scholarly journals Transcriptional and mutational signatures of the aging germline

2021 ◽  
Author(s):  
Evan Witt ◽  
Christopher B Langer ◽  
Li Zhao
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Cell Types ◽  
Mutational Load ◽  
De Novo Mutations ◽  
Genome Maintenance ◽  
Mutational Signatures ◽  
Evolutionary Innovation ◽  
Complex Biological Process ◽  
Older Males

Aging is a complex biological process which is accompanied by changes in gene expression and mutational load. In many species including humans, old fathers pass on more paternally-derived de novo mutations, however, the cellular basis and cell types driving this pattern are still unclear. To understand the root causes of this phenomenon, we performed single-cell RNA-sequencing (scRNA-seq) on testes from young and old male Drosophila, as well as genomic sequencing (DNA-seq) on somatic tissue from the same flies. We found that early germ cells from old and young flies have similar mutational loads, but older flies are less able to remove mutations during spermatogenesis. This indicates that germline mutations arise from primarily non-replicative factors, and that the increased mutational load of older males is due to differences in genome maintenance activities such as repairs to DNA damage. We also found that T>A mutations are enriched in older flies, and transcription-related enrichment terms are depleted in older males. Early spermatogenesis-enriched genes have lower dN/dS than late spermatogenesis-enriched genes, supporting the hypothesis that late spermatogenesis is the source of evolutionary innovation. This transcriptional disruption is reflected in the decreased expression of genome maintenance genes in early germ cells of older flies, as well as potentially aberrant transcription of transposable elements in the aging germline. Our results provide novel insights into the transcriptional and mutational signatures of the male germline.

scholarly journals Guide Cells Support Muscle Regeneration and Affect Neuro-Muscular Junction Organization

2021 ◽  
Vol 22 (4) ◽  
pp. 1939
Author(s):  
Flavio L. Ronzoni ◽  
Nefele Giarratana ◽  
Stefania Crippa ◽  
Mattia Quattrocelli ◽  
Marco Cassano ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Muscle Injury ◽  
De Novo ◽  
Neuromuscular Junctions ◽  
Myogenic Differentiation ◽  
Cell Types ◽  
Acute Injury ◽  
Complex Biological Process ◽  
Junction Formation

Muscular regeneration is a complex biological process that occurs during acute injury and chronic degeneration, implicating several cell types. One of the earliest events of muscle regeneration is the inflammatory response, followed by the activation and differentiation of muscle progenitor cells. However, the process of novel neuromuscular junction formation during muscle regeneration is still largely unexplored. Here, we identify by single-cell RNA sequencing and isolate a subset of vessel-associated cells able to improve myogenic differentiation. We termed them ‘guide’ cells because of their remarkable ability to improve myogenesis without fusing with the newly formed fibers. In vitro, these cells showed a marked mobility and ability to contact the forming myotubes. We found that these cells are characterized by CD44 and CD34 surface markers and the expression of Ng2 and Ncam2. In addition, in a murine model of acute muscle injury and regeneration, injection of guide cells correlated with increased numbers of newly formed neuromuscular junctions. Thus, we propose that guide cells modulate de novo generation of neuromuscular junctions in regenerating myofibers. Further studies are necessary to investigate the origin of those cells and the extent to which they are required for terminal specification of regenerating myofibers.

scholarly journals Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

2021 ◽  
Vol 134 (13) ◽  
Author(s):  
Priyanka Sandal ◽  
Chian Ju Jong ◽  
Ronald A. Merrill ◽  
Jianing Song ◽  
Stefan Strack
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Phosphatase ◽  
Mammalian Cells ◽  
Large Scale ◽  
De Novo ◽  
Protein Phosphatase 2A ◽  
Cell Types ◽  
De Novo Mutations ◽  
Sequencing Studies ◽  
Phosphatase 2A

ABSTRACT Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits. PP2A can exist in nearly 100 different subunit combinations in mammalian cells, dictating distinct localizations, substrates and regulatory mechanisms. PP2A is well established as a regulator of cell division, growth, and differentiation, and the roles of PP2A in cancer and various neurodegenerative disorders, such as Alzheimer's disease, have been reviewed in detail. This Review summarizes and discusses recent reports on NDDs associated with mutations of PP2A subunits and PP2A-associated proteins. We also discuss the potential impact of these mutations on the structure and function of the PP2A holoenzymes and the etiology of NDDs.

scholarly journals Testis single-cell RNA-seq reveals the dynamics of de novo gene transcription and germline mutational bias in Drosophila

2019 ◽  
Author(s):  
Evan Witt ◽  
Sigi Benjamin ◽  
Nicolas Svetec ◽  
Li Zhao
Keyword(s):  
Single Cell ◽  
De Novo ◽  
Gene Evolution ◽  
Expression Patterns ◽  
Reproductive Function ◽  
Cell Types ◽  
Mutational Bias ◽  
Evolutionary Innovation ◽  
New Genes ◽  
De Novo Gene

SummaryThe testis is a peculiar tissue in many respects. It shows patterns of rapid gene evolution and provides a hotspot for the origination of genetic novelties such as de novo genes, duplications and mutations. To investigate the expression patterns of genetic novelties across cell types, we performed single-cell RNA-sequencing of adult Drosophila testis. We found that new genes were expressed in various cell types, the patterns of which may be influenced by their mode of origination. In particular, lineage-specific de novo genes are commonly expressed in early spermatocytes, while young duplicated genes are often bimodally expressed. Analysis of germline substitutions suggests that spermatogenesis is a highly reparative process, with the mutational load of germ cells decreasing as spermatogenesis progresses. By elucidating the distribution of genetic novelties across spermatogenesis, this study provides a deeper understanding of how the testis maintains its core reproductive function while being a hotbed of evolutionary innovation.

scholarly journals Testis single-cell RNA-seq reveals the dynamics of de novo gene transcription and germline mutational bias in Drosophila

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Evan Witt ◽  
Sigi Benjamin ◽  
Nicolas Svetec ◽  
Li Zhao
Keyword(s):  
Single Cell ◽  
De Novo ◽  
Gene Evolution ◽  
Expression Patterns ◽  
Reproductive Function ◽  
Cell Types ◽  
Mutational Bias ◽  
Evolutionary Innovation ◽  
New Genes ◽  
De Novo Genes

The testis is a peculiar tissue in many respects. It shows patterns of rapid gene evolution and provides a hotspot for the origination of genetic novelties such as de novo genes, duplications and mutations. To investigate the expression patterns of genetic novelties across cell types, we performed single-cell RNA-sequencing of adult Drosophila testis. We found that new genes were expressed in various cell types, the patterns of which may be influenced by their mode of origination. In particular, lineage-specific de novo genes are commonly expressed in early spermatocytes, while young duplicated genes are often bimodally expressed. Analysis of germline substitutions suggests that spermatogenesis is a highly reparative process, with the mutational load of germ cells decreasing as spermatogenesis progresses. By elucidating the distribution of genetic novelties across spermatogenesis, this study provides a deeper understanding of how the testis maintains its core reproductive function while being a hotbed of evolutionary innovation.

scholarly journals Male-driven de novo mutations in haploid germ cells

2013 ◽  
Vol 19 (8) ◽  
pp. 495-499 ◽  
Author(s):  
M.-C. Gregoire ◽  
J. Massonneau ◽  
O. Simard ◽  
A. Gouraud ◽  
M.-A. Brazeau ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
De Novo Mutations

scholarly journals Trajectory and uniqueness of mutational signatures in yeast mutators

2020 ◽  
Vol 117 (40) ◽  
pp. 24947-24956 ◽  
Author(s):  
Sophie Loeillet ◽  
Mareike Herzog ◽  
Fabio Puddu ◽  
Patricia Legoix ◽  
Sylvain Baulande ◽  
...  
Keyword(s):  
De Novo ◽  
Clonal Evolution ◽  
De Novo Mutations ◽  
Mutational Signatures ◽  
Base Substitutions ◽  
Strong Stimulation ◽  
Conserved Genes ◽  
Genome Variations ◽  
Selective Forces ◽  
Brca1 Brca2

The acquisition of mutations plays critical roles in adaptation, evolution, senescence, and tumorigenesis. Massive genome sequencing has allowed extraction of specific features of many mutational landscapes but it remains difficult to retrospectively determine the mechanistic origin(s), selective forces, and trajectories of transient or persistent mutations and genome rearrangements. Here, we conducted a prospective reciprocal approach to inactivate 13 single or multiple evolutionary conserved genes involved in distinct genome maintenance processes and characterize de novo mutations in 274 diploid Saccharomyces cerevisiae mutation accumulation lines. This approach revealed the diversity, complexity, and ultimate uniqueness of mutational landscapes, differently composed of base substitutions, small insertions/deletions (InDels), structural variants, and/or ploidy variations. Several landscapes parallel the repertoire of mutational signatures in human cancers while others are either novel or composites of subsignatures resulting from distinct DNA damage lesions. Notably, the increase of base substitutions in the homologous recombination-deficient Rad51 mutant, specifically dependent on the Polζ translesion polymerase, yields COSMIC signature 3 observed in BRCA1/BRCA2-mutant breast cancer tumors. Furthermore, “mutome” analyses in highly polymorphic diploids and single-cell bottleneck lineages revealed a diverse spectrum of loss-of-heterozygosity (LOH) signatures characterized by interstitial and terminal chromosomal events resulting from interhomolog mitotic cross-overs. Following the appearance of heterozygous mutations, the strong stimulation of LOHs in the rad27/FEN1 and tsa1/PRDX1 backgrounds leads to fixation of homozygous mutations or their loss along the lineage. Overall, these mutomes and their trajectories provide a mechanistic framework to understand the origin and dynamics of genome variations that accumulate during clonal evolution.

scholarly journals Heritability and De Novo Mutations in Oesophageal Atresia and Tracheoesophageal Fistula Aetiology

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1595
Author(s):  
Erwin Brosens ◽  
Rutger W. W. Brouwer ◽  
Hannie Douben ◽  
Yolande van Bever ◽  
Alice S. Brooks ◽  
...  
Keyword(s):  
Animal Models ◽  
Tracheoesophageal Fistula ◽  
De Novo ◽  
Oesophageal Atresia ◽  
Diagnostic Yield ◽  
Survival Rates ◽  
Cell Types ◽  
Genetic Mutation ◽  
De Novo Mutations ◽  
Genetic Syndromes

Tracheoesophageal Fistula (TOF) is a congenital anomaly for which the cause is unknown in the majority of patients. OA/TOF is a variable feature in many (often mono-) genetic syndromes. Research using animal models targeting genes involved in candidate pathways often result in tracheoesophageal phenotypes. However, there is limited overlap in the genes implicated by animal models and those found in OA/TOF-related syndromic anomalies. Knowledge on affected pathways in animal models is accumulating, but our understanding on these pathways in patients lags behind. If an affected pathway is associated with both animals and patients, the mechanisms linking the genetic mutation, affected cell types or cellular defect, and the phenotype are often not well understood. The locus heterogeneity and the uncertainty of the exact heritability of OA/TOF results in a relative low diagnostic yield. OA/TOF is a sporadic finding with a low familial recurrence rate. As parents are usually unaffected, de novo dominant mutations seems to be a plausible explanation. The survival rates of patients born with OA/TOF have increased substantially and these patients start families; thus, the detection and a proper interpretation of these dominant inherited pathogenic variants are of great importance for these patients and for our understanding of OA/TOF aetiology.

scholarly journals Recurrence of de novo mutations in families

2017 ◽  
Author(s):  
Hákon Jónsson ◽  
Patrick Sulem ◽  
Gudny A. Arnadottir ◽  
Gunnar Pálsson ◽  
Hannes P. Eggertsson ◽  
...  
Keyword(s):  
Germ Cells ◽  
De Novo ◽  
Large Fraction ◽  
Genetic Diseases ◽  
De Novo Mutations ◽  
Sibling Pairs ◽  
Rare Genetic Diseases ◽  
Early Embryos ◽  
Parent Of Origin ◽  
Serious Disease

ABSTRACTDe novo mutations (DNMs) cause a large fraction of severe rare diseases of childhood. DNMs that occur in early embryos may result in mosaicism of both somatic and germ cells. Such early mutations may be transmitted to more than one offspring and cause recurrence of serious disease. We scanned 1,007 sibling pairs from 251 families and identified 885 DNMs shared by siblings (ssDNMs) at 451 genomic sites. We estimated the probability of DNM recurrence based on presence in the blood of the parent, sharing by other siblings, parent-of-origin, mutation type, and genomic position. We detected 52.1% of ssDNMs in the parental blood. The probability of a DNM being shared goes down by 2.28% per year for paternal DNMs and 1.82% for maternal DNMs. Shared paternal DNMs are more likely to be T>C mutations than maternal ones, but less likely to be C>T mutations. Depending on DNM properties, the probability of recurrence in a younger sibling ranges from 0.013% to 29.6%. We have launched an online DNM recurrence probability calculator, to use in genetic counselling in cases of rare genetic diseases.

Homology, Genes, and Evolutionary Innovation

2014 ◽  
Author(s):  
Günter P. Wagner
Keyword(s):  
Evolutionary Biology ◽  
Regulatory Networks ◽  
Biological Diversity ◽  
Cell Types ◽  
Origin And Evolution ◽  
Major Transitions ◽  
Form And Function ◽  
Historical Continuity ◽  
Evolutionary Innovation ◽  
Character Identity

Homology—a similar trait shared by different species and derived from common ancestry, such as a seal's fin and a bird's wing—is one of the most fundamental yet challenging concepts in evolutionary biology. This book provides the first mechanistically based theory of what homology is and how it arises in evolution. The book argues that homology, or character identity, can be explained through the historical continuity of character identity networks—that is, the gene regulatory networks that enable differential gene expression. It shows how character identity is independent of the form and function of the character itself because the same network can activate different effector genes and thus control the development of different shapes, sizes, and qualities of the character. Demonstrating how this theoretical model can provide a foundation for understanding the evolutionary origin of novel characters, the book applies it to the origin and evolution of specific systems, such as cell types; skin, hair, and feathers; limbs and digits; and flowers. The first major synthesis of homology to be published in decades, this book reveals how a mechanistically based theory can serve as a unifying concept for any branch of science concerned with the structure and development of organisms, and how it can help explain major transitions in evolution and broad patterns of biological diversity.

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