Publications by authors named "Torsten Held"

8 Publications

  • Page 1 of 1

Survival of the simplest in microbial evolution.

Nat Commun 2019 06 6;10(1):2472. Epub 2019 Jun 6.

Institut für Biologische Physik, Universität zu Köln, Zülpicherstr. 77, 50937, Köln, Germany.

The evolution of microbial and viral organisms often generates clonal interference, a mode of competition between genetic clades within a population. Here we show how interference impacts systems biology by constraining genetic and phenotypic complexity. Our analysis uses biophysically grounded evolutionary models for molecular phenotypes, such as fold stability and enzymatic activity of genes. We find a generic mode of phenotypic interference that couples the function of individual genes and the population's global evolutionary dynamics. Biological implications of phenotypic interference include rapid collateral system degradation in adaptation experiments and long-term selection against genome complexity: each additional gene carries a cost proportional to the total number of genes. Recombination above a threshold rate can eliminate this cost, which establishes a universal, biophysically grounded scenario for the evolution of sex. In a broader context, our analysis suggests that the systems biology of microbes is strongly intertwined with their mode of evolution.
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http://dx.doi.org/10.1038/s41467-019-10413-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554311PMC
June 2019

Adaptive Evolution of Gene Expression in Drosophila.

Cell Rep 2017 08;20(6):1385-1395

Institut für Theoretische Physik, Universität zu Köln, Zülpicher Str. 77, 50937 Köln, Germany. Electronic address:

Gene expression levels are important quantitative traits that link genotypes to molecular functions and fitness. In Drosophila, population-genetic studies have revealed substantial adaptive evolution at the genomic level, but the evolutionary modes of gene expression remain controversial. Here, we present evidence that adaptation dominates the evolution of gene expression levels in flies. We show that 64% of the observed expression divergence across seven Drosophila species are adaptive changes driven by directional selection. Our results are derived from time-resolved data of gene expression divergence across a family of related species, using a probabilistic inference method for gene-specific selection. Adaptive gene expression is stronger in specific functional classes, including regulation, sensory perception, sexual behavior, and morphology. Moreover, we identify a large group of genes with sex-specific adaptation of expression, which predominantly occurs in males. Our analysis opens an avenue to map system-wide selection on molecular quantitative traits independently of their genetic basis.
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http://dx.doi.org/10.1016/j.celrep.2017.07.033DOI Listing
August 2017

Universality and predictability in molecular quantitative genetics.

Curr Opin Genet Dev 2013 Dec 28;23(6):684-93. Epub 2013 Nov 28.

Joseph-Henri Laboratories of Physics and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, United States.

Molecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus on universal evolutionary characteristics: these are largely independent of a trait's genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology.
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http://dx.doi.org/10.1016/j.gde.2013.11.001DOI Listing
December 2013

Respiratory distress and early neonatal lethality in Hspa4l/Hspa4 double-mutant mice.

Am J Respir Cell Mol Biol 2014 Apr;50(4):817-24

1 Institute of Human Genetics, and.

Heat shock proteins HSPA4L and HSPA4 are closely related members of the HSP110 family and act as cochaperones. We generated Hspa4l(-/-)Hspa4(-/-) mice to investigate a functional complementarity between HSPA4L and HSPA4 during embryonic development. Hspa4l(-/-)Hspa4(-/-) embryos exhibited marked pulmonary hypoplasia and neonatal death. Compared with lungs of wild-type, Hspa4l(-/-), and Hspa4(-/-) embryos, Hspa4l(-/-)Hspa4(-/-) lungs were characterized by diminished saccular spaces and increased mesenchymal septa. Mesenchymal hypercellularity was determined to be due to an increased cell proliferation index and decreased cell death. A significant increase in expression levels of prosurvival protein B cell leukemia/lymphoma 2 may be the cause for inhibition of apoptotic process in lungs of Hspa4(-/-)Hspa4l(-/-) embryos. Accumulation of glycogen and diminished expression of surfactant protein B, prosurfactant protein C, and aquaporin 5 in saccular epithelium suggested impaired maturation of type II and type I pneumocytes in the Hspa4l(-/-)Hspa4(-/-) lungs. Further experiments showed a significant accumulation of ubiquitinated proteins in the lungs of Hspa4l(-/-)Hspa4(-/-) embryos, indicating an impaired chaperone activity. Our study demonstrates that HSPA4L and HSPA4 collaborate in embryonic lung maturation, which is necessary for adaptation to air breathing at birth.
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http://dx.doi.org/10.1165/rcmb.2013-0132OCDOI Listing
April 2014

HDAC1 regulates fear extinction in mice.

J Neurosci 2012 Apr;32(15):5062-73

Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany.

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.
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http://dx.doi.org/10.1523/JNEUROSCI.0079-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622110PMC
April 2012

Heat-shock protein HSPA4 is required for progression of spermatogenesis.

Reproduction 2011 Jul 12;142(1):133-44. Epub 2011 Apr 12.

Institute of Human Genetics, University of Göttingen, Göttingen, Germany.

Heat-shock protein 110 (HSP110) family members act as nucleotide exchange factors (NEF) of mammalian and yeast HSP70 chaperones during the ATP hydrolysis cycle. In this study, we describe the expression pattern of murine HSPA4, a member of the HSP110 family, during testis development and the consequence of HSPA4 deficiency on male fertility. HSPA4 is ubiquitously expressed in all the examined tissues. During prenatal and postnatal development of gonad, HSPA4 is expressed in both somatic and germ cells; however, expression was much higher in germ cells of prenatal gonads. Analyses of Hspa4-deficient mice revealed that all homozygous mice on the hybrid C57BL/6J×129/Sv genetic background were apparently healthy. Although HSPA4 is expressed as early as E13.5 in male gonad, a lack of histological differences between Hspa4(-/-) and control littermates suggests that Hspa4 deficiency does not impair the gonocytes or their development to spermatogonia. Remarkably, an increased number of the Hspa4-deficient males displayed impaired fertility, whereas females were fertile. The total number of spermatozoa and their motility were drastically reduced in infertile Hspa4-deficient mice compared with wild-type littermates. The majority of pachytene spermatocytes in the juvenile Hspa4(-/-) mice failed to complete the first meiotic prophase and became apoptotic. Furthermore, down-regulation of transcription levels of genes known to be expressed in spermatocytes at late stages of prophase I and post-meiotic spermatids leads to suggest that the development of most spermatogenic cells is arrested at late stages of meiotic prophase I. These results provide evidence that HSPA4 is required for normal spermatogenesis.
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http://dx.doi.org/10.1530/REP-11-0023DOI Listing
July 2011

Fas-associated factor (FAF1) is required for the early cleavage-stages of mouse embryo.

Mol Hum Reprod 2008 Apr 26;14(4):207-13. Epub 2008 Feb 26.

Institute of Human Genetics, Faculty of Medicine, University of Göttingen, 37073 Göttingen, Germany.

FAF1 was initially isolated as a Fas-associated factor and was subsequently found to interact with a subset of additional proteins that are involved in many cellular events including Fas-mediated apoptosis, heat shock signalling pathways and ubiquitin-dependent processes. Here, we describe that the 74-kDa FAF1 is ubiquitously expressed, while the expression of its post-translational-processed 49-kDa isoform is restricted to post-meiotic male germ cells. In ovary, FAF1 protein is localized predominantly in the cytoplasm of oocytes in all follicle stages. To determine the function of FAF1 in vivo, we analysed a mouse mutant line in which a gene trap vector was inserted in the Faf1 locus. The mutation disrupts the Faf1 and leads to lethality of the Faf1(GT/GT) embryos near the 2-cell stage. Analysis of FAF1 expression revealed that the protein is present in early preimplantation stages, while embryonic expression of Faf1 mRNA becomes appreciable at 4-cell stage. These results indicate that the death of Faf1(GT/GT) at the 2-cell stage may coincide with the depletion of maternal FAF1 in these embryos. Thus, our results indicate that the FAF1 gene product is necessary for early embryonic development.
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http://dx.doi.org/10.1093/molehr/gan009DOI Listing
April 2008

Hspa4l-deficient mice display increased incidence of male infertility and hydronephrosis development.

Mol Cell Biol 2006 Nov 21;26(21):8099-108. Epub 2006 Aug 21.

Institute of Human Genetics, University of Göttingen, Germany.

The Hspa4l gene, also known as Apg1 or Osp94, belongs to the HSP110 heat shock gene family, which includes three genes encoding highly conserved proteins. This study shows that Hspa4l is expressed ubiquitously and predominantly in the testis. The protein is highly expressed in spermatogenic cells, from late pachytene spermatocytes to postmeiotic spermatids. In the kidney, the protein is restricted to cortical segments of distal tubules. To study the physiological role of this gene in vivo, we generated mice deficient in Hspa4l by gene targeting. Hspa4l-deficient mice were born at expected ratios and appeared healthy. However, approximately 42% of Hspa4l(-/-) male mice suffered from fertility defects. Whereas the seminiferous tubules of Hspa4l(-/-) testes contained all stages of germ cells, the number of mature sperm in the epididymis and sperm motility were drastically reduced. The reduction of the sperm count was due to the elimination of a significant number of developing germ cells via apoptosis. No defects in fertility were observed in female mutants. In addition, 12% of null mutant mice developed hydronephrosis. Concentrations of plasma and urine electrolytes in Hspa4l(-/-) mice were similar to wild-type values, suggesting that the renal function was not impaired. However, Hspa4l(-/-) animals were preferentially susceptible to osmotic stress. These results provide evidence that Hspa4l is required for normal spermatogenesis and suggest that Hspa4l plays a role in osmotolerance.
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http://dx.doi.org/10.1128/MCB.01332-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636758PMC
November 2006