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The size of eukaryotic genomes can vary by several orders of magnitude, yet genome size does not correlate with the number of genes nor with the size or complexity of the organism. Although “whole”-genome sequences, such as those now available for 12 Drosophila species, provide information about euchromatic DNA content, they cannot give an accurate estimate of genome sizes that include heterochromatin or repetitive DNA content. Moreover, genome sequences typically represent only one strain or isolate of a single species that does not reflect intraspecies variation. To more accurately estimate whole-genome DNA content and compare these estimates to newly assembled genomes, we used flow cytometry to measure the 2C genome values, relative to Drosophila melanogaster. We estimated genome sizes for the 12 sequenced Drosophila species as well as 91 different strains of 38 species of Drosophilidae. Significant differences in intra- and interspecific 2C genome values exist within the Drosophilidae. Furthermore, by measuring polyploid 16C ovarian follicle cell underreplication we estimated the amount of satellite DNA in each of these species. We found a strong correlation between genome size and amount of satellite underreplication. Addition and loss of heterochromatin satellite repeat elements appear to have made major contributions to the large differences in genome size observed in the Drosophilidae.
Analysis of Drosophila Species Genome Size and Satellite DNA Content Reveals Significant Differences Among Strains as Well as Between Species
Giovanni Bosco, Paula Campbell, Joao T. Leiva-Neto, Therese A. Markow
Deletions within the mitochondrial DNA (mtDNA) cause Kearns Sayre Syndrome (KSS) and Chronic Progressive External Opthalmoplegia (CPEO). The clinical signs of KSS include muscle weakness, heart block, pigmentary retinopathy, ataxia, deafness, short stature, and dementia. The identical deletions occur and rise exponentially as humans age, particularly in substantia nigra. Deletions at >30% concentration cause deficits in basic bioenergetic parameters, including membrane potential and ATP synthesis, but it is poorly understood how these alterations cause the pathologies observed in patients. To better understand the consequences of mtDNA deletions, we microarrayed 6 cell types containing mtDNA deletions from KSS and CPEO patients. There was a prominent inhibition of transcripts encoding ubiquitin-mediated proteasome activity, and a prominent induction of transcripts involved in the AMP kinase pathway, macroautophagy, and amino acid degradation. In mutant cells, we confirmed a decrease in proteasome biochemical activity, significantly lower concentration of several amino acids, and induction of an autophagic transcript. An interpretation consistent with the data is that mtDNA deletions increase protein damage, inhibit the ubiquitin-proteasome system, decrease amino acid salvage, and activate autophagy. This provides a novel pathophysiological mechanism for these diseases, and suggests potential therapeutic strategies.
Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript
Mansour Alemi, Alessandro Prigione, Alice Wong, Robert Schoenfeld, Salvatore DiMauro, Michio Hirano, Franco Taroni, Gino Cortopassi
2007 Jul 20.
The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.
We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10?6) and a candidate threshold (1.6 × 10?4).
No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99).
We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.
Autoimmune disorder, Complement, Genetic association, Human leukocyte antigen, Major depressive disorder, Major histocompatibility complex
Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression
Kylie P. Glanville, Jonathan R.I. Coleman, Ken B. Hanscombe, Jack Euesden, Shing Wan Choi, Kirstin L. Purves, Gerome Breen, Tracy M. Air, Till F.M. Andlauer, Bernhard T. Baune, Elisabeth B. Binder, Douglas H.R. Blackwood, Dorret I. Boomsma, Henriette N. Buttenschøn, Lucia Colodro-Conde, Udo Dannlowski, Nese Direk, Erin C. Dunn, Andreas J. Forstner, Eco J.C. de Geus, Hans J. Grabe, Steven P. Hamilton, Ian Jones, Lisa A. Jones, James A. Knowles, Zoltan Kutalik, Douglas F. Levinson, Glyn Lewis, Penelope A. Lind, Susanne Lucae, Patrik K. Magnusson, Peter McGuffin, Andrew M. McIntosh, Yuri Milaneschi, Ole Mors, Sara Mostafavi, Bertram Muller-Myhsok, Nancy L. Pedersen, Brenda W.J.H. Penninx, James B. Potash, Martin Preisig, Stephan Ripke, Jianxin Shi, Stanley I. Shyn, Jordan W. Smoller, Fabian Streit, Patrick F. Sullivan, Henning Tiemeier, Rudolf Uher, Sandra Van der Auwera, Myrna M. Weissman, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Paul F. O'Reilly, Cathryn M. Lewis
2020 Mar 1;