scholarly journals Meiotic Cas9 expression mediates gene conversion in the male and female mouse germline

PLoS Biology ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. e3001478
Author(s):  
Alexander J. Weitzel ◽  
Hannah A. Grunwald ◽  
Ceri Weber ◽  
Rimma Levina ◽  
Valentino M. Gantz ◽  
...  
Keyword(s):  
Gene Conversion ◽  
Disease Transmission ◽  
Female Mouse ◽  
Low Frequency ◽  
Mendelian Inheritance ◽  
Gene Drive ◽  
Genetic Traits ◽  
Male And Female ◽  
Indel Mutation ◽  
Meiosis I

Highly efficient gene conversion systems have the potential to facilitate the study of complex genetic traits using laboratory mice and, if implemented as a “gene drive,” to limit loss of biodiversity and disease transmission caused by wild rodent populations. We previously showed that such a system of gene conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double-strand DNA break (DSB) is feasible in the female mouse germline. In the male germline, however, all DSBs were instead repaired by end joining (EJ) mechanisms to form an “insertion/deletion” (indel) mutation. These observations suggested that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology-directed repair (HDR) mechanisms predominate. Here, using a Cas9 knock-in allele at the Spo11 locus, we show that meiotic expression of Cas9 does indeed mediate gene conversion in the male as well as in the female germline. However, the low frequency of both HDR and indel mutation in both male and female germlines suggests that Cas9 may be expressed from the Spo11 locus at levels too low for efficient DSB formation. We suggest that more robust Cas9 expression initiated during early meiosis I may improve the efficiency of gene conversion and further increase the rate of “super-mendelian” inheritance from both male and female mice.

scholarly journals Meiotic Cas9 expression mediates genotype conversion in the male and female mouse germline

2021 ◽  
Author(s):  
Alexander J Weitzel ◽  
Hannah A Grunwald ◽  
Rimma Levina ◽  
Valentino M Gantz ◽  
Stephen M Hedrick ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Female Mouse ◽  
Low Frequency ◽  
Mendelian Inheritance ◽  
Genetic Traits ◽  
Male And Female ◽  
Indel Mutation ◽  
Dna Break ◽  
Meiosis I ◽  
Double Strand Dna

Highly efficient genotype conversion systems have potential to facilitate the study of complex genetic traits using laboratory mice and to limit loss of biodiversity and disease transmission caused by wild rodent populations. We previously showed that such a system of genotype conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double strand DNA break is feasible in the female mouse germline. In the male germline, however, all double strand breaks were instead repaired by end joining mechanisms to form an 'insertion/deletion' (indel) mutation. These observations suggested that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology directed repair (HDR) mechanisms predominate. Here, using a Cas9 knock-in allele at the Spo11 locus, we show that meiotic expression of Cas9 does indeed mediate genotype conversion in the male as well as in the female germline. However, the low frequency of both HDR and indel mutation in both male and female germlines suggests that Cas9 may be expressed from the Spo11 locus at levels too low for efficient double strand DNA break formation. We suggest that more robust Cas9 expression initiated during early meiosis I may improve the efficiency of genotype conversion and further increase the rate of 'super-Mendelian' inheritance from both male and female mice.

scholarly journals Coevolution of theS-Locus GenesSRK,SLGandSP11/SCRinBrassica oleraceaandB. rapa

Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 931-940 ◽  
Author(s):  
Keiichi Sato ◽  
Takeshi Nishio ◽  
Ryo Kimura ◽  
Makoto Kusaba ◽  
Tohru Suzuki ◽  
...  
Keyword(s):  
Brassica Oleracea ◽  
Gene Conversion ◽  
Phylogenetic Trees ◽  
Hypervariable Region ◽  
Recognition System ◽  
Self Incompatibility ◽  
Male And Female ◽  
Diversifying Selection ◽  
Tight Linkage ◽  
Nonsynonymous Site

AbstractBrassica self-incompatibility (SI) is controlled by SLG and SRK expressed in the stigma and by SP11/SCR expressed in the anther. We determined the sequences of the S domains of 36 SRK alleles, 13 SLG alleles, and 14 SP11 alleles from Brassica oleracea and B. rapa. We found three S haplotypes lacking SLG genes in B. rapa, confirming that SLG is not essential for the SI recognition system. Together with reported sequences, the nucleotide diversities per synonymous and nonsynonymous site (πS and πN) at the SRK, SLG, and SP11 loci within B. oleracea were computed. The ratios of πN:πS for SP11 and the hypervariable region of SRK were significantly >1, suggesting operation of diversifying selection to maintain the diversity of these regions. In the phylogenetic trees of 12 SP11 sequences and their linked SRK alleles, the tree topology was not significantly different between SP11 and SRK, suggesting a tight linkage of male and female SI determinants during the evolutionary course of these haplotypes. Genetic exchanges between SLG and SRK seem to be frequent; three such recent exchanges were detected. The evolution of S haplotypes and the effect of gene conversion on self-incompatibility are discussed.

scholarly journals Anopheles gambiae Genome Conservation as a Resource for Rational Gene Drive Target Site Selection

Insects ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 97
Author(s):  
Nace Kranjc ◽  
Andrea Crisanti ◽  
Tony Nolan ◽  
Federica Bernardini
Keyword(s):  
Anopheles Gambiae ◽  
Data Storage ◽  
Genomic Variation ◽  
Malaria Vectors ◽  
Anopheles Coluzzii ◽  
Structural Constraints ◽  
Gene Drive ◽  
Genetic Traits ◽  
A Genome ◽  
Insight Into

The increase in molecular tools for the genetic engineering of insect pests and disease vectors, such as Anopheles mosquitoes that transmit malaria, has led to an unprecedented investigation of the genomic landscape of these organisms. The understanding of genome variability in wild mosquito populations is of primary importance for vector control strategies. This is particularly the case for gene drive systems, which look to introduce genetic traits into a population by targeting specific genomic regions. Gene drive targets with functional or structural constraints are highly desirable as they are less likely to tolerate mutations that prevent targeting by the gene drive and consequent failure of the technology. In this study we describe a bioinformatic pipeline that allows the analysis of whole genome data for the identification of highly conserved regions that can point at potential functional or structural constraints. The analysis was conducted across the genomes of 22 insect species separated by more than hundred million years of evolution and includes the observed genomic variation within field caught samples of Anopheles gambiae and Anopheles coluzzii, the two most dominant malaria vectors. This study offers insight into the level of conservation at a genome-wide scale as well as at per base-pair resolution. The results of this analysis are gathered in a data storage system that allows for flexible extraction and bioinformatic manipulation. Furthermore, it represents a valuable resource that could provide insight into population structure and dynamics of the species in the complex and benefit the development and implementation of genetic strategies to tackle malaria.

scholarly journals Author Correction: Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline

Nature ◽  
2020 ◽  
Vol 577 (7792) ◽  
pp. E8-E8 ◽  
Author(s):  
Hannah A. Grunwald ◽  
Valentino M. Gantz ◽  
Gunnar Poplawski ◽  
Xiang-Ru S. Xu ◽  
Ethan Bier ◽  
...  
Keyword(s):  
Female Mouse ◽  
Mendelian Inheritance

scholarly journals Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julie E. Horowitz ◽  
Neil Warner ◽  
Jeffrey Staples ◽  
Eileen Crowley ◽  
Nehal Gosalia ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Protein Function ◽  
Early Onset ◽  
Low Frequency ◽  
Mendelian Inheritance ◽  
Clinical Population ◽  
Mendelian Disease ◽  
Recessive Inheritance ◽  
Pediatric Onset

AbstractInflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

Age-related changes in ischemic tolerance in male and female mouse hearts

2005 ◽  
Vol 38 (2) ◽  
pp. 245-256 ◽  
Author(s):  
L WILLEMS ◽  
A ZATTA ◽  
K HOLMGREN ◽  
K ASHTON ◽  
J HEADRICK
Keyword(s):  
Female Mouse ◽  
Ischemic Tolerance ◽  
Male And Female ◽  
Age Related ◽  
Age Related Changes

scholarly journals Distribution of androgen receptor mRNA in the prepubertal male and female mouse brain

2021 ◽  
Author(s):  
Alexandra L. Cara ◽  
Emily L. Henson ◽  
Bethany G. Beekly ◽  
Carol F. Elias
Keyword(s):  
Androgen Receptor ◽  
Mouse Brain ◽  
Female Mouse ◽  
Male And Female ◽  
Receptor Mrna

scholarly journals Sexual Differentiation in the Male and Female Mouse from Days 0 to 21: A Detailed and Novel Morphometric Description

2013 ◽  
Vol 190 (4S) ◽  
pp. 1610-1617 ◽  
Author(s):  
Bruce J. Schlomer ◽  
Max Feretti ◽  
Esequiel Rodriguez ◽  
Sarah Blaschko ◽  
Gerald Cunha ◽  
...  
Keyword(s):  
Sexual Differentiation ◽  
Female Mouse ◽  
Male And Female

scholarly journals Field assessment of behavioural responses of southern stingrays ( Hypanus americanus ) to acoustic stimuli

2020 ◽  
Vol 7 (1) ◽  
pp. 191544
Author(s):  
Megan F. Mickle ◽  
Rachel H. Pieniazek ◽  
Dennis M. Higgs
Keyword(s):  
Low Frequency ◽  
Free Swimming ◽  
Male And Female ◽  
Behavioural Responses ◽  
Acoustic Stimuli ◽  
Field Assessment ◽  
Rest Time ◽  
Field Setting ◽  
Behavioural Audiogram

The ability of elasmobranchs to detect and use sound cues has been heavily debated in previous research and has only recently received revived attention. To properly understand the importance of sound to elasmobranchs, assessing their responses to acoustic stimuli in a field setting is vital. Here, we establish a behavioural audiogram of free-swimming male and female southern stingrays ( Hypanus americanus ) exposed to low-frequency tones. We demonstrate that female stingrays exposed to tones (50–500 Hz) exhibit significant changes in swimming behaviours (increased time spent swimming, decreased rest time, increased surface breaches and increased side swimming with pectoral flapping) at 140 dB re 1 µPa (−2.08 to −2.40 dB re 1 m s −2 ) while males exposed to the same tones did not exhibit a change in these behaviours until 160 dB re 1 µPa (−1.13 to −1.21 dB re 1 m s −2 ). Our results are the first demonstration of field responses to sound in the Batoidea and show a distinct sensitivity to low-frequency acoustic inputs.

scholarly journals Using Gene Drive Technologies to Control Vector-Borne Infectious Diseases

2018 ◽  
Vol 10 (12) ◽  
pp. 4789 ◽  
Author(s):  
Stephanie James ◽  
Karen Tountas
Keyword(s):  
Disease Transmission ◽  
Sub Saharan Africa ◽  
Reproductive Capacity ◽  
World Health ◽  
Mosquito Vector ◽  
Gene Drive ◽  
African Region ◽  
Safety Testing ◽  
Malaria Burden ◽  
Health Organization

After years of success in reducing the global malaria burden, the World Health Organization (WHO) recently reported that progress has stalled. Over 90% of malaria deaths world-wide occurred in the WHO African Region. New tools are needed to regain momentum and further decrease the burden of malaria. Gene drive, an emerging technology that can enhance the inheritance of beneficial genes, offers potentially transformative solutions for overcoming these challenges. Gene drives may decrease disease transmission by interfering with the growth of the malaria parasite in the mosquito vector or reducing mosquito reproductive capacity. Like other emerging technologies, development of gene drive products faces technical and non-technical challenges and uncertainties. In 2018, to begin addressing such challenges, a multidisciplinary group of international experts published comprehensive recommendations for responsible testing and implementation of gene drive-modified mosquitoes to combat malaria in Sub-Saharan Africa. Considering requirements for containment, efficacy and safety testing, monitoring, stakeholder engagement and authorization, as well as policy and regulatory issues, the group concluded that gene drive products for malaria can be tested safely and ethically, but that this will require substantial coordination, planning, and capacity development. The group emphasized the importance of co-development and co-ownership of products by in-country scientists.

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