Genomic Rearrangements Research Articles

RARE-05. MOLECULAR HETEROGENEITY OF PEDIATRIC CHOROID PLEXUS CARCINOMAS

Abstract BACKGROUND: Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li–Fraumenisyndrome, though only about a half of CPCs develop fromsyndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course. METHODS: This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted5.2 years (absolute range 2.8–12.6 years). RESULTS: All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. Inseven tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0±17.9% vs. 85.7±13.2%; p=0.009. Transcriptomically, the cohort split into two polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3±17.8% vs. 100%; p=0.012. CONCLUSION: CPCs split into at least two molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates withsurvival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.

HGG-09. GLIOMATOSIS CEREBRI IN CHILDREN: A POOR PROGNOSTIC, HIGHLY INFILTRATIVE PHENOTYPE OF DIFFUSE PEDIATRIC HIGH-GRADE GLIOMAS WITH DISTINCT MOLECULAR FEATURES

Abstract Gliomatosis cerebri (GC), a radiologically defined highly infiltrating supratentorial glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the central nervous system (CNS). So far, neither prognostic factors, nor molecular GC-associated features have been established. We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive radiological, clinical and (epi-)genetic characterization. Within a median follow-up of 15.5 months (range, 2.3–138.8), 93 patients (89.4%) had died, four (3.8%) were lost to follow-up and seven (6.8%) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3–14.0) and 15.5 months (10.9–27.7), respectively. Available histopathological grading correlated significantly with median OS: CNS-WHO grade II: 47.8 months (25.2–55.7); grade III: 15.9 months (11.4–26.3); grade IV: 10.4 months (8.8–14.4). In GC with high-grade features, radiochemotherapy achieved longest PFS (median 9.6 months [5.7–14.0]). According to methylation profiling [n=49] and exome-sequencing [n=45], most cases were considered as IDH-/H3-wildtype gliomas (n=32/52, 61.5%) enriched with the subclasses pedHGG_RTK2A/B (n=19), pedHGG_A/B (n=6) and pedHGG_MYCN (n=5), but exhibited only one pedHGG_RTK1A/B/C case. Within the IDH-/H3-wildtype gliomas, EGFR-alterations were most common (n=10). Expected genetic alterations of unselected hemispheric pedHGG affecting CDKN2A/B, ATRX or PDGFRA were virtually absent. Additionally, we observed structural aberrations in chromosome 6 comprising complex genomic rearrangements, large areas of loss, or even gain/amplification at similar breakpoints in 16/49 cases (32.7%). We assembled the largest pediatric GC cohort providing evidence that GC may have a strong predilection to arise on the background of specific molecular features (pedHGG_RTK2A/B, pedHGG_A/B and pedHGG_MYCN; EGFR- and chromosome 6-alterations). Taken together, these findings expand on the current understanding of GC and provide insight into disease biology of extensively infiltrating gliomas in children.

Phylogenomic analyses provide insights into primate evolution.

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution.

Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate of Aeromonas hydrophila.

Excessive discharge of quaternary ammonium disinfectants such as benzalkonium chloride (BAC) into aquatic systems can trigger several physiological responses in environmental microorganisms. In this study, we isolated a less-susceptible strain of Aeromonas hydrophila to BAC, designated as INISA09, from a wastewater treatment plant in Costa Rica. We characterized its phenotypic response upon exposure to three different concentrations of BAC and characterized mechanisms related to its resistance using genomic and proteomic approaches. The genome of the strain, mapped against 52 different sequenced A. hydrophila strains, consists of approximately 4.6 Mb with 4,273 genes. We found a massive genome rearrangement and thousands of missense mutations compared to the reference strain A. hydrophila ATCC 7966. We identified 15,762 missense mutations mainly associated with transport, antimicrobial resistance, and outer membrane proteins. In addition, a quantitative proteomic analysis revealed a significant upregulation of several efflux pumps and the downregulation of porins when the strain was exposed to three BAC concentrations. Other genes related to membrane fatty acid metabolism and redox metabolic reactions also showed an altered expression. Our findings indicate that the response of A. hydrophila INISA09 to BAC primarily occurs at the envelop level, which is the primary target of BAC. Our study elucidates the mechanisms of antimicrobial susceptibility in aquatic environments against a widely used disinfectant and will help better understand how bacteria can adapt to biocide pollution. To our knowledge, this is the first study addressing the resistance to BAC in an environmental A. hydrophila isolate. We propose that this bacterial species could also serve as a new model to study antimicrobial pollution in aquatic environments.

Extensive ITR expansion of the 2022 Mpox virus genome through gene duplication and gene loss

Poxviruses are known to evolve slower than RNA viruses with only 1–2 mutations/genome/year. Rather than single mutations, rearrangements such as gene gain and loss, which have been discussed as a possible driver for host adaption, were described in poxviruses. In 2022 and 2023 the world is being challenged by the largest global outbreak so far of Mpox virus, and the virus seems to have established itself in the human community for an extended period of time. Here, we report five Mpox virus genomes from Germany with extensive gene duplication and loss, leading to the expansion of the ITR regions from 6400 to up to 24,600 bp. We describe duplications of up to 18,200 bp to the opposed genome end, and deletions at the site of insertion of up to 16,900 bp. Deletions and duplications of genes with functions of supposed immune modulation, virulence and host adaption as B19R, B21R, B22R and D10L are described. In summary, we highlight the need for monitoring rearrangements of the Mpox virus genome rather than for monitoring single mutations only.

Molecular Characterization of Indigenous Rhizobia from Kenyan Soils Nodulating with Common Beans.

Kenya is the seventh most prominent producer of common beans globally and the second leading producer in East Africa. However, the annual national productivity is low due to insufficient quantities of vital nutrients and nitrogen in the soils. Rhizobia are symbiotic bacteria that fix nitrogen through their interaction with leguminous plants. Nevertheless, inoculating beans with commercial rhizobia inoculants results in sparse nodulation and low nitrogen supply to the host plants because these strains are poorly adapted to the local soils. Several studies describe native rhizobia with much better symbiotic capabilities than commercial strains, but only a few have conducted field studies. This study aimed to test the competence of new rhizobia strains that we isolated from Western Kenya soils and for which the symbiotic efficiency was successfully determined in greenhouse experiments. Furthermore, we present and analyze the whole-genome sequence for a promising candidate for agricultural application, which has high nitrogen fixation features and promotes common bean yields in field studies. Plants inoculated with the rhizobial isolate S3 or with a consortium of local isolates (COMB), including S3, produced a significantly higher number of seeds and seed dry weight when compared to uninoculated control plants at two study sites. The performance of plants inoculated with commercial isolate CIAT899 was not significantly different from uninoculated plants (p > 0.05), indicating tight competition from native rhizobia for nodule occupancy. Pangenome analysis and the overall genome-related indices showed that S3 is a member of R. phaseoli. However, synteny analysis revealed significant differences in the gene order, orientation, and copy numbers between S3 and the reference R. phaseoli. Isolate S3 is phylogenomically similar to R. phaseoli. However, it has undergone significant genome rearrangements (global mutagenesis) to adapt to harsh conditions in Kenyan soils. Its high nitrogen fixation ability shows optimal adaptation to Kenyan soils, and the strain can potentially replace nitrogenous fertilizer application. We recommend that extensive fieldwork in other parts of the country over a period of five years be performed on S3 to check on how the yield changes with varying whether conditions.

The pangenome structure of human pathogen Mycobacterium kansasii

The non-tuberculous Mycobacterium kansasii, is the causative agent of destructive pulmonary and extrapulmonary infections in immunocompromised persons. Incessant use of multiple antibiotics and lack of effective vaccines did little to combat M. kansasii mediated infections. Here, a bioinformatic analysis has been carried out using PanExplorer, to analyze the pangenome aimed at functional characterization of the bacterium, understanding it’s pathogenic lifestyle and recognize the factors shaping evolution and variations amongst strains. M. kansasii had a large core genome (60.2%), a small (11.9%) dispensable genome and 27.9% strain-specific genes. The core genome of M. kansasii had a high concentration of COGs (Cluster of orthologous genes) linked to energy production and conversion, amino acid transport and metabolism, nucleotide transport and metabolism, coenzyme transport and metabolism, and secondary me-tabolite biosynthesis, transport and metabolism. Interestingly, numerous genes within the core and dispensable genome were associated with pathogenesis and virulence. Noteworthy among them were type VII secretion, ESX, PP and PPE family proteins. Although, M. kansasii genomes revealed overall relatedness and conservation, genomic rearrangements caused variability within the strains. The information from this analysis could assist future microbial genomics research on M. kansasii, and further studies, e.g., concerning distinctive gene clusters, and evolution.

Schizosaccharomyces lindneri sp. nov., a fission yeast occurring in honey.

Two strains of fission yeast were isolated from honey. They differ from the type strain of Schizosaccharomyces octosporus by three substitutions in the D1/D2 domain of the nuclear 26S large subunit ribosomal RNA(rRNA) gene sequence, resulting in a 99.5% identity. In the internal transcribed spacer (ITS) region (consisting of ITS1, 5.8S rDNA, and ITS2), the strains differ from S. octosporus by 16 gaps and 91 substitutions, which is equivalent to an identity of 88.1%. Genome sequencing on one of the new strains revealed that the average nucleotide identity (ANI) between its genome and the reference genome of S. octosporus is 90.43% and there exist major genome rearrangements between the two genomes. Mating analysis revealed that S. octosporus and one of the new strains are completely reproductively separated. A strong prezygotic barrier exists and the few mating products consist of diploid hybrids that do not form recombinant ascospores. In the new strains, asci are either zygotic, arising from conjugation, or they develop without conjugation from asexual cells (azygotic). Compared to the currently recognized Schizosaccharomyces species, the spectrum of nutrients that are assimilated by the new strains is restricted. Of the 43 carbohydrates that were included in the physiological standard tests, only 7 were assimilated. According to the results of the genome sequence analysis, the mating trials, and the phenotypic characterization, the new species Schizosaccharomyces lindneri is described to accommodate the two strains(holotype: CBS 18203T and ex-type: MUCL 58363; MycoBank no.: MB 847838).

Organizational Aspects of the Implementation and Use of Whole Genome Sequencing and Whole Exome Sequencing in the Pediatric Population in Italy: Results of a Survey.

This study explores the organizational aspects of whole genome sequencing (WGS) implementation for pediatric patients with suspected genetic disorders in Italy, comparing it with whole exome sequencing (WES). Health professionals' opinions were collected through an internet-based survey and analyzed using a qualitative summative content analysis methodology. Among the 16 respondents, most were clinical geneticists performing only WES, while 5 also used WGS. The key differences identified include higher needs for analyzing genome rearrangements following WES, greater data storage and security requirements for WGS, and WGS only being performed in specific research studies. No difference was detected in centralization and decentralization issues. The main cost factors included genetic consultations, library preparation and sequencing, bioinformatic analysis, interpretation and confirmation, data storage, and complementary diagnostic investigations. Both WES and WGS decreased the need for additional diagnostic analyses when not used as last-resort tests. Organizational aspects were similar for WGS and WES, but economic evidence gaps may exist for WGS in clinical settings. As sequencing costs decline, WGS will likely replace WES and traditional genetic testing. Tailored genomic policies and cost-effectiveness analyses are needed for WGS implementation in health systems. WGS shows promise for enhancing genetics knowledge and expediting diagnoses for pediatric patients with genetic disorders.

Reversal and Transposition Distance on Unbalanced Genomes Using Intergenic Information.

The most common way to calculate the rearrangement distance between two genomes is to use the size of a minimum length sequence of rearrangements that transforms one of the two given genomes into the other, where the genomes are represented as permutations using only their gene order, based on the assumption that genomes have the same gene content. With the advance of research in genome rearrangements, new works extended the classical models by either considering genomes with different gene content (unbalanced genomes) or including more genomic characteristics to the mathematical representation of the genomes, such as the distribution of intergenic regions sizes. In this study, we study the Reversal, Transposition, and Indel (Insertion and Deletion) Distance using intergenic information, which allows comparing unbalanced genomes, because indels are included in the rearrangement model (i.e., the set of possible rearrangements allowed when we compute the distance). For the particular case of transpositions and indels on unbalanced genomes, we present a 4-approximation algorithm, improving a previous 4.5 approximation. This algorithm is extended so as to deal with gene orientation and to maintain the 4-approximation factor for the Reversal, Transposition, and Indel Distance on unbalanced genomes. Furthermore, we evaluate the proposed algorithms using experiments on simulated data.

Evolution of Mycobacterium abscessus in the human lung: Cumulative mutations and genomic rearrangement of porin genes in patient isolates

ABSTRACT Background Mycobacterium abscessus subspecies massiliense (M. massiliense) is increasingly recognized as an emerging bacterial pathogen, particularly in cystic fibrosis (CF) patients and CF centres’ respiratory outbreaks. We characterized genomic and phenotypic changes in 15 serial isolates from two CF patients (1S and 2B) with chronic pulmonary M. massiliense infection leading to death, as well as four isolates from a CF centre outbreak in which patient 2B was the index case. Results Comparative genomic analysis revealed the mutations affecting growth rate, metabolism, transport, lipids (loss of glycopeptidolipids), antibiotic susceptibility (macrolides and aminoglycosides resistance), and virulence factors. Mutations in 23S rRNA, mmpL4, porin locus and tetR genes occurred in isolates from both CF patients. Interestingly, we identified two different spontaneous mutation events at the mycobacterial porin locus: a fusion of two tandem porin paralogs in patient 1S and a partial deletion of the first porin paralog in patient 2B. These genomic changes correlated with reduced porin protein expression, diminished 14C-glucose uptake, slower bacterial growth rates, and enhanced TNF-α induction in mycobacteria-infected THP-1 human cells. Porin gene complementation of porin mutants partly restored 14C-glucose uptake, growth rate and TNF-α levels to those of intact porin strains. Conclusions We hypothesize that specific mutations accumulated and maintained over time in M. massiliense, including mutations shared among transmissible strains, collectively lead to more virulent, host adapted lineages in CF patients and other susceptible hosts.

Chromosome Painting in Cercopithecus petaurista (Schreber, 1774) Compared to Other Monkeys of the Cercopithecini Tribe (Catarrhini, Primates).

The Cercopithecini tribe includes terrestrial and arboreal clades whose relationships are controversial, with a high level of chromosome rearrangements. In order to provide new insights on the tribe's phylogeny, chromosome painting, using the complete set of human syntenic probes, was performed in Cercopithecus petaurista, a representative species of the Cercopithecini tribe. The results show C. petaurista with a highly rearranged karyotype characterized by the fission of human chromosomes 1, 2, 3, 5, 6, 8, 11, and 12. These results compared with the literature data permit us to confirm the monophyly of the Cercopithecini tribe (fissions of chromosomes 5 and 6), as previously proposed by chromosomal and molecular data. Furthermore, we support the monophyly of the strictly arboreal Cercopithecus clade, previously proposed by the molecular approach, identifying chromosomal synapomorphies (fissions of chromosomes 1, 2, 3, 11, 12). We also add additional markers that can be useful for deciphering arboreal Cercopithecini phylogeny. For example, the fission of chromosome 8 is synapomorphy linking C. petaurista, C. erythrogaster, and C. nictitans among the arboreal species. Finally, a telomeric sequence probe was mapped on C. petaurista, showing only classic telomeric signals and giving no support to a previous hypothesis regarding a link between interspersed telomeric sequences in high rearranged genomes.

Molecular analysis and prenatal diagnosis of seven Chinese families with genetic epilepsy.

Genetic epilepsy is a large group of clinically and genetically heterogeneous neurological disorders characterized by recurrent seizures, which have a clear association with genetic defects. In this study, we have recruited seven families from China with neurodevelopmental abnormalities in which epilepsy was a predominant manifestation, aiming to elucidate the underlying causes and make a precise diagnosis for the cases. Whole-exome sequencing (WES) combined with Sanger sequencing was used to identify the causative variants associated with the diseases in addition to essential imaging and biomedical examination. A gross intragenic deletion detected in MFSD8 was investigated via gap-polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and mRNA sequence analysis. We identified 11 variants in seven genes (ALDH7A1, CDKL5, PCDH19, QARS1, POLG, GRIN2A, and MFSD8) responsible for genetic epilepsy in the seven families, respectively. A total of six variants (c.1408T>G in ALDH7A1, c.1994_1997del in CDKL5, c.794G>A in QARS1, c.2453C>T in GRIN2A, and c.217dup and c.863+995_998+1480del in MFSD8) have not yet been reported to be associated with diseases and were all evaluated to be pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Based on the molecular findings, we have associated the intragenic deletion in MFSD8 with the mutagenesis mechanism of Alu-mediated genomic rearrangements for the first time and provided genetic counseling, medical suggestions, and prenatal diagnosis for the families. In conclusion, molecular diagnosis is crucial to obtain improved medical outcomes and recurrence risk evaluation for genetic epilepsy.

Mitotic clustering of pulverized chromosomes from micronuclei

Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1–5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A–TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A–TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements—termed balanced chromothripsis—across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.

Mito-nuclear discordance within Anthozoa, with notes on unique properties of their mitochondrial genomes

Whole mitochondrial genomes are often used in phylogenetic reconstruction. However, discordant patterns in species relationships between mitochondrial and nuclear phylogenies are commonly observed. Within Anthozoa (Phylum Cnidaria), mitochondrial (mt)-nuclear discordance has not yet been examined using a large and comparable dataset. Here, we used data obtained from target-capture enrichment sequencing to assemble and annotate mt genomes and reconstruct phylogenies for comparisons to phylogenies inferred from hundreds of nuclear loci obtained from the same samples. The datasets comprised 108 hexacorals and 94 octocorals representing all orders and > 50% of extant families. Results indicated rampant discordance between datasets at every taxonomic level. This discordance is not attributable to substitution saturation, but rather likely caused by introgressive hybridization and unique properties of mt genomes, including slow rates of evolution driven by strong purifying selection and substitution rate variation. Strong purifying selection across the mt genomes caution their use in analyses that rely on assumptions of neutrality. Furthermore, unique properties of the mt genomes were noted, including genome rearrangements and the presence of nad5 introns. Specifically, we note the presence of the homing endonuclease in ceriantharians. This large dataset of mitochondrial genomes further demonstrates the utility of off-target reads generated from target-capture data for mt genome assembly and adds to the growing knowledge of anthozoan evolution.

Genomic and Transcriptional Profiles of Kelch-like (klhl) Gene Family in Polyploid Carassius Complex.

Genome duplication supplies raw genetic materials and has been thought to be essential for evolutionary innovation and ecological adaptation. Here, we select Kelch-like (klhl) genes to study the evolution of the duplicated genes in the polyploid Carassius complex, including amphidiploid C. auratus and amphitriploid C. gibelio. Phylogenetic, chromosomal location and read coverage analyses indicate that most of Carassius klhl genes exhibit a 2:1 relationship with zebrafish orthologs and confirm two rounds of polyploidy, an allotetraploidy followed by an autotriploidy, occurred during Carassius evolution. The lineage-specific expansion and biased retention/loss of klhl genes are also found in Carassius. Transcriptome analyses across eight adult tissues and seven embryogenesis stages reveal varied expression dominance and divergence between the two species. The expression of klhls in response to Carassius herpesvirus 2 infection shows different expression changes corresponding to distinct herpesvirus resistances in three C. gibelio gynogenetic clones. Finally, we find that most C. gibelio klhl genes possess three alleles except eight genes that have lost one or two alleles due to genome rearrangement. The allele expression bias is prosperous for Cgklhl genes and varies during embryogenesis owning to the sequential expression manner of the alleles. The current study provides global insights into the genomic and transcriptional evolution of duplicated genes in a given superfamily resulting from multiple rounds of polyploidization.

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Triplications of chromosome 1p36.3, including the genes GABRD and SKI, are associated with a developmental disorder and a facial gestalt.

Triplication of chromosomal region 1p36.3 is a rare genomic rearrangement. In this report, we delineate the phenotypic spectrum associated with 1p36.3 triplications. We describe four patients with microtriplications of variable size, but with a strong phenotypic overlap, and compare them to previously described patients with an isolated triplication or duplication of this region. The 1p36.3 triplication syndrome is associated with a distinct phenotype, characterized by global developmental delay, moderate intellectual disability, seizures, behavioral problems, and specific facial dysmorphic features, including ptosis, hypertelorism, and arched eyebrows. The de novo occurrence of these microtriplications demonstrates the reduced reproductive fitness associated with this genotype, in contrast to 1p36.3 duplications which are mostly inherited and can be associated with similar facial features but with a less severe developmental phenotype. The shared triplicated region encompasses four disease-related genes of which GABRD and SKI are most likely to contribute to the phenotype.

Reversal and Indel Distance With Intergenic Region Information.

Recent works on genome rearrangements have shown that incorporating intergenic region information along with gene order in models provides better estimations for the rearrangement distance than using gene order alone. The reversal distance is one of the main problems in genome rearrangements. It has a polynomial time algorithm when only gene order is used to model genomes, assuming that repeated genes do not exist and that gene orientation is known, even when the genomes have distinct gene sets. The reversal distance is NP-hard and has a 2-approximation algorithm when incorporating intergenic regions. However, the problem has only been studied assuming genomes with the same set of genes. In this work, we consider the variation that incorporates intergenic regions and that allows genomes to have distinct sets of genes, a scenario that leads us to include indels operations (insertions and deletions). We present a 2.5-approximation algorithm using the labeled intergenic breakpoint graph, which is based on the well-known breakpoint graph structure. We also present an experimental analysis of the proposed algorithm using simulated data, which showed that the practical approximation factor is considerably less than 2.5. Furthermore, we used the algorithm in real genomes to construct a phylogenetic tree.

Genome Rearrangement Distance With a Flexible Intergenic Regions Aspect.

Most mathematical models for genome rearrangement problems have considered only gene order. In this way, the rearrangement distance considering some set of events, such as reversal and transposition events, is commonly defined as the minimum number of rearrangement events that transform the gene order from a genome G1 into the gene order from a genome G2. Recent works initiate incorporating more information such as the sizes of the intergenic regions (i.e., number of nucleotides between pairs of consecutive genes), which yields good results for estimated distances on real data. In these models, besides transforming the gene order, the sequence of rearrangement events must transform the list of intergenic regions sizes from G1 into the list of intergenic regions sizes from G2 (target list). We study a new variation where the target list is flexible, in the sense that each target intergenic region size is in a range of acceptable values. This allows us to model scenarios where the main objective is still to transform the order of genes from the source genome into the target genome, allowing flexibility in the sizes of the intergenic regions, since the nucleotides in these regions tend to undergo more changes when compared to genes. We investigate the rearrangement distance considering three sets of events, two with the exclusive use of reversals or transpositions, and the other allowing both rearrangement events. We present approximation algorithms for the problems and an NP-hardness proof. Our results rely on the Flexible Weighted Cycle Graph, adapted from the breakpoint graph to deal with flexible intergenic regions sizes.