A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Platypus globin genes and flanking loci suggest a new insertional model for beta-globin evolution in birds and mammals

Background: Vertebrate alpha (a)- and beta (ß)-globin gene families exemplify the way in which genomes evolve to produce functional complexity. From tandem duplication of a single globin locus, the a- and ß-globin clusters expanded, and then were separated onto different chromosomes. The previous finding of a fossil ß-globin gene (?) in the marsupial a-cluster, however, suggested that duplication of the a-ß cluster onto two chromosomes, followed by lineage-specific gene loss and duplication, produced paralogous a- and ß-globin clusters in birds and mammals. Here we analyse genomic data from an egg-laying monotreme mammal, the platypus (Ornithorhynchus anatinus), to explore haemoglobin evolution at the stem of the mammalian radiation. Results: The platypus a-globin cluster (chromosome 21) contains embryonic and adult a- globin genes, a ß-like ?-globin gene, and the GBY globin gene with homology to cytoglobin, arranged as 5'-?-?'-aD-a3-a2-a1-?-GBY-3'. The platypus ß-globin cluster (chromosome 2) contains single embryonic and adult globin genes arranged as 5'-e-ß-3'. Surprisingly, all of these globin genes were expressed in some adult tissues. Comparison of flanking sequences revealed that all jawed vertebrate a-globin clusters are flanked by MPG-C16orf35 and LUC7L, whereas all bird and mammal ß-globin clusters are embedded in olfactory genes. Thus, the mammalian a- and ß-globin clusters are orthologous to the bird a-and ß-globin clusters respectively. Conclusion: We propose that a- and ß-globin clusters evolved from an ancient MPG-C16orf35-a-ß-GBY-LUC7L arrangement 410 million years ago. A copy of the original ß (represented by ? in marsupials and monotremes) was inserted into an array of olfactory genes before the amniote radiation (>315 million years ago), then duplicated and diverged to form orthologous clusters of ß-globin genes with different expression profiles in different lineages

Toward Sequencing the Sorghum Genome: A U.S. National Science Foundation-Sponsored Workshop Report

Members of the worldwide sorghum (Sorghum spp.) community, including private sector and international scientists as well as community representatives from closely related crops such as sugarcane (Saccharum spp.) and maize (Zea mays), met in St. Louis, Missouri, on November 9, 2004, to lay the groundwork for future advances in sorghum genomics and, in particular, to coordinate plans for sequencing of the sorghum genome. Key developments that made this workshop timely included advances in knowledge of the sorghum genome that provide for the development of a genetically anchored physical map to guide sequence assembly and annotation, the growing role of the sorghum genome as a nucleation point for comparative genomics of diverse tropical grasses including many leading crops, and the need for dramatically increased sorghum production to sustain human populations in many regions where its inherent abiotic stress tolerance makes it an essential staple. This report reviews current knowledge of the sorghum genome, a community-endorsed schema for integrating this knowledge into a finished sequence, and early plans for translating the sequence into sustained advances to benefit a worldwide group of stakeholders

The TESS-Keck Survey: Science Goals and Target Selection

The Kepler and TESS missions have demonstrated that planets are ubiquitous. However, the success of these missions heavily depends on ground-based radial velocity (RV) surveys, which combined with transit photometry can yield bulk densities and orbital properties. While most Kepler host stars are too faint for detailed follow-up observations, TESS is detecting planets orbiting nearby bright stars that are more amenable to RV characterization. Here, we introduce the TESS-Keck Survey (TKS), an RV program using ∼100 nights on Keck/HIRES to study exoplanets identified by TESS. The primary survey aims are investigating the link between stellar properties and the compositions of small planets; studying how the diversity of system architectures depends on dynamical configurations or planet multiplicity; identifying prime candidates for atmospheric studies with JWST; and understanding the role of stellar evolution in shaping planetary systems. We present a fully automated target selection algorithm, which yielded 103 planets in 86 systems for the final TKS sample. Most TKS hosts are inactive, solar-like, main-sequence stars (4500 K ≤ Teff <6000 K) at a wide range of metallicities. The selected TKS sample contains 71 small planets (Rp ≤ 4 R⊕), 11 systems with multiple transiting candidates, six sub-day-period planets and three planets that are in or near the habitable zone (Sinc ≤ 10 S⊕) of their host star. The target selection described here will facilitate the comparison of measured planet masses, densities, and eccentricities to predictions from planet population models. Our target selection software is publicly available and can be adapted for any survey that requires a balance of multiple science interests within a given telescope allocation

A second planet transiting LTT 1445A and a determination of the masses of both worlds

K.H. acknowledges support from STFC grant ST/R000824/1.LTT 1445 is a hierarchical triple M-dwarf star system located at a distance of 6.86 pc. The primary star LTT 1445A (0.257 M⊙) is known to host the transiting planet LTT 1445Ab with an orbital period of 5.36 days, making it the second-closest known transiting exoplanet system, and the closest one for which the host is an M dwarf. Using Transiting Exoplanet Survey Satellite data, we present the discovery of a second planet in the LTT 1445 system, with an orbital period of 3.12 days. We combine radial-velocity measurements obtained from the five spectrographs, Echelle Spectrograph for Rocky Exoplanets and Stable Spectroscopic Observations, High Accuracy Radial Velocity Planet Searcher, High-Resolution Echelle Spectrometer, MAROON-X, and Planet Finder Spectrograph to establish that the new world also orbits LTT 1445A. We determine the mass and radius of LTT 1445Ab to be 2.87 ± 0.25 M⊕ and 1.304-0.060+0.067 R⊕, consistent with an Earth-like composition. For the newly discovered LTT 1445Ac, we measure a mass of 1.54-0.19+0.20 M⊕ and a minimum radius of 1.15 R⊕, but we cannot determine the radius directly as the signal-to-noise ratio of our light curve permits both grazing and nongrazing configurations. Using MEarth photometry and ground-based spectroscopy, we establish that star C (0.161 M⊙) is likely the source of the 1.4 day rotation period, and star B (0.215 M⊙) has a likely rotation period of 6.7 days. We estimate a probable rotation period of 85 days for LTT 1445A. Thus, this triple M-dwarf system appears to be in a special evolutionary stage where the most massive M dwarf has spun down, the intermediate mass M dwarf is in the process of spinning down, while the least massive stellar component has not yet begun to spin down.Publisher PDFPeer reviewe

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

AbstractAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele