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Genetics and exercise: an introduction
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Claude Bouchard, Henning Wackerhage
Two important events of meiosis contribute to human genetic diversity: Independent assortment of chromosomes. Of each chromosome pair in somatic cells, gametes receive only one chromosome. Is it the mothers or fathers chromosome? This is a random process and so each spermatocyte or oocyte will have a random combination of chromosomes from maternal and paternal origins.Homologous recombination. During meiosis, before chromosomes migrate to daughter cells, chromosomes cross over and exchange equivalent segments. For instance, a crossing over may occur between maternal and paternal chromosome 3, resulting in an exchange of DNA between the two chromosomes. About 50–60 recombinations take place between all pairs of homologous chromosomes (i.e. pairs of chromosomes of maternal and paternal descent) during meiosis.
Pest Control in Modern Public Health
Published in Jerome Goddard, Public Health Entomology, 2022
Additionally, genomic editing can be very expensive, especially on the scale of altering entire populations of insects, not just lab colonies. Yes, genome editing systems are becoming more accessible and simpler to use, but applying this technology to a system that will be released to the wild requires (first of all) certainty that the gene drive is working correctly. Genomic editing, and especially those technologies involving cutting the DNA, requires precision of the cut and some means of repairing the cut sequences using homologous recombination instead of non-homologous recombination. These molecular conditions determine whether a gene drive will work at all.
The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
Plausible biological explanations exist for recurrent aneuploidy. Meiosis and mitosis are under genetic control. Mutations may result from faulty DNA repair, failed chromosomal synapsis, or perturbed homologous recombination. Chromosomal disjunction can result in embryos having chromosomal abnormalities that manifest as either trisomic miscarriages or trisomic liveborns. Chromosomal status of miscarriages can be determined through so-called non-invasive 24-chromosome cell-free DNA analysis recovered from maternal plasma. This methodology is used routinely to assess liveborn trisomies 13, 18, and 21 in ongoing pregnancies, but can be applied to all chromosome in all pregnancies, including those having resulted in miscarriages.
Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2022
Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello
The exchange of DNA strands between a pair of DNA segments of the double helix that have a very similar or identical sequence is defined as homologous recombination. This exchange allows one stretch of DNA double helix to act as a template to restore lost or damaged information to the other stretch. It is particularly challenging to repair DNA damage affecting both strands of the double helix that occur in somatic cells during meiosis [16]. Germline mutations in several other HR genes have been linked to tumor predisposition. The most relevant include tumor suppressors BRCA1 and BRCA2 mutations that have a key role in different stages of HR, mainly associated with familial breast and ovarian cancers [17]. However, around 20–25% of epithelial ovarian cancer patients have pathogenic variants in several genes that mostly encode for proteins involved in DDR pathways [18]. Indeed, next generation sequencing revealed that beyond BRCA1/2, mutations in HR genes, such as PALB2, RAD51, ATM, BRIP1, BARD1, and CHEK2 occurs in up to a fifth of the patients with high-grade serous ovarian cancer [18]. Failure in the HR repair system can compromise the elimination of genome mutations and increasing the risk of oncogenesis after the accumulation of DNA damage events [19].
The biology and management of dyskeratosis congenita and related disorders of telomeres
Published in Expert Review of Hematology, 2022
Hemanth Tummala, Amanda Walne, Inderjeet Dokal
Biallelic RTEL1 variants were first identified in 2013 in a subset of patients with features of HH [44,45]. An autosomal recessive founder mutation was also been reported in HH patients from two unrelated families of Ashkenazi Jewish ancestry [46]. RTEL1 functions as a helicase (Figure 3). It is critical for telomere maintenance. It also has a role in homologous recombination. Patients with biallelic RTEL1 variants usually have very short telomeres as there is impaired resolution of T-loops. However, patient cells do not have significant defects in homologous recombination, since peripheral blood lymphocytes usually have normal chromosomal breakage score following treatment with diepoxybutane or mitomycin-C [45]. These patients have very homogeneous clinical features which include global BM failure, immune deficiency, and cerebellar hypoplasia. Subsequently, it has been observed heterozygous RTEL1 variants are responsible for some cases of pulmonary fibrosis [47]. Furthermore, a subgroup of patients with a combination of MDS and liver disease are associated with heterozygous loss of function variants in RTEL1 [48].
An update on the safety of olaparib for treating ovarian cancer
Published in Expert Opinion on Drug Safety, 2022
Kelsi Cottrell, Caroline L. Clark, Richard T. Penson
Single-strand breaks (SSBs) are a second type of DNA damage to frequently occur under normal replicating conditions and are commonly repaired by the poly(ADP-ribose) polymerase (PARP)-mediated mechanism [15]. PARP enzymes facilitate repair of these breaks by acting as signal transducers, sending other DNA repair proteins to the site of interest [2]. Olaparib works by inhibiting the PARP-mediated repair of SSBs, eliminating the error-free repair mechanism for a replicating cell experiencing a single-strand break. When olaparib is introduced to a cell that also expresses a BRCA-mutation, the cell is unable to repair both the SSBs and the inevitable DSBs that occur, forcing the cell to rely on more error-prone repair mechanisms and producing synthetic lethality in the replicating mutated cell. PARP inhibitors such as olaparib exploit the underlying weakness of BRCA-mutated cells, eliminating their most successful replication method and undermining the proliferation of tumor cells. Homologous recombination deficiency is a cellular flaw found in cells with a BRCA-mutation, but can also be caused by issues like germline mutations, somatic mutations, and epigenetic modifications of the genes that code for the proteins involved in the homologous recombination mechanism [16]. This expanded prevalence of homologous recombination deficiency increases the potential applications of PARP inhibitors such as olaparib.