The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

morton_2023_oi_221502_1674145740.31597.pdf

   Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD) but medical and sociodemographic factors explain only one third of variance in outcome.  Objective: To determine whether predicted damaging de novo variants (dDNV) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD. A post-hoc aim sought to determine whether some dDNV or rare predicted loss-of-function (pLOF) variants in specific gene categories are associated with outcomes.  Design: Prospective observational study from September 2017-June 2020.  Setting: Multicenter Participants: Participants were drawn from the Pediatric Cardiac Genomics Consortium (n=197) or Single Ventricle Reconstruction trial (n=24). Inclusion criteria were CHD, ≥ age 8 years, and available exome sequencing data. Individuals with pathogenic variants in known CHD- or neurodevelopmental-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. All 221 participants were included in post-hoc analyses, and 219 in case/control analysis.  Exposure: Participants were heterozygous for (cases) or lacked (controls) predicted dDNV in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNV or pLOF variants in four gene categories: chromatin-modifying, constrained, high-brain-expressed, and neurodevelopmental risk.  Main Outcomes and Measures: Neurodevelopmental and brain MRI metrics.  Results: Participants were median 15.0 years, interquartile range [IQR] 10.0-21.2; 50% (110/219) were male. Case and control participants had similar outcomes. dDNV/pLOF variants in chromatin-modifying genes were associated with worse verbal comprehension (n=16 vs. 200 participants, mean±SD: 91.4±20.4 vs. 103.4±17.8, p=0.01), social responsiveness (n=15 vs. 183, 57.3±17.2 vs. 49.4±11.2, p=0.03), and working memory (n=5 vs. 87, 73.8±16.4 vs. 97.3±15.7, p=0.03), as well as higher likelihood of autism spectrum disorder (4/14 vs. 8/153, 28.6% vs. 5.2%, p = 0.01). dDNV/pLOF variants in constrained genes were associated with impaired memory (immediated story memory: n=95 vs. 122, 9.7±3.7 vs. 10.7±3.0, p=0.03; immediate picture memory: n= 93 vs 116, 7.8±3.1 vs. 9.0±2.9, p=0.01). Adults with dDNV/pLOF variants in high-brain-expressed genes had greater hyperactivity symptoms (n=42 vs 33, 55.5±15.4 vs. 46.6±12.3, p=0.01).  Conclusions and Relevance: Neurodevelopmental outcomes are not associated with dDNV as a group, but may be worse in those with dDNV/pLOF variants in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific variants to brain function and structure.</p