualized treatments. Somatic mutations are now increasingly being implicated in neurological disorders beyond cancer, particularly in children with congenital brain and cerebrovascular diseases. Teams of neurosurgeons and scientists are performing gene sequencing on surgical brain samples from these patients- paving the way to expand understanding of nononcologic brain disease through the study of somatic mutations.

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Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014年第38期111卷 13948-13953页

作者： Ghosh, Debadyuti Bagley, Alexander F. Na, Young Jeong Birrer, Michael J. Bhatia, Sangeeta N. Belcher, Angela M. MIT Koch Inst Integrat Canc Res Cambridge MA 02139 USA MIT Dept Mat Sci & Engn Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA MIT Harvard MIT Div Hlth Sci & Technol Cambridge MA 02139 USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA MIT Howard Hughes Med Inst Cambridge MA 02139 USA Harvard Univ Biophys Program Boston MA 02115 USA Harvard Univ Sch Med MD PhD Program Boston MA 02115 USA Harvard Univ Sch Med Massachusetts Gen Hosp Dept Med Boston MA 02114 USA

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery.

关键词： cancer imaging fluorescence-guided surgery M13 bacteriophage

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ISWI Remodelers Slide Nucleosomes with Coordinated Multi-Base-Pair Entry Steps and Single-Base-Pair Exit Steps

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CELL 2013年第3期152卷 442-452页

作者： Deindl, Sebastian Hwang, William L. Hota, Swetansu K. Blosser, Timothy R. Prasad, Punit Bartholomew, Blaine Zhuang, Xiaowei Harvard Univ Howard Hughes Med Inst Cambridge MA 02138 USA Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Harvard Univ Dept Phys Cambridge MA 02138 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA So Illinois Univ Sch Med Dept Biochem & Mol Biol Carbondale IL 62901 USA

ISWI-family enzymes remodel chromatin by sliding nucleosomes along DNA, but the nucleosome translocation mechanism remains unclear. Here we use single-molecule FRET to probe nucleosome translocation by ISWI-family remodelers. Distinct ISWI-family members translocate nucleosomes with a similar stepping pattern maintained by the catalytic subunit of the enzyme. Nucleosome remodeling begins with a 7 bp step of DNA translocation followed by 3 bp subsequent steps toward the exit side of nucleosomes. These multi-bp, compound steps are comprised of 1 bp substeps. DNA movement on the entry side of the nucleosome occurs only after 7 bp of exit-side translocation, and each entry-side step draws in a 3 bp equivalent of DNA that allows three additional base pairs to be moved to the exit side. Our results suggest a remodeling mechanism with well-defined coordination at different nucleosomal sites featuring DNA translocation toward the exit side in 1 bp steps preceding multi-bp steps of DNA movement on the entry side.

关键词： CHROMATIN-remodeling complexes DNA probes TRANSLOCATION (Genetics) ENZYMES BINDING sites (Biochemistry) GENETICS

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Optimisation and evaluation of viral genomic sequencing of SARS-CoV-2 rapid diagnostic tests: a laboratory and cohort-based study

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LANCET MICROBE 2024年第5期5卷 e468-e477页

作者： Paull, Jillian S. Petros, Brittany A. Brock-Fisher, Taylor M. Jalbert, Samantha A. Selser, Victoria M. Messer, Katelyn S. Dobbins, Sabrina T. DeRuff, Katherine C. Deng, Davy Springer, Michael Sabeti, Pardis C. Harvard Med Sch Dept Syst Biol Boston MA USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Div Hlth Sci & Technol Cambridge MA USA MIT Cambridge MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Howard Hughes Med Inst Chevy Chase MD USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Montachusett Publ Hlth Network Fitchburg MA USA Harvard Univ Wyss Inst Biol Inspired Engn Boston MA USA Harvard Univ Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA USA

Background Sequencing of SARS-CoV-2 from rapid diagnostic tests (RDTs) can bolster viral genomic surveillance efforts;however, approaches to maximise and standardise pathogen genome recovery from RDTs remain underdeveloped. We aimed to systematically optimise the elution of genetic material from RDT components and to evaluate the eff i cacy of RDT sequencing for outbreak investigation. Methods In this laboratory and cohort -based study we seeded RDTs with inactivated SARS-CoV-2 to optimise the elution of genomic material from RDT lateral fl ow strips. We measured the effect of changes in buffer type, time in buffer, and rotation on PCR cycle threshold (Ct) value. We recruited individuals older than 18 years residing in the greater Boston area, MA, USA, from July 18 to Nov 5, 2022, via email advertising to students and staff at harvard University, MA, USA, and via broad social media advertising. All individuals recruited were within 5 days of a positive diagnostic test for SARS-CoV-2;no other relevant exclusion criteria were applied. Each individual completed two RDTs and one PCR swab. On Dec 29, 2022, we also collected RDTs from a convenience sample of individuals who were positive for SARS-CoV-2 and associated with an outbreak at a senior housing facility in MA, USA. We extracted all returned PCR swabs and RDT components (ie, swab, strip, or buffer);samples with a Ct of less than 40 were subject to amplicon sequencing. We compared the eff i cacy of elution and sequencing across RDT brands and components and used RDT-derived sequences to infer transmission links within the outbreak at the senior housing facility. We conducted metagenomic sequencing of negative RDTs from symptomatic individuals living in the senior housing facility. Findings Neither elution duration of greater than 10 min nor rotation during elution impacted viral titres. Elution in Buffer AVL (Ct=31 . 4) and Tris-EDTA Buffer (Ct=30 . 8) were equivalent (p=0 . 34);AVL outperformed elution in lysis bu

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