Maternal Inheritance Research Articles

MmisAT and MmisP: an efficient and accurate suite of variant analysis toolkit for primary mitochondrial diseases

Recent advances in next-generation sequencing (NGS) technology have greatly accelerated the need for efficient annotation to accurately interpret clinically relevant genetic variants in human diseases. Therefore, it is crucial to develop appropriate analytical tools to improve the interpretation of disease variants. Given the unique genetic characteristics of mitochondria, including haplogroup, heteroplasmy, and maternal inheritance, we developed a suite of variant analysis toolkits specifically designed for primary mitochondrial diseases: the Mitochondrial Missense Variant Annotation Tool (MmisAT) and the Mitochondrial Missense Variant Pathogenicity Predictor (MmisP). MmisAT can handle protein-coding variants from both nuclear DNA and mtDNA and generate 349 annotation types across six categories. It processes 4.78 million variant data in 76 min, making it a valuable resource for clinical and research applications. Additionally, MmisP provides pathogenicity scores to predict the pathogenicity of genetic variations in mitochondrial disease. It has been validated using cross-validation and external datasets and demonstrated higher overall discriminant accuracy with a receiver operating characteristic (ROC) curve area under the curve (AUC) of 0.94, outperforming existing pathogenicity predictors. In conclusion, the MmisAT is an efficient tool that greatly facilitates the process of variant annotation, expanding the scope of variant annotation information. Furthermore, the development of MmisP provides valuable insights into the creation of disease-specific, phenotype-specific, and even gene-specific predictors of pathogenicity, further advancing our understanding of specific fields.

The Islamic Worldview and Customary Law on Patterns of Inheritance Distribution

This study discusses customary issues that arise in Indonesian culture, namely the inheritance distribution tradition in the patrilineal inheritance system in Betawi culture and the matrilineal inheritance system in Minangkabau culture. These two traditions highlight different approaches to inheritance and gender roles in society. Through interviews with traditional leaders, researchers seek to understand the concept of sharia in order to maintain a more beneficial cultural continuity. The triangulation method was used to verify information from respondents in various contexts to compare ethnic views and Islamic concepts. The results of the study show differences in understanding and its impact on economic conditions. The inheritance distribution tradition of the Betawi tribe reflects cultural adaptation to values of gender equality that are in line with the Islamic Worldview, but still faces challenges in fully integrating Islamic principles. Meanwhile, the Minangkabau matrilineal inheritance system emphasizes the role of women in the family structure and inheritance, but creates complexity in asset management.

Mitochondrial heteroplasmy as a marker for premature coronary artery disease: analysis of the poly-C tract of the control region sequence

Abstract Mitochondrial DNA (mtDNA) differs from the nuclear genome in many aspects: a maternal inheritance pattern, being more prone to acquire somatic novo mutations, accumulative with age; and the possible coexistence of different mtDNA alleles (heteroplasmy). Mitochondria are key cellular organelles responsible for energy production, involved in complex mechanisms, including atherosclerosis. In this scenario, we aimed to evaluate mtDNA variants that could be associated with premature cardiovascular disease. We evaluated 188 consecutive patients presenting with premature myocardial infarction with ST elevation (STEMI) confirmed by coronary angiogram. mtDNA polymorphisms and clinical data were evaluated and compared with 271 individuals from the same population (control group). Tobacco consumption (80.85% vs 21.21%, p<0.01) and dyslipidemia (38.83% vs 28.41%, p=0.02) were significant more frequent among STEMI patients. Besides, C16223T mtDNA mutation and poly-C heteroplasmy were significantly more frequent among premature STEMI cases than in controls. The OR associated C16223T mtDNA mutation with an increased presence of cardiovascular risk factors. Our data suggest that mtDNA C16223T mutation and poly-C heteroplasmy may be associated with unstable atherosclerosis disease. Moreover, the presence of cardiovascular risk factors (CVRFs) was associated to C16223T mtDNA mutation, with a cumulative effect. Protective mitochondrial pathways are potential therapeutic targets. Thus, preventing exposure to the damaging mechanisms associated to CVRFs is of the utmost importancemtDNA sanger analysisBaseline characteristics.

Developmental and epileptic encephalopathy 82 (DEE82) with novel compound heterozygous mutations of GOT2 gene

PurposeDevelopmental and Epileptic Encephalopathies (DEEs) are rare neurological disorders characterized by early-onset medically resistant epileptic seizures, structural brain malformations, and severe developmental delays. These disorders can arise from mutations in genes involved in vital metabolic pathways, including those within the brain. Recent studies have implicated defects in the mitochondrial malate aspartate shuttle (MAS) as potential contributors to the clinical manifestation of infantile epileptic encephalopathy. Although rare, mutations in MDH1, MDH2, AGC1, or GOT2 genes have been reported in patients exhibiting neurological symptoms such as global developmental delay, epilepsy, and progressive microcephaly. MethodIn this study, we employed exome data analysis of a patient diagnosed with DEE, focusing on the screening of 1896 epilepsy-related genes listed in the HPO and ClinVar databases. Sanger sequencing was subsequently conducted to validate and assess the inheritance pattern of the identified variants within the family. The evolutionary conservation scores of the mutated residues were evaluated using the ConSurf Database. Furthermore, the impacts of the causative variations on protein stability were analyzed through I-Mutant and MuPro bioinformatic tools. Structural comparisons between wild-type and mutant proteins were performed using PyMOL, and the physicochemical effects of the mutations were assessed using Project Hope. ResultsExome data analysis unveiled the presence of novel compound heterozygous mutations in the GOT2 gene coding for mitochondrial glutamate aspartate transaminase. Sanger sequencing confirmed the paternal inheritance of the p.Asp257Asn mutation and the maternal inheritance of the p.Arg262Cys mutation. The affected individual exhibited plasma metabolic disturbances, including hyperhomocysteinemia, hyperlactatemia, and reduced levels of methionine and arginine. Detailed bioinformatic analysis indicated that the mutations were located within evolutionarily conserved domains of the enzyme, resulting in disruptions to protein stability and structure. ConclusionHerein, we describe a case with DEE82 (MIM: # 618721) with pathologic novel biallelic mutations in the GOT2 gene. Early genetic diagnosis of metabolic epilepsies is crucial for long-term neurodevelopmental improvements and seizure control as targeted treatments can be administered based on the affected metabolic pathways.

On Widening the Hybrid Zone for Chars of Genus Salvelinus, Kundscha S. leucomaenis and Northern Dolly Varden S. malma (Salmonidae), in Rivers of Kamchatka Peninsula

The data on widening the zone for hybridization between the chars of the genus Salvelinus, kundscha S. leucomaenis and northern dolly varden S. malma (Salmonidae), in rivers of the Kamchatka Peninsula are reported. If the hybrids between the kundscha and the northern dolly varden could be previously observed only in the Utkholok River in the northwest of the peninsula, the mass hybridization between these species have occurred in two more nearby rivers, the Kvachina and Snatolveem Rivers since 2009. A microsatellite analysis has shown that hybrid specimens are characterized by intermediate values for allelic diversity, when compared to that in the representatives of parental species, while the mean expected heterozygosity values for hybrids are higher than that in Dolly Varden and kundscha fish. The analysis results for maternal inheritance in hybrid specimens from the Kvachina River coincide with that obtained in the surveys previously performed in the Utkholok River. Thus, the same haplotype specific for the kundscha fish was revealed in all the hybrid specimens, which can indicate that the hybrids originate from kundscha females and Dolly Varden males. The appearance and coloration of kundscha × northern dolly varden hybrids in the Kvachina and Snatolveem Rivers are similar to that in the specimens in the Utkholok River. Rather similar chacteristics of hybrid specimens in all three rivers can give reason to consider that a mechanism of their occurrence in the Kvachina and Snatolveem Rivers is simalr to that in the Utkholok River, since the kundscha eggs are inseminated by the Dolly Varden dwarf males. The increased local biological production of rivers due to increased sizes of spawning stocks of pink salmon Oncorhynchus gorbuscha along with large-scale climate changes in the North Pacific are considered as a possible cause of disturbances of isolation between species. It is quite probable that these two factors have contributed to improving the environmental conditions for fattening the Dolly Varden fish in the freshwater phase of their life cycle and, as a resultl of this process, increasing the number of Dolly Varden male fish matuaring in the river.

THU143 A Novel Maternally Inherited GNAS Variant In A Family With Hyperphagia And Obesity

Abstract Disclosure: P. Purushothaman: None. A. Ramakrishnan: None. E.F. Gevers: None. Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP) characterized by developmental delay, short stature, obesity, hormone resistance and bone abnormalities. Recently, GNAS variants were also described in 1% of patients in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling. Here, we report another novel GNAS variant in family with hyperphagia and obesity and only mild features of PHP. Case: The proband presented at 6 years with hyperphagia and obesity from age 3 years. BMI was 30.4 (4.1 SDS) with height +1.9 SDS, and head circumference (HC) + 3.0 SDS. She had subtle brachydactyly, short toes and a café au lait patch. Developmental milestones and cognitive achievements were mildly delayed. Her 12-year-old brother [ height +2.1 SDS, weight +3.1 SDS, BMI 29.55 (2.9 SDS), HC +3.6 SDS] had been followed in an obesity clinic for a few years with hyperphagia, obesity, delayed developmental milestones and a recent diagnosis of autism. He also had subtle brachydactyly, as did the mother who was also obese (BMI 38.9) with a normal height but had normal cognition. Results: In the proband, initial investigations did not suggest hormone resistance. However, at 8.7 years, PTH was high [9.5 pmol/L (0.7-5.6)] with normal calcium and Vitamin D; TSH 6.6 mU/L (<6), FT4 11.8 pmol/L (10.8 - 19.0). She had hyperlipidaemia and fatty liver. X-ray hand showed generalised mild brachydactyly with a short right fifth metacarpal. In the brother, PTH tested for the first time at 12.9 years was 18.4 pmol/L (1.6-6.9), calcium and vitamin D were normal; TSH 4.04 mU/L (<4.2) and FT4 13.4 pmol/L. Next Generation Sequencing using the Cambridge Obesity gene panel detected a novel heterozygous (c.791A>C, p.(Asn264Thr) variant in exon 10 of GNAS in the proband and subsequently in the mother and brother confirming maternal inheritance. This variant has not been reported in control databases (1000 Genomes, ESP, ExAC and gnomAD, Human Gene Mutation Database and ClinVar). The variant is in a highly conserved region susceptible to missense mutations and has been classified as pathogenic using ACMG and ACGS guidelines. Discussion: In conclusion, we describe a novel heterozygous inactivating GNAS variant c.791A>C, p.Asn264Thr resulting in hyperphagia, obesity, developmental delay, macrocephaly, mild brachydactyly, tall stature and variable biochemical mild hormone resistance in 2 siblings and resulting in obesity, mild brachydactyly without cognitive impairment in the mother. These cases demonstrate the clinical heterogeneity of the monogenic disease. Clinical and biochemical screening for PHP and genetic screening for GNAS variants should be performed in patients presenting with obesity, even in the absence of classical signs of PHP, to reduce diagnostic delay. Presentation: Thursday, June 15, 2023

Chloroplast Genome Engineering: A Plausible Approach to Combat Chili Thrips and Other Agronomic Insect Pests of Crops.

The world population's growing demand for food is expected to increase dramatically by 2050. The agronomic productivity for food is severely affected due to biotic and abiotic constraints. At a global level, insect pests alone account for ~20% loss in crop yield every year. Deployment of noxious chemical pesticides to control insect pests always has a threatening effect on human health and environmental sustainability. Consequently, this necessitates for the establishment of innovative, environmentally friendly, cost-effective, and alternative means to mitigate insect pest management strategies. According to a recent study, using chloroplasts engineered with double-strand RNA (dsRNA) is novel successful combinatorial strategy deployed to effectively control the most vexing pest, the western flower thrips (WFT: Frankliniella occidentalis). Such biotechnological avenues allowed us to recapitulate the recent progress of research methods, such as RNAi, CRISPR/Cas, mini chromosomes, and RNA-binding proteins with plastid engineering for a plausible approach to effectively mitigate agronomic insect pests. We further discussed the significance of the maternal inheritance of the chloroplast, which is the major advantage of chloroplast genome engineering.

Development of chloroplast derived SSR markers for genus Allium and their characterization in the allies for genetic improvement of Alliums

Alliums are the most popular for their culinary usage and nutraceutical benefits. Their production is greatly affected by the multiple biotic and abiotic stresses. Poor characterizations of genetic resources are the major bottleneck in the genetic improvement of Alliums. Chloroplast-derived simple sequence repeat has recently gained much popularity due to their maternal inheritance and low recombination along with their hypervariable nature. In this study, 22 of the 28 chloroplast-derived markers from chloroplast genomes of A. cepa and A. sativum were reported as polymorphic and cross-transferable. Tetra nucleotide repeats were more prevalent (52 %) in these 22 cpSSR markers as compared to other repeat motifs. Further polymorphic information content of these 22cpSSR markers ranged from 0.007 to 0.427. Based on the genotyping of 22cpSSR markers, 25 Alliums were clustered into two groups (groups I, IIA, and IIB). This showed that cultivated Allium cepa and Allium sativum belong to group II rather than the majority of wild Alliums, which belong to group I. Hence This proved the widespread use of these AccpSSR and AscpSSR markers. Additionally, it was clear from 79 Alliums morphological and genotyping-based clustering that these 79 wild Alliums exhibit strong clustering consistency in genotyping and phenotyping-based dendrograms, hence confirming these cpSSR's discrimination potential. Allium tuberosum Rottler ex. Spreng is quite distinct from Allium fistulosum L, A. schoenoprasumas as well as Allium cepa var. aggregatum G.Don. Further Allium fistulosum L, A. schoenoprasum and Allium cepa var. aggregatum are closely related, according to genotyping-based dendrograms of 79 wild Alliums. Hence Allium fistulosum L, A. schoenoprasum, and Allium cepa provide a brilliant opportunity for introgression of the high total soluble content, high quercetin content, and allicin content of cultivated Allium into wild Allium as well as the biotic and abiotic stress tolerance of wild Alliums into cultivated Alliums. Subsequent clustering of 79 Alliums further allowed us to identify diverse Alliums for constructing a core collection. Hence present study will be useful for molecular breeding and genomic selection-based crop improvement.

Endophytic bacterial community diversity in genetically related hybrid rice seeds.

The Food and Agriculture Organization of the United Nations (FAO) has identified hybrid rice as ideal for addressing food scarcity in poor nations. A comprehensive investigation of the endophytic bacteria in hybrid rice seeds is essential from a microecological perspective to illuminate the mechanisms underlying its high yield, high quality, and multi-resistance. The endophytic bacterial diversity and community structures of 11 genetically correlated hybrid rice seeds with different rice blast resistance levels were studied using high-throughput sequencing (HTS) on the Illumina MiSeq platform to reveal their "core microbiota" and explore the effect of genotypes, genetic relationships, and resistance. Proteobacteria (78.15-99.15%) represented the most abundant group in the 11 hybrid rice cultivars, while Pantoea, Pseudomonas, and Microbacterium comprised the "core microbiota." Hybrid rice seeds with different genotypes, genetic correlations, and rice blast resistance displayed endophytic bacterial community structure and diversity variation. In addition, the network relationships between the rice seed endophytic bacteria of "the same female parent but different male parents" were more complex than those from "the same male parent but different female parents." Matrilineal inheritance may be the primary method of passing on endophytic bacteria in rice from generation to generation. The endophytic bacterial interaction network in rice blast-resistant hybrid rice seed varieties was more complicated than in susceptible varieties. In summary, this study demonstrated that the genotype, genetic relationship, and rice blast resistance were important factors affecting the community structures and diversity of endophytic bacteria in hybrid rice seeds, which was vital for revealing the interaction between endophytic bacteria and the host. KEY POINTS: • Pantoea, Pseudomonas, and Microbacterium represent the main endophytic bacteria in hybrid rice seeds. • Genotype is the primary factor affecting endophytic bacterial diversity in hybrid rice seeds. • The diversity of the endophytic bacterial community in hybrid rice seeds is related to their genotypes, genetic relationships, and rice blast resistance.

Plastid Inheritance Revisited: Emerging Role ofOrganelle DNA Degradation inAngiosperms.

Plastids are essential organelles in angiosperms and show non-Mendelian inheritance due to their evolution as endosymbionts. In approximately 80% of angiosperms, plastids are thought to be inherited from the maternal parent, whereas other species transmit plastids biparentally. Maternal inheritance can be generally explained by the stochastic segregation of maternal plastids after fertilization because the zygote is overwhelmed by the maternal cytoplasm. In contrast, biparental inheritance shows the transmission of organelles from both parents. In some species, maternal inheritance is not absolute and paternal leakage occurs at a very low frequency (∼10-5). A key process controlling the inheritance mode lies in the behavior of plastids during male gametophyte (pollen) development, with accumulating evidence indicating that the plastids themselves or their DNAs are eliminated during pollen maturation or at fertilization. Cytological observations in numerous angiosperm species have revealed several critical steps that mutually influence the degree of plastid transmission quantitatively among different species. This review revisits plastid inheritance from a mechanistic viewpoint. Particularly, we focus on a recent finding demonstrating that both low temperature and plastid DNA degradation mediated by the organelle exonuclease DEFECTIVE IN POLLEN ORGANELLE DNA DEGRADATION1 (DPD1) influence the degree of paternal leakage significantly in tobacco. Given these findings, we also highlight the emerging role of DPD1 in organelle DNA degradation.

Characterization and Comparison of the Two Mitochondrial Genomes in the Genus Rana.

The mitochondrial genome (mitogenome) possesses several invaluable attributes, including limited recombination, maternal inheritance, a fast evolutionary rate, compact size, and relatively conserved gene arrangement, all of which make it particularly useful for applications in phylogenetic reconstruction, population genetics, and evolutionary research. In this study, we aimed to determine the complete mitogenomes of two morphologically similar Rana species (Rana hanluica and Rana longicrus) using next-generation sequencing. The entire circular mitogenome was successfully identified, with a length of 19,395 bp for R. hanluica and 17,833 bp for R. longicrus. The mitogenomes of both species contained 37 genes, including 13 protein-coding genes (PCGs), two ribosomal RNA genes, 22 transfer RNA genes, and one control region; mitogenome size varied predominantly with the length of the control region. The two synonymous codon usages in 13 PCGs showed that T and A were used more frequently than G and C. The ratios of non-synonymous to synonymous substitutions of all 13 PCGs were <1 in the Rana species, indicating that the PCGs were under purifying selection. Finally, phylogenetic relationship analyses suggested that R. hanluica and R. longicrus were classified in the R. japonica group. Our study provides valuable reference material for the taxonomy of the genus Rana.

Heterosis for biomass yield and quality traits in a reciprocal cross population between Miscanthus sinensis and Miscanthus lutarioriparius

Heterosis plays an important role in plant breeding and has been widely used in the production of a variety of food crops. However, cross-breeding is particularly important in the breeding of new varieties of the energy crop miscanthus due to its characteristics of self-incompatibility and lack of interspecific reproductive isolation. Therefore, in the current study, 30 direct cross hybrids and 150 reciprocal cross hybrids were obtained from a cross between M. sinensis and M. lutarioriparius. These hybrids were significantly different in phenotype and were used for a detailed analysis of heterosis. The mid-parent, over-parent and over-standard heterosis of the hybrids for yield-related agronomic traits were analyzed. The results showed that the hybrids from direct and reciprocal crosses exhibited significant trait segregation and acquired dominant agronomic traits from both parents, showing mid-parent, over-parent and over-standard heterosis. Plant height, tiller number, stem node number, and stem diameter showed maternal inheritance. Principal component analysis was used to construct the linear combination relationship of yield-related agronomic traits. Excellent hybrids were screened against the commercial miscanthus variety Miscanthus × giganteus. These hybrids were superior to their two parents and M. × giganteus in terms of phenotypic yield-related agronomic traits, biomass yield, and quality. These results not only confirmed the feasibility of breeding miscanthus by remote crosses, but also provided a reference for the application, cross-breeding and breeding of new miscanthus varieties.

'Candidatus Tisiphia' is a widespread Rickettsiaceae symbiont in the mosquito Anopheles plumbeus (Diptera: Culicidae).

Symbiotic bacteria can alter host biology by providing protection from natural enemies, or alter reproduction or vectoral competence. Symbiont-linked control of vector-borne disease in Anopheles has been hampered by a lack of symbioses that can establish stable vertical transmission in the host. Previous screening found the symbiont 'Candidatus Tisiphia' in Anopheles plumbeus, an aggressive biter and potential secondary vector of malaria parasites and West Nile virus. We screened samples collected over 10-years across Germany and used climate databases to assess environmental influence on incidence. We observed a 95% infection rate, and that the frequency of infection did not fluctuate with broad environmental factors. Maternal inheritance is indicated by presence in the ovaries through FISH microscopy. Finally, we assembled a high-quality 1.6 Mbp draft genome of 'Ca. Tisiphia' to explore its phylogeny and potential metabolic competence. The infection is closely related to strains found in Culicoides biting midges and shows similar patterns of metabolism, providing no evidence of the capacity to synthesize B-vitamins. This infection offers avenues for onward research in anopheline mosquito symbioses. Additionally, it provides future opportunity to study the impact of 'Ca. Tisiphia' on natural and transinfected hosts, especially in relation to reproductive fitness and vectorial competence and capacity.

Surnames in population genetics: pros and cons

The article presents arguments regarding the perspective of studying the population using surnames as a tool of population genetic research. The model of a virtual polyallelic locus linked to the Y chromosome in peoples with patrilineal inheritance and linked to mtDNA in peoples with matrilineal inheritance is presented, which allows analyzing the distribution of surnames by means of population genetics. It is proved that the change of surnames at the time of marriage, false paternity and spelling errors do not affect the overall result of the calculations. Attention is drawn to the selective neutrality of surnames in relation to the natural environment and selectivity to the social environment. Examples of the advantages of surnames as population markers are given: quick obtaining of results, low financial cost of works compared to effectiveness, absence of statistical and ethical problems. The expediency of using surnames for the study of Ukrainian populations is proven by their compliance with the conditions put forward for markers. In conditions that make it impossible to collect actual material in populations and laboratory analysis of biological samples, working with lists of surnames is best suited for undergraduates and graduate students conducting research in anthropogenetics.

Cosegregation of recombinant chromatids maintains genome-wide heterozygosity in an asexual nematode.

In asexual animals, female meiosis is modified to produce diploid oocytes. If meiosis still involves recombination, this is expected to lead to a rapid loss of heterozygosity, with adverse effects on fitness. Many asexuals, however, have a heterozygous genome, the underlying mechanisms being most often unknown. Cytological and population genomic analyses in the nematode Mesorhabditis belari revealed another case of recombining asexual being highly heterozygous genome-wide. We demonstrated that heterozygosity is maintained despite recombination because the recombinant chromatids of each chromosome pair cosegregate during the unique meiotic division. A theoretical model confirmed that this segregation bias is necessary to account for the observed pattern and likely to evolve under a wide range of conditions. Our study uncovers an unexpected type of non-Mendelian genetic inheritance involving cosegregation of recombinant chromatids.

The mutational analysis of mitochondrial DNA in maternal inheritance of polycystic ovarian syndrome.

Polycystic Ovarian Syndrome (PCOS) is a globally prevalent condition that leads to infertility in women. While environmental factors contribute to PCOS, maternal genetics also play a significant role. Currently, there is no definitive test for identifying predisposition to PCOS. Hence, our objective is to discover novel maternal genetic risk factors for PCOS by investigating the genomes of patients from Pakistan. We utilized Next-Generation Sequencing (NGS) to sequence the complete mitochondrial DNA of three PCOS patients. Subsequently, we employed MitoTIP (Mitochondrial tRNA Informatics Predictor) and PON-mt-tRNA tools to identify variations in the mitochondrial DNA. Our analysis focused on the genes MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB, which displayed common variations in all three genomes. Additionally, we observed individual variations. The D-loop region exhibited the highest frequency of mutations, followed by the non-coding regions of RNR1 and RNR2 genes. Moreover, we detected frameshift mutations in the mitochondrially encoded NADH Dehydrogenase 2 (MT-ND2) and mitochondrially encoded NADH Dehydrogenase 5 (ND5) genes within individual genomes. Our analysis unveiled six regions with common variations in the mitochondrial DNA of all three PCOS patients. Notably, the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes exhibited these variations. Additionally, we identified individual variations in the mitochondrial DNA. The D-loop region displayed the highest mutation frequency, followed by the non-coding regions of RNR1 and RNR2 genes. Furthermore, frameshift mutations were detected in the MT-ND2 and ND5 genes within individual genomes. Through our study, we have identified variations in mitochondrial DNA that may be associated with the development of PCOS and have the potential to serve as predisposition tests. Our findings highlight the presence of novel mutations in the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes, as well as frameshift mutations in the MT-ND2 and ND5 genes. Pathogenicity analysis indicated that most variants were likely to result in benign cysts. However, the frameshift mutations in the ND2 gene were associated with a high risk of complications and pathogenicity in PCOS. This is the first report identifying these mutations and their association with PCOS, contributing to our understanding of the genetic factors underlying the condition.

Variable Cre Recombination Efficiency in Placentas of Cyp19-Cre ROSAmT/mG Transgenic Mice.

The aromatase-Cre recombinase (Cyp19-Cre) transgenic mouse model has been extensively used for placenta-specific gene inactivation. In a pilot study, we observed unexpected phenotypes using this mouse strain, which prompted an extensive characterization of Cyp19-Cre placental phenotypes using ROSAmT/mG transgenic reporter mice. The two strains were mated to generate bi-transgenic Cyp19-Cre;ROSAmT/mG mice following a standard transgenic breeding scheme, and placental and fetal tissues were analyzed on embryonic day 17.5. Both maternal and paternal Cre inheritance were analyzed by mating the respective Cyp19-Cre and ROSAmT/mG males and females. The genotype results showed the expected percentage of Cyp19-Cre;ROSAmT/mG fetuses (73%) and Cre mRNA was expressed in all of the Cyp19-Cre placentas. However, surprisingly, only about 50% of the Cyp19-Cre;ROSAmT/mG placentas showed Cre-mediated recombinase activity as demonstrated by placental enhanced green fluorescent protein (EGFP) expression. Further genetic excision analysis of the placentas revealed consistent results showing the absence of excision of the tdTomato in all of the Cyp19-Cre;ROSAmT/mG placentas lacking EGFP expression. Moreover, among the EGFP-expressing placentas, there was wide variability in recombination efficiency, even in placentas from the same litter, leading to a mosaic pattern of EGFP expression in different zones and cell types of the placentas. In addition, we observed a significantly higher percentage of Cre recombination activity in placentas with maternal Cre inheritance. Our results show frequent mosaicism, inconsistent recombination activity, and parent-of-origin effects in placentas from Cyp19-Cre;ROSAmT/mG mice, suggesting that tail-biopsy genotype results may not necessarily indicate the excision of floxed genes in Cyp19-Cre positive placentas. Thus, placenta-specific mutagenesis studies using the Cyp19-Cre model require extensive characterization and careful interpretation of the placental phenotypes for each floxed allele.

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations

BackgroundThe retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (RBP4), encoding...

Refining the Global Phylogeny of Mitochondrial N1a, X, and HV2 Haplogroups Based on Rare Mitogenomes from Croatian Isolates.

Mitochondrial DNA (mtDNA) has been used for decades as a predominant tool in population genetics and as a valuable addition to forensic genetic research, owing to its unique maternal inheritance pattern that enables the tracing of individuals along the maternal lineage across numerous generations. The dynamic interplay between evolutionary forces, primarily genetic drift, bottlenecks, and the founder effect, can exert significant influence on genetic profiles. Consequently, the Adriatic islands have accumulated a subset of lineages that exhibits remarkable absence or rarity within other European populations. This distinctive genetic composition underscores the islands' potential as a significant resource in phylogenetic research, with implications reaching beyond regional boundaries to contribute to a global understanding. In the initial attempt to expand the mitochondrial forensic database of the Croatian population with haplotypes from small isolated communities, we sequenced mitogenomes of rare haplogroups from different Croatian island and mainland populations using next-generation sequencing (NGS). In the next step and based on the obtained results, we refined the global phylogeny of haplogroup N1a, HV2, and X by analyzing rare haplotypes, which are absent from the current phylogenetic tree. The trees were based on 16 novel and 52 previously published samples, revealing completely novel branches in the X and HV2 haplogroups and a new European cluster in the ancestral N1a variant, previously believed to be an exclusively African-Asian haplogroup. The research emphasizes the importance of investigating geographically isolated populations and their unique characteristics within a global context.

The Inheritance of Property and the Position of Sons in Accordance with the Matrilinial System in the Minangkabau Indigenous People and Its Relationship with the Rules of al-Adah Muhakkamah

Inheritance according to Islamic law regulates the principles of inheritance, terms and pillars of inheritance, heirs, and arrangements regarding the amount of inheritance received by heirs. Fundamentally related to inheritance matters have been regulated in Islamic law, but in reality not all Muslims share the inheritance with reference to the provisions regarding the distribution of inheritance in the fiqh Mawaris. Customs and habits that grow in a person's social environment, become the reason that person is bound by a law. Such as Minangkabau customary inheritance law is one area that still uses customary law as a reference for the division of inheritance. The matrilineal inheritance distribution system makes the position of the woman's party higher in terms of inheritance portion than the male's. Whereas in the syar'i texts and in what has been taught the portion of men is twice as large as women. The acceptance of custom or urf as a proposition is a form of Islamic law's attention to the customs that apply in society. Meanwhile, related to the rule of al-adah muhakkamah with custom or urf there is a dispute with the syar'i text. This journal writing method uses a normative juridical type of writing, which is a research method that uses studies and explanations in laws and materials that contain law to regulate the legal issues studied.