Modelling mitochondrial site polymorphisms to infer the number of segregating units and mutation rate

We present a mathematical model of mitochondrial inheritance evolving under neutral evolution to interpret the heteroplasmies observed at some sites. A comparison of the levels of heteroplasmies transmitted from mother to her offspring allows us to estimate the number Nx of inherited mitochondrial genomes (segregating units). The model demonstrates the necessity of accounting for both the multiplicity of an unknown number Nx, and the threshold θ, below which heteroplasmy cannot be detected reliably, in order to estimate the mitochondrial mutation rate μm in the maternal line of descent. Our model is applicable to pedigree studies of any eukaryotic species where site heteroplasmies are observed in regions of the mitochondria, provided neutrality can be assumed. The model is illustrated with an analysis of site heteroplasmies in the first hypervariable region of mitochondrial sequence data sampled from Adélie penguin families, providing an estimate Nx and μm. This estimate of μm was found to be consistent with earlier estimates from ancient DNA analysis

The Local Bubble and Interstellar Material Near the Sun

The properties of interstellar matter (ISM) at the Sun are regulated by our location with respect to the Local Bubble (LB) void in the ISM. The LB is bounded by associations of massive stars and fossil supernovae that have disrupted natal ISM and driven intermediate velocity ISM into the LB interior void. The Sun is located in such a driven ISM parcel. The Local Fluff has a bulk velocity of 19 km/s in the LSR, and an upwind direction towards the center of the gas and dust ring formed by the Loop I supernova remnant interaction with the LB. When the ram pressure of the LIC is included in the total LIC pressure, and if magnetic thermal and cosmic ray pressures are similar, the LIC appears to be in pressure equilibrium with the local hot bubble plasma.Comment: Proceedings of Symposium on the Composition of Matter, honoring Johannes Geiss on the occasion of his 80th birthday. Space Science Reviews (in press

HI in the Outskirts of Nearby Galaxies

The HI in disk galaxies frequently extends beyond the optical image, and can trace the dark matter there. I briefly highlight the history of high spatial resolution HI imaging, the contribution it made to the dark matter problem, and the current tension between several dynamical methods to break the disk-halo degeneracy. I then turn to the flaring problem, which could in principle probe the shape of the dark halo. Instead, however, a lot of attention is now devoted to understanding the role of gas accretion via galactic fountains. The current $\rm \Lambda$ cold dark matter theory has problems on galactic scales, such as the core-cusp problem, which can be addressed with HI observations of dwarf galaxies. For a similar range in rotation velocities, galaxies of type Sd have thin disks, while those of type Im are much thicker. After a few comments on modified Newtonian dynamics and on irregular galaxies, I close with statistics on the HI extent of galaxies.Comment: 38 pages, 17 figures, invited review, book chapter in "Outskirts of Galaxies", Eds. J. H. Knapen, J. C. Lee and A. Gil de Paz, Astrophysics and Space Science Library, Springer, in pres

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease