Congenital cerebral palsy: genetic cause and nosological integrity

The review provides an analysis of 73 full-text articles, the source of which was the Medline, OMIM, NCBI, Pubmed, Scopus, eLibrary.ru databases. The data of studies of the main pathogenetic mechanisms of the formation of the cerebral palsy (CP) phenotype, such as chromosomal aberrations, copy number variations, single nucleotide polymorphisms, associated with the development of the CP phenotype, are reviewed and analyzed. Epigenetic effects on the genome, as well as the effects of the genome on the mechanisms of epigenomic regulation, are examined in detail. The data on the genetic determinism of concomitant pathology and reactivity to therapeutic tactics are presented. Based on the study of data from numerous studies, the authors draw the following conclusions:1) the pathogenesis of the phenotype of CP includes a large number of genes that determine violations of cellular metabolism, neuroontogenesis, brain resistance to hypoxia, etc;2) genes whose abnormalities form a syndromic pathology are involved in the pathogenesis of CP;3) the multidirectionality and breadth of the effects of the gene pool with the outcome in a syndrome-specific distinctive picture of the CP allows us to propose the concept of a neurotropic genome;4) the mechanisms of gene involvement can vary from aberrations to epigenetic imbalances;5) different groups of genes can differentially influence the formation of individual syndromes in the phenotype of CP;6) there are data indicating a genetic determinism of the tendency to contracture, pharmacoreactivity to drugs that reduce muscle tone, reactivity to habilitation effects;7) genomic-epigenomic interactions normally ensure the body’s adaptation to environmental conditions, and with pathology, they increase the likelihood of regulatory breakdowns that lead to the formation of a CP phenotype;8) the exclusion from the diagnosis of CP of genetically determined cases of phenotype development is incorrect.The authors present two anthropogenic reasons for the increase in the frequency of occurrence of de novo identified gene abnormalities:1) anthropogenic impact on the environment, increasing the number of anomalies of the genome de novo; 2) iatrogenic effects of technologies for preserving life, vitality and reproductive ability of carriers of genomic anomalies. This effect leads to the fixation of anomalies in the genome of the population.A paradox is formulated, according to which, in the presence of technologies capable of preserving the life of carriers of genomic anomalies, in vivo technologies for genome correction are only just beginning to be put into practice. Based on this, it is concluded that it is necessary to intensify the development of methods for prenatal diagnosis and gene therapy of CP.

Insights about variation in meiosis from 31,228 human sperm genomes

Meiosis, while critical for reproduction, is also highly variable and error prone: crossover rates vary among humans and individual gametes, and chromosome nondisjunction leads to aneuploidy, a leading cause of miscarriage. To study variation in meiotic outcomes within and across individuals, we developed a way to sequence many individual sperm genomes at once. We used this method to sequence the genomes of 31,228 gametes from 20 sperm donors, identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic anomalies. Different sperm donors varied four-fold in the frequency of aneuploid sperm, and aneuploid chromosomes gained in meiosis I had 36% fewer crossovers than corresponding non-aneuploid chromosomes. Diverse recombination phenotypes were surprisingly coordinated: donors with high average crossover rates also made a larger fraction of their crossovers in centromere-proximal regions and placed their crossovers closer together. These same relationships were also evident in the variation among individual gametes from the same donor: sperm with more crossovers tended to have made crossovers closer together and in centromere-proximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation across chromosomes, gametes, and individuals.

eGARD: Extracting associations between genomic anomalies and drug responses from text

Tumor molecular profiling plays an integral role in identifying genomic anomalies which may help in personalizing cancer treatments, improving patient outcomes and minimizing risks associated with different therapies. However, critical information regarding the evidence of clinical utility of such anomalies is largely buried in biomedical literature. It is becoming prohibitive for biocurators, clinical researchers and oncologists to keep up with the rapidly growing volume and breadth of information, especially those that describe therapeutic implications of biomarkers and therefore relevant for treatment selection. In an effort to improve and speed up the process of manually reviewing and extracting relevant information from literature, we have developed a natural language processing (NLP)-based text mining (TM) system called eGARD (extracting Genomic Anomalies association with Response to Drugs). This system relies on the syntactic nature of sentences coupled with various textual features to extract relations between genomic anomalies and drug response from MEDLINE abstracts. Our system achieved high precision, recall and F-measure of up to 0.95, 0.86 and 0.90, respectively, on annotated evaluation datasets created in-house and obtained externally from PharmGKB. Additionally, the system extracted information that helps determine the confidence level of extraction to support prioritization of curation. Such a system will enable clinical researchers to explore the use of published markers to stratify patients upfront for ‘best-fit’ therapies and readily generate hypotheses for new clinical trials.

Genomic profiling of metastatic prostate cancer through analysis of circulating tumor DNA (ctDNA).

174 Background: We have performed genomic analysis of circulating tumor DNA (ctDNA) to identify actionable anomalies in 55 patients with metastatic prostate cancer. Methods: A publically-accessible assay (Guardant Health) was used to analyze 68 known cancer genes for anomalies (missense mutations, amplifications) by a digital PCR technique. The racial profile included Caucasian (27), African-American (27), Asian (1) patients. Most subjects (82%) had CRPC and had been treated with multiple forms of androgen deprivation and chemotherapy. Results: Genomic anomalies were found in 52/55 subjects. 127 missense mutations and 78 amplifications were identified in 35 genes. Missense mutations in each gene were overwhelmingly single (98/127). African-American patients each had an average of 3.9 genomic anomalies, whereas Caucasian patients each had an average of 2.7 anomalies (p = NS). Anomalies most commonly involved TP53 (43.2%), AR (43.4%), MYC (21.8%), BRAF (21.8%), and DNA repair genes (BRCA1, BRCA2, or ATM; 16.4%). Taxane-based chemotherapy was given to 24/55 subjects with mCRPC. These 24 patients were grouped by TP53 status (WT, n = 13; MUT, n = 11) and progression-free survival (PFS) was determined by PCWG2 criteria (PSA or imaging). Data for PFS vs time were presented as Kaplan-Meier plots and compared by the log rank test. Median PFS during taxane chemotherapy was approximately twice as long for subjects with MUT TP53, compared with that of subjects with WT TP53 (p = 0.013; HR = 2.5 [1.1-6.0]). Conclusions: 1. Genomic analysis on ctDNA from patients with metastatic prostate cancer is feasible and identifies anomalies in most patients. 2. Within the limits of the assay, ctDNA analysis provides similar findings to those identified by analysis of FFPE tissue (Robinson et al., Cell, 2015). 3. ctDNA analysis can identify missense mutations that are associated with an improved PFS from taxane-based chemotherapy. ctDNA analysis may help clinicians to judge the potential benefits of chemotherapy in subjects with mCRPC.

Pigeon-Associated Strains of Salmonella enterica Serovar Typhimurium Phage Type DT2 Have Genomic Rearrangements at rRNA Operons

ABSTRACT Strains from a subgroup of Salmonella enterica serovar Typhimurium frequently associated with pigeon infections were tested for genomic anomalies and virulence in mice. Some strains have a genomic inversion between rrn operons. Two prophages found in the common laboratory strain LT2 were absent. Pigeon-associated strains are still virulent in mice.