Hasil untuk "Genetics"

B. Lakowski, S. Hekimi

J. Hey

S. Kryazhimskiy, J. Plotkin

Evolutionary pressures on proteins are often quantified by the ratio of substitution rates at non-synonymous and synonymous sites. The dN/dS ratio was originally developed for application to distantly diverged sequences, the differences among which represent substitutions that have fixed along independent lineages. Nevertheless, the dN/dS measure is often applied to sequences sampled from a single population, the differences among which represent segregating polymorphisms. Here, we study the expected dN/dS ratio for samples drawn from a single population under selection, and we find that in this context, dN/dS is relatively insensitive to the selection coefficient. Moreover, the hallmark signature of positive selection over divergent lineages, dN/dS>1, is violated within a population. For population samples, the relationship between selection and dN/dS does not follow a monotonic function, and so it may be impossible to infer selection pressures from dN/dS. These results have significant implications for the interpretation of dN/dS measurements among population-genetic samples.

E. Turkheimer

R. Frankham, J. Ballou, D. Briscoe et al.

K. Laland, J. Odling-Smee, S. Myles

M. B. Lauritsen, H. Ewald

J. Wendland, F. McMahon

S. Narum

B. Stranger, E. Stahl, T. Raj

J. Trinh, M. Farrer

F. Kronenberg, G. Utermann

Gilles Guillot, A. Estoup, F. Mortier et al.

Muneesh Joshi, Kuhu Sharma

Periodontitis is a chronic inflammatory disease that affects the tissues supporting teeth and represents a significant global health issue. Traditional diagnostic and treatment methods often use a broad approach and fall short due to the complex interactions of genetics, various microbial communities, and environmental factors. Precision periodontics is an emerging field that seeks to transform periodontal care by shifting away from a one-size-fits-all strategy to a more tailored patient management approach. This article examines the fundamental principles, cutting-edge diagnostic tools, innovative treatment strategies, and future directions in precision periodontics. It highlights the importance of understanding the host response, oral microbiome, and genetic factors in creating personalized prevention and treatment plans. We also discuss developments in biomarkers, digital dentistry, regenerative medicine, and new technologies such as artificial intelligence, nanotechnology, and gene editing, all of which aim to improve the predictability of periodontal health outcomes. In addition, the ethical aspects of this personalized approach are addressed, such as informed consent, data privacy, and fair access to advanced care. By combining knowledge from multiple disciplines and leveraging technological advances, precision periodontics promises to greatly enhance patient outcomes and reshape periodontal clinical practice.

J. Diniz-Filho, T. Soares, J. Lima et al.

The comparison of genetic divergence or genetic distances, estimated by pairwise FST and related statistics, with geographical distances by Mantel test is one of the most popular approaches to evaluate spatial processes driving population structure. There have been, however, recent criticisms and discussions on the statistical performance of the Mantel test. Simultaneously, alternative frameworks for data analyses are being proposed. Here, we review the Mantel test and its variations, including Mantel correlograms and partial correlations and regressions. For illustrative purposes, we studied spatial genetic divergence among 25 populations of Dipteryx alata (“Baru”), a tree species endemic to the Cerrado, the Brazilian savannas, based on 8 microsatellite loci. We also applied alternative methods to analyze spatial patterns in this dataset, especially a multivariate generalization of Spatial Eigenfunction Analysis based on redundancy analysis. The different approaches resulted in similar estimates of the magnitude of spatial structure in the genetic data. Furthermore, the results were expected based on previous knowledge of the ecological and evolutionary processes underlying genetic variation in this species. Our review shows that a careful application and interpretation of Mantel tests, especially Mantel correlograms, can overcome some potential statistical problems and provide a simple and useful tool for multivariate analysis of spatial patterns of genetic divergence.

S. Viatte, D. Plant, S. Raychaudhuri

Evgeniya Melnik, Daria Akimova, Tatiana Markova et al.

Arthrogryposis multiplex congenita (AMC) is a large group of congenital conditions characterized by joint contractures affecting two or more body areas. A part of AMC type is caused by heterozygous pathogenic variants in genes encoding sarcomeric components of skeletal muscle fibers. Here we report a 7-year-old boy with a phenotype including AMC with dysmorphic facial features, short stature, congenital malformations of brain, colon and lacrimal canal. Trio whole-genome sequencing identified compound heterozygosity in the UTRN gene, consisting of a splicing variant in intron 57 (c.8434 + 1G>A) and a large heterozygous deletion spanning exons 3–51 (NM_007124.3). It is known that utrophin, the product of the UTRN gene, is an autosomal homologue and a fetal form of a protein of skeletal muscles - dystrophin. The presence of multiple malformations in the patient’s phenotype is consistent with ubiquitous expression of utrophin in the embryonic period. The RNA-seq analysis revealed that the splicing variant introduces a premature termination codon, which is predicted to result in a truncated protein shorter by 615 amino acids (p.Val2786Argfs*34), and the deletion leads to transcription of a shortened RNA isoform. We suggest that these variants are hypomorphic and partially retain protein function, which explains the clinical picture in the patient. In aggregate, our findings provide evidence that rare biallelic recessive variants in UTRN cause a novel autosomal recessive multiple congenital arthrogryposis.

Sarah Frank, Elisa Gabassi, Stephan Käseberg et al.

Molecular and cellular phenotyping of human brain organoids carrying various MID1 mutations reveals an unexpected role of the composition of the MID1 isoform pool during early patterning processes. The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 . Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.

José Alberto Choreño-Parra, José Alberto Choreño-Parra, Lucero A. Ramon-Luing et al.

IntroductionThe proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation.MethodsHere, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models.ResultsOur results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts.ConclusionThese findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

Giacomo Zaccone, Alessio Alesci, Doaa M. Mokhtar et al.

The recognition and elimination of invading pathogens are vital for host survival. Macrophages play a central role in host protection and cells functionally reminiscent of vertebrate macrophages are present in all multicellular organisms. A pattern responsible for bacterial recognition found on the surface of macrophages is CD14. These cells possess a repertoire of antimicrobial molecules stored in their granules and lysosomes. Polarization states observed in mammalian macrophages termed M1 and M2 also likely exist in fish macrophages. Markers for macrophage subtypes are slowly but definitively emerging in fish species. In the present study cell markers such as CD14, acetylcholine, alpha 7 acetylcholine nicotinic receptor (nAChR) subtype, the inducible nitric oxidase synthase (iNOS), and the antimicrobial peptide piscidin 1 are reported for the first time in the intestinal macrophages of both catfish <i>Heteropneustes fossilis</i> (Bloch, 1794) and the African bonytongue <i>Heterotis niloticus</i> (Cuvier, 1829) along the anterior and the posterior axis and the concentric muscle layers. Many antimicrobial effector responses of vertebrate macrophages including respiratory burst and NO induction are similar across the diverse animal taxa. Antibodies against calbindin coupled with ones to VAChT and tubulin revealed the localization of myenteric and submucosal plexuses, which are made up of enteric neurons, glial cells, and nerves near macrophages. Current studies allow for the elucidation of multiple roles of macrophages in disease models providing an insight into their in vivo function in fish.