Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders

Translation Levels Control Multi-Spanning Membrane Protein Expression

Attempts to express eukaryotic multi-spanning membrane proteins at high-levels have been generally unsuccessful. In order to investigate the cause of this limitation and gain insight into the rate limiting processes involved, we have analyzed the effect of translation levels on the expression of several human membrane proteins in Escherichia coli (E. coli). These results demonstrate that excessive translation initiation rates of membrane proteins cause a block in protein synthesis and ultimately prevent the high-level accumulation of these proteins. Moderate translation rates allow coupling of peptide synthesis and membrane targeting, resulting in a significant increase in protein expression and accumulation over time. The current study evaluates four membrane proteins, CD20 (4-transmembrane (TM) helixes), the G-protein coupled receptors (GPCRs, 7-TMs) RA1c and EG-VEGFR1, and Patched 1 (12-TMs), and demonstrates the critical role of translation initiation rates in the targeting, insertion and folding of integral membrane proteins in the E. coli membrane

Does heating stimulate germination in Leptospermum scoparium (mānuka; Myrtaceae)?

Fire regimes are powerful selective filters. In New Zealand, fire activity was rare before human settlement, and New Zealand’s indigenous woody flora shows little adaptation to frequent fire. One of the few woody indigenous species to show adaptation to frequent fire is Leptospermum scoparium (Myrtaceae), a Plio-Pleistocene immigrant from Australia. Leptospermum scoparium is a widespread early-successional shrub to small tree that frequently dominates post-fire successions, and shows geographically-variable pyriscent serotiny, a fire-adaptation in which seeds are retained in the canopy and open post-fire. Another widespread reproductive adaptation to fire is heat-stimulated germination. Some Australian Leptospermum respond positively to heat treatment, and observations in New Zealand suggest that the seeds of L. scoparium within thick-walled capsules open immediately after fire and successfully germinate, indicating at least no deleterious effect of heating. In some fire-prone systems such as Mediterranean shrublands, traits such as serotiny and heat-stimulated germination have been positively associated with traits associated with flammability (e.g. retention of dead fuel). Here we evaluate the effect of heat stimulation (short exposure to high temperatures) of capsules on germination in L. scoparium from New Zealand, and evaluate links between germination, serotiny and shoot-level flammability. Germination trials using seed collected from 12 populations indicated no consistent positive or negative effect of heat treatment on germination success (germinability). These trials suggest that the capsules of L. scoparium at least provide adequate insulation to heating. Germinability was not consistently related to either serotiny or flammability; nor was it related to latitude or elevation. While taxa from other fire-prone ecosystems may show coordinated trait responses to fire, the lack of association between physical measures of flammability and germination rates indicate that this is not the case in L. scoparium, New Zealand’s most fire-adapted indigenous woody species

Exploring fire adaptation in a land with little fire: Serotiny in Leptospermum scoparium (Myrtaceae)

Aim: Immigrant floras often have distinctive traits, well suited to the host region but absent from the autochthonous flora. An example is serotiny in the New Zealand (NZ) small tree, Leptospermum scoparium (Myrtaceae) belonging to a strongly fire-adapted Australian clade. Serotiny in L. scoparium has been attributed either to strong selection by fire since human settlement, or taken as evidence that prehistoric fire in NZ was more important than assumed. By integrating field-data, experimental analyses and long-term fire histories we sought to explain the spatial pattern of serotiny in L. scoparium in NZ, and evaluate these two explanations. Location: New Zealand. Methods: We quantified the distribution of serotiny in L. scoparium by analysing 137 populations distributed across NZ (two previous studies and ours), including 31 with Holocene fire histories. We assessed the relationship of serotiny with a suite of fire and climate environmental predictors, and between serotiny and shoot-level flammability. Results: Serotiny was strongly positively associated with latitude (more in the north), lower rainfall and higher temperatures. Serotinous populations were rare at sites with no history of fire. Serotiny was most prevalent in northern wetlands, where fire was recurrent during the Holocene, but was nearly absent from the southwestern Southern Alps. Shoot-level flammability and serotiny were not correlated. Main conclusions: The distribution of serotiny in L. scoparium relates not only to current environments, but also to the legacy of regional shifts in vegetation during Quaternary glacial-interglacial cycles. Serotiny was maintained where the landscape experienced sporadic fire, but it is absent from NZ’s southern South Island because the sparse, open vegetation during the glacials did not support fire. Serotinous L. scoparium populations were therefore more common in the northern North Island. Human transformation of the fire regime over the last 750 years has likely favoured the spread of serotinous populations.This work was supported by Core Funding for Crown Research Institutes, from the New Zealand Ministry of Business, Innovation and Employment's Science and Innovation Group. T.J.C. was supported by Lincoln University Research Fund and Lincoln University Early Career Researcher awards

Fiery Cores: Bursty and Smooth Star Formation Distributions across Galaxy Centers in Cosmological Zoom-in Simulations

We present an analysis of the R less than or similar to 1.5 kpc core regions of seven simulated Milky Way-mass galaxies, from the FIRE-2 (Feedback in Realistic Environments) cosmological zoom-in simulation suite, for a finely sampled period (Delta t = 2.2 Myr) of 22 Myr at z 0, and compare them with star formation rate (SFR) and gas surface density observations of the Milky Way's Central Molecular Zone (CMZ). Despite not being tuned to reproduce the detailed structure of the CMZ, we find that four of these galaxies are consistent with CMZ observations at some point during this 22 Myr period. The galaxies presented here are not homogeneous in their central structures, roughly dividing into two morphological classes; (a) several of the galaxies have very asymmetric gas and SFR distributions, with intense (compact) starbursts occurring over a period of roughly 10 Myr, and structures on highly eccentric orbits through the CMZ, whereas (b) others have smoother gas and SFR distributions, with only slowly varying SFRs over the period analyzed. In class (a) centers, the orbital motion of gas and star-forming complexes across small apertures (R less than or similar to 150 pc, analogously divide l divide < 1 degrees in the CMZ observations) contributes as much to tracers of star formation/dense gas appearing in those apertures, as the internal evolution of those structures does. These asymmetric/bursty galactic centers can simultaneously match CMZ gas and SFR observations, demonstrating that time-varying star formation can explain the CMZ's low star formation efficiency

Fiery Cores: Bursty and Smooth Star Formation Distributions across Galaxy Centers in Cosmological Zoom-in Simulations

We present an analysis of the R ≲ 1.5 kpc core regions of seven simulated Milky Way-mass galaxies, from the FIRE-2 (Feedback in Realistic Environments) cosmological zoom-in simulation suite, for a finely sampled period (Δt = 2.2 Myr) of 22 Myr at z ≈ 0, and compare them with star formation rate (SFR) and gas surface density observations of the Milky Way's Central Molecular Zone (CMZ). Despite not being tuned to reproduce the detailed structure of the CMZ, we find that four of these galaxies are consistent with CMZ observations at some point during this 22 Myr period. The galaxies presented here are not homogeneous in their central structures, roughly dividing into two morphological classes; (a) several of the galaxies have very asymmetric gas and SFR distributions, with intense (compact) starbursts occurring over a period of roughly 10 Myr, and structures on highly eccentric orbits through the CMZ, whereas (b) others have smoother gas and SFR distributions, with only slowly varying SFRs over the period analyzed. In class (a) centers, the orbital motion of gas and star-forming complexes across small apertures (R ≲ 150 pc, analogously |l| < 1° in the CMZ observations) contributes as much to tracers of star formation/dense gas appearing in those apertures, as the internal evolution of those structures does. These asymmetric/bursty galactic centers can simultaneously match CMZ gas and SFR observations, demonstrating that time-varying star formation can explain the CMZ's low star formation efficiency

Quantitative comparison of catalytic mechanisms and overall reactions in convergently evolved enzymes : implications for classification of enzyme function

The authors thank the National Institutes of Health (NIH R01 GM60595 to PCB) and the Scottish Universities Life Sciences Alliance (SULSA to JBOM) for funding.Functionally analogous enzymes are those that catalyze similar reactions on similar substrates but do not share common ancestry, providing a window on the different structural strategies nature has used to evolve required catalysts. Identification and use of this information to improve reaction classification and computational annotation of enzymes newly discovered in the genome projects would benefit from systematic determination of reaction similarities. Here, we quantified similarity in bond changes for overall reactions and catalytic mechanisms for 95 pairs of functionally analogous enzymes (non-homologous enzymes with identical first three numbers of their EC codes) from the MACiE database. Similarity of overall reactions was computed by comparing the sets of bond changes in the transformations from substrates to products. For similarity of mechanisms, sets of bond changes occurring in each mechanistic step were compared; these similarities were then used to guide global and local alignments of mechanistic steps. Using this metric, only 44% of pairs of functionally analogous enzymes in the dataset had significantly similar overall reactions. For these enzymes, convergence to the same mechanism occurred in 33% of cases, with most pairs having at least one identical mechanistic step. Using our metric, overall reaction similarity serves as an upper bound for mechanistic similarity in functional analogs. For example, the four carbon-oxygen lyases acting on phosphates (EC 4.2.3) show neither significant overall reaction similarity nor significant mechanistic similarity. By contrast, the three carboxylic-ester hydrolases (EC 3.1.1) catalyze overall reactions with identical bond changes and have converged to almost identical mechanisms. The large proportion of enzyme pairs that do not show significant overall reaction similarity (56%) suggests that at least for the functionally analogous enzymes studied here, more stringent criteria could be used to refine definitions of EC sub-subclasses for improved discrimination in their classification of enzyme reactions. The results also indicate that mechanistic convergence of reaction steps is widespread, suggesting that quantitative measurement of mechanistic similarity can inform approaches for functional annotation.Publisher PDFPeer reviewe