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Fulltext AarF Domain Containing Kinase 3 (ADCK3) Mutant Cells Display Signs of Oxidative Stress, Defects in Mitochondrial Homeostasis and Lysosomal Accumulation

Cullen JK, Abdul Murad N, Yeo A, McKenzie M, Ward M, Chong KL, et al.

PLoS One, 2016;11(2):e0148213.
PMID: 26866375 DOI: 10.1371/journal.pone.0148213

Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients.
Fulltext The cultivation regimes of Morchella sextelata trigger shifts in the community assemblage and ecological traits of soil bacteria

Zhang Y, Zhao Q, Uroz S, Gao T, Li J, He F, et al.

Front Microbiol, 2023;14:1257905.
PMID: 37808313 DOI: 10.3389/fmicb.2023.1257905

The successful large-scale cultivation of morel mushrooms (Morchella sextelata) requires a comprehensive understanding of the soil bacterial communities associated with morel-farming beds, as the interactions between fungi and bacteria play a crucial role in shaping the soil microbiome. In this study, we investigated the temporal distribution and ecological characteristics of soil bacteria associated with morel fruiting bodies at different stages, specifically the conidial and primordial stages, under two cropping regimes, non-continuous cropping (NCC) and continuous cropping (CC). Our findings revealed a significant reduction in the yield of morel primordia during the third year following 2 years of CC (0.29 ± 0.25 primordia/grid), in comparison to the NCC regime (12.39 ± 6.09 primordia/grid). Furthermore, inoculation with morel mycelia had a notable impact on soil bacterial diversity, decreasing it in the NCC regime and increasing the number of generalist bacterial members in the CC regime. The latter regime also led to the accumulation of nutrients in the soil beds, resulting in a shift from a stochastic to a deterministic process in the composition of the bacterial community, which differed from the NCC regime. Additionally, mycelial inoculation had a positive effect on the abundance of potential copiotrophic/denitrifying and N-fixing bacteria while decreasing the abundance of oligotrophic/nitrifying bacteria. Interestingly, this effect was more pronounced in the NCC regime than in the CC regime. These results suggest that the increase in potential copiotrophic/denitrifying and N-fixing bacteria facilitated the decomposition of nutrients in exogenous nutrient bags by morel mushrooms, thereby maintaining nitrogen balance in the soil. Overall, our study provides valuable insights into the interactions between morel mycelia and the associated soil bacteriome as well as the influence of different cultivation regimes on these interactions. These findings contribute to our understanding of the complex dynamics of the soil microbiome and can inform strategies for optimizing morel mushroom cultivation.
Fulltext Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Ma A, Yousoof S, Grigg JR, Flaherty M, Minoche AE, Cowley MJ, et al.

Genet Med, 2020 10;22(10):1623-1632.
PMID: 32499604 DOI: 10.1038/s41436-020-0854-x

PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion.
METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases.
RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6.
CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.
Fulltext Towards complete and error-free genome assemblies of all vertebrate species

Rhie A, McCarthy SA, Fedrigo O, Damas J, Formenti G, Koren S, et al.

Nature, 2021 Apr;592(7856):737-746.
PMID: 33911273 DOI: 10.1038/s41586-021-03451-0

High-quality and complete reference genome assemblies are fundamental for the application of genomics to biology, disease, and biodiversity conservation. However, such assemblies are available for only a few non-microbial species1-4. To address this issue, the international Genome 10K (G10K) consortium5,6 has worked over a five-year period to evaluate and develop cost-effective methods for assembling highly accurate and nearly complete reference genomes. Here we present lessons learned from generating assemblies for 16 species that represent six major vertebrate lineages. We confirm that long-read sequencing technologies are essential for maximizing genome quality, and that unresolved complex repeats and haplotype heterozygosity are major sources of assembly error when not handled correctly. Our assemblies correct substantial errors, add missing sequence in some of the best historical reference genomes, and reveal biological discoveries. These include the identification of many false gene duplications, increases in gene sizes, chromosome rearrangements that are specific to lineages, a repeated independent chromosome breakpoint in bat genomes, and a canonical GC-rich pattern in protein-coding genes and their regulatory regions. Adopting these lessons, we have embarked on the Vertebrate Genomes Project (VGP), an international effort to generate high-quality, complete reference genomes for all of the roughly 70,000 extant vertebrate species and to help to enable a new era of discovery across the life sciences.