scholarly journals Mutant screen for reproduction unveils depression-associated Piccolo’s control over reproductive behavior

2018 ◽  
Author(s):  
Gerardo A. Medrano ◽  
Manvendra Singh ◽  
Erik J. Plautz ◽  
Levi B. Good ◽  
Karen M. Chapman ◽  
...  
Keyword(s):  
Reproductive Behavior ◽  
Epileptiform Activity ◽  
Gene Mutations ◽  
Sleeping Beauty ◽  
Forward Genetics ◽  
Human Populations ◽  
Mutant Screen ◽  
Animal Physiology ◽  
Rat Genetics ◽  
Presynaptic Vesicle

AbstractSuccessful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Ata13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive. Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction.Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact one’s emotions, including depression and bipolar disorder. Although studies in human populations implicate changes to Piccolo’s DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutation-dependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.

scholarly journals ATR regulates neuronal activity by modulating presynaptic firing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Murat Kirtay ◽  
Josefine Sell ◽  
Christian Marx ◽  
Holger Haselmann ◽  
Mihai Ceanga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neuronal Activity ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Physiological Function ◽  
Epileptiform Activity ◽  
Damage Response ◽  
Dividing Cells ◽  
Presynaptic Vesicle ◽  
Essential Function

AbstractAtaxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.

Characterization of T-Cell Lymphoblastic Leukemia Genetic Etiology

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5128-5128
Author(s):  
Luke Drury ◽  
Benjamin Brett ◽  
Todd Sheetz ◽  
Adam J Dupuy
Keyword(s):  
T Cell ◽  
Network Analysis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Sleeping Beauty ◽  
Forward Genetics ◽  
Genetic Etiology ◽  
Illumina Hiseq ◽  
Transposon Insertion ◽  
Background Events

Abstract Abstract 5128 Introduction. T-cell lymphoblastic leukemia (T-ALL) is inflict nearly 1500 children annually in the US. We recently reported using Sleeping Beauty mutagenesis as a forward genetics approach to model two major subtypes of T-ALL, typical and early T-cell precursor (ETP). The genetic mutations that define these subtypes is incomplete. Moreover, identifying driver from passenger mutations within these tumors is paramount for developing targeted therapeutics to specific genetic lesions. Method. T-ALL tumors were generated using a Cre-inducible Sleeping Beauty system to drive mutagenesis at either early (Vav-iCre) or late (CD4-Cre) stage of T-cell development. Synthetic gene standards were spiked into samples at known concentrations to permit quantitation of transposon insertion events within individual tumors. Samples were prepared by ligation mediated PCR and sequenced using an Illumina HiSeq. Using the standard as a barometer, common insertion sites (CIS) were defined as initiating, transition, or progression based on their abundance. We further developed a network analysis pathway to identify CISs within similar signaling axes. Results. Spiked standards were reproducibly seen at expected abundances in several replicated tumors. Further, we are able to distinguish insertions found at high abundances in tumors from lower occurring or background events. Together this allowed us to identify the order of mutations in each tumor and characterize mutations as initiators or progression events. Using our network analysis pathway we found Myc and Stat5b signaling axes driving the majority of ETP-ALL and Notch1 signaling driving typical T-ALL. Conclusions. Our data are the first to utilize NextGen sequencing techniques to quantitate CIS events to understand the genetic etiology of T-ALL. Coupled with our network analysis software, we are able to more accurately identify driving pathways in individual T-ALL tumors induced by Sleeping Beauty mutagenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Brazil's Missing Infants: Zika Risk Changes Reproductive Behavior

2019 ◽  
Author(s):  
Marcos Rangel ◽  
Jenna Nobles ◽  
Amar Hamoudi
Keyword(s):  
Reproductive Behavior ◽  
Large Scale ◽  
Infant Health ◽  
Biological Effects ◽  
Vital Statistics ◽  
Human Populations ◽  
Family Planning Services ◽  
Scale Population ◽  
Inference Techniques ◽  
Population Effects

Zika virus epidemics have potential large-scale population effects. Controlled studies of mice and non-human primates indicate Zika affects fecundity, raising concerns about miscarriage in human populations. In regions of Brazil, Zika risk peaked months before residents learned about the epidemic and its relation to congenital anomalies. This spatiotemporal variation supports analysis of both biological effects of Zika infection on fertility and the effects of learning about Zika risk on reproductive behavior. Causal inference techniques used with vital statistics indicate that the epidemic caused reductions of approximately one-quarter in birth cohort size 18 months after Zika infection risk peaked, but 10 months after public health messages advocated childbearing delay. The evidence is consistent with small, but not statistically detectable, biological reductions in fecundity, as well as large strategic changes in reproductive behavior to temporally align childbearing with reduced risk to infant health. The behavioral effects are larger for more educated and older women, which may reflect facilitated access to information and to family planning services within high-risk, mosquito-infested urban locations, as well as perceptions about the opportunity costs of risks to pregnancy and infant survival.

Mutation as a cause of genetic disease

1988 ◽  
Vol 319 (1194) ◽  
pp. 325-340 ◽  
Keyword(s):  
Single Gene ◽  
Somatic Cells ◽  
Gene Mutations ◽  
Human Populations ◽  
Inherited Disease ◽  
Chemical Mutagens ◽  
Age Dependent ◽  
Chromosomal Mutations ◽  
In Cells

Mutational changes can be conveniently classified into two sorts: those that appear to involve single genes and are generally referred to as gene mutations, and those that involve chromosomal segments containing m any genes, or even whole chromosomes, and are referred to as chromosomal mutations. Both of these kinds of mutation occur in germ-cell lineages and contribute substantially to inherited disease, or predisposition to disease, and both also occur in somatic cells and contribute to acquired disease. The mutation rates for inherited disease ascribed to mutation in a single gene differ for different genes and are age-dependent. Moreover, a single disease entity, such as haemophilia B, may be the result of any one of a number of different alterations within the gene responsible for the disease. The mutation rate for inherited chromosomal mutation is also age-dependent, particularly so in the case of mutations involving alterations in chromosome number. Studies in experimental animals demonstrate that exposure to physical or chemical mutagens results in increasing the incidence of inherited gene and chromosomal mutations. However, such increases have not been unequivocally demonstrated in human populations exposed to known mutagens. Studies on mutation in human lymphoid or epithelial somatic cells clearly demonstrate an increased frequency in cells taken from people exposed to ionizing radiations or chemical mutagens or in cells exposed in vitro . The consequences of such mutations will depend upon their nature and the origins and functions of the cells in which they occur. Of particular importance are mutations influencing cell growth and proliferation, and both gene and chromosomal mutations are implicated as causal factors in the development of hum an cancers.

The sense of obligation is culturally modulated

2020 ◽  
Vol 43 ◽  
Author(s):  
Andrea Bender
Keyword(s):  
Cultural Studies ◽  
Cross Cultural ◽  
Human Populations ◽  
Cultural Group ◽  
Target Article ◽  
Sense Of Obligation ◽  
Cross Cultural Studies

Abstract Tomasello argues in the target article that, in generalizing the concrete obligations originating from interdependent collaboration to one's entire cultural group, humans become “ultra-cooperators.” But are all human populations cooperative in similar ways? Based on cross-cultural studies and my own fieldwork in Polynesia, I argue that cooperation varies along several dimensions, and that the underlying sense of obligation is culturally modulated.

WT1 GENE MUTATIONS IN DENYS‐DRASH AND FRASIER SYNDROME

Nephrology ◽  
2000 ◽  
Vol 5 (3) ◽  
pp. A110-A110
Author(s):  
McTaggart Sj ◽  
Algar E ◽  
Chow Cw ◽  
Powell Hr ◽  
Jones CL.
Keyword(s):  
Gene Mutations ◽  
Wt1 Gene ◽  
Frasier Syndrome

1068: TP53 Gene Mutations as a Prognostic Marker for PSA Progression in Early Stage Prostate Cancer

2004 ◽  
Vol 171 (4S) ◽  
pp. 282-282
Author(s):  
Markus D. Sachs ◽  
Horst Schlechte ◽  
Katrin Schiemenz ◽  
Severin V. Lenk ◽  
Dietmar Schnorr ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Marker ◽  
Early Stage ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Psa Progression ◽  
Tp53 Gene Mutations
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